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6 Metal Complexes of Amino-acids, Peptides, and Proteins BY R. W. HAY AND D. R. WILLIAMS 1 Introduction This chapter describes work published during the years 1975 and 1976 in the general field indicated by the title. Attention has been concentrated on those aspects which relate to the modification of the reactivity and other properties of the organic ligand when attached to a metal; however, it is clear that many inorganic chemists find the chapter of value and so we have included appropriate material. There has been little in the way of unusual developments but some very elegant applications of known chemistry to more complicated systems have occurred. The area defined in the title can be regarded as a section of the wider field of bio-inorganic chemistry. A considerable number of general review articles and books have appeared : ‘Metal Chelates and Physiological Reactions’,l ‘Recent Progress in the Study of Metalloenzymes’,2‘Electron-transfer Proteins’,s ‘Calcium in Biological system^',^ ‘Mechanisms for the Reactions of Molybdenum in Enzymes’,6 ‘Lanthanide Ions as Structural Probes in Biological and Model Systems’,6 ‘Trace Metals in Biological system^',^ ‘Copper Chelates as Possible Active Forms of the Antiarthritic Agents’,* ‘Selenium and Can~er’,~ ‘Inorganic Oxygen Carriers as Models for Biological Systerns’,l0 ‘Inorganic Medicinal Chemistry’,ll ‘Transition Metal Complexes Containing Tridentate Amino- acids’,l2 ‘Metall~thionein’,~~ ‘Binding of Metal Ions to Membranes and its consequence^',^^ and ‘Structural Aspects of Molybdenum(rv), Molybdenum(v), and Molybdenum(w) Complexes’.16 E. Kimura, Kagaku No Ryoiki, 1975,29,413. M. Nozaki, Taisha, 1975, 12, 229. G. R. Moore and R. J. P. Williams, Coordination Chem. Rev., 1976, 18, 125. R. H. Kretsinger and D. J. Nelson, Coordination Chem. Rev., 1976, 18, 29. R. A. D. Wentworth, Coordination Chem. Rev, 1976, 18, 1. R. Nieboer, Struct. Bonding (Berlin), 1975, 22, 1. S. M. McKenzie, Pentacol 1975, 13, 54. * J. R. J. Sorenson, J. Medicin. Chem., 1976,19, 135; Trace Subst. Enuiron. Health, 1974,8, 305; Inflammation, 1976,1, 317. G. N. Schrauzer, Bioinorg. Chem., 1976, 5, 275. lo G. McLendon and A. E. Martell, Coordination Chem. Rev., 1976, 19, 1. D. D. Perrin, in ‘Inorganic Biochemistry’, Topics in Current Chemistry 64, Springer-Verlag, Berlin, 1976, Chapter 3. l2 See ‘Progress in Inorganic Chemistry’, Vol. 19, ed. S. J. Lippard. l3 N. Kimura, Tuisha, 1975, 12, 205. l4 R. J. P. Williams, Biological Membranes’, ed. D. S. Parsons, Oxford University Press, Oxford, 1975, p. 106. lS B. Spivack and Z. Dori, Coordination Chem. Rev., 1975,17,99. 494 Downloaded by Stanford University on 27 September 2012 Published on 31 October 2007 on http://pubs.rsc.org | doi:10.1039/9781847557339-00494

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6 Metal Complexes of Amino-acids, Peptides, and Proteins

BY R. W. HAY AND D. R. WILLIAMS

1 Introduction This chapter describes work published during the years 1975 and 1976 in the general field indicated by the title. Attention has been concentrated on those aspects which relate to the modification of the reactivity and other properties of the organic ligand when attached to a metal; however, it is clear that many inorganic chemists find the chapter of value and so we have included appropriate material. There has been little in the way of unusual developments but some very elegant applications of known chemistry to more complicated systems have occurred.

The area defined in the title can be regarded as a section of the wider field of bio-inorganic chemistry. A considerable number of general review articles and books have appeared : ‘Metal Chelates and Physiological Reactions’,l ‘Recent Progress in the Study of Metalloenzymes’,2 ‘Electron-transfer Proteins’,s ‘Calcium in Biological system^',^ ‘Mechanisms for the Reactions of Molybdenum in Enzymes’,6 ‘Lanthanide Ions as Structural Probes in Biological and Model Systems’,6 ‘Trace Metals in Biological system^',^ ‘Copper Chelates as Possible Active Forms of the Antiarthritic Agents’,* ‘Selenium and Can~er’ ,~ ‘Inorganic Oxygen Carriers as Models for Biological Systerns’,l0 ‘Inorganic Medicinal Chemistry’,ll ‘Transition Metal Complexes Containing Tridentate Amino- acids’,l2 ‘Metall~thionein’,~~ ‘Binding of Metal Ions to Membranes and its consequence^',^^ and ‘Structural Aspects of Molybdenum(rv), Molybdenum(v), and Molybdenum(w) Complexes’.16

E. Kimura, Kagaku No Ryoiki, 1975,29,413. M. Nozaki, Taisha, 1975, 12, 229. G. R. Moore and R. J. P. Williams, Coordination Chem. Rev., 1976, 18, 125. R. H. Kretsinger and D. J. Nelson, Coordination Chem. Rev., 1976, 18, 29. R. A. D. Wentworth, Coordination Chem. Rev, 1976, 18, 1. R. Nieboer, Struct. Bonding (Berlin), 1975, 22, 1. ’ S. M. McKenzie, Pentacol 1975, 13, 54.

* J. R. J. Sorenson, J. Medicin. Chem., 1976,19, 135; Trace Subst. Enuiron. Health, 1974,8, 305; Inflammation, 1976,1, 317. G. N. Schrauzer, Bioinorg. Chem., 1976, 5, 275.

lo G. McLendon and A. E. Martell, Coordination Chem. Rev., 1976, 19, 1. D. D. Perrin, in ‘Inorganic Biochemistry’, Topics in Current Chemistry 64, Springer-Verlag, Berlin, 1976, Chapter 3.

l2 See ‘Progress in Inorganic Chemistry’, Vol. 19, ed. S. J. Lippard. l3 N. Kimura, Tuisha, 1975, 12, 205. l4 R. J. P. Williams, Biological Membranes’, ed. D. S. Parsons, Oxford University Press, Oxford,

1975, p. 106. lS B. Spivack and Z. Dori, Coordination Chem. Rev., 1975,17,99.

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Metal Complexes of Amino-acids, Peptides, and Proteins 495

Volume 5 of Sigel's 'Metal Ions in Biological Systems' has been published,la and contains the following articles : formation of Schiff bases in the co-ordination sphere of metal ions ; metal-ion promoted hydrolysis of amino-acid esters and peptides ; the catalytic activity of poly-L,a-amino-acid metal complexes and their use as enzyme models, molybdenum complexes as models for biological systems and the interaction of copper(1) complexes with dioxygen. A new edition of Falk's 'Porphyrins and Metalloporphyrins' has been published,l' as has an introductory text on the general area of bio-inorganic chemistry.18

There has been a growing awareness of the possible uses of metal complexes in chemotherapy.ll The use of platinum complexes in cancer chemotherapy has done much to stimulate interest in this area. Sorenson8 has observed that copper(1r) acetate monohydrate has anti-inflammatory activity in the carrageenan foot edema model of inflammation. (It is noteworthy that all clinically useful antiarthritic compounds are chelating agents.) Various copper(I1) amino-acid complexes have been screened for anti-inflammatory and antiulcer activity and many of these have high activity. The superoxide ion (0,:) has been implicated in the initiation of inflammatory types of arthritis,la in ageing, and in carcinogenesis. The enzyme superoxide dismutase 2o is a blue copper(r1) protein (mol. wt. 34 000,0.35% copper, with a broad d-d band at 675 nm) which catalyses the dismutation of superoxide, 2H+ + 20; -+ 2H202 + 0,. Copper(n) complexes have been shown 21 to act as superoxide scavengers, and it is suggested that this accounts for their activity as anti-inflammatory agents.

2 Amino-acids Binding.-There seems to have been a resurgence of interest in the determination of formation constants of complexes in solution. Formation constants are being reported with greater precision as a result of improved equipment and computational aids. Groups of authors are collaborating to collect critical surveys of published constants.22 Ternary complex formation is attracting much at tent ion.

A number of unsaturated amino-acids have been synthesized and their complexing with Cu", Nil', Zn", Co", Cd", and Ag' has been Silver(1) is the only ion where significant bonding to the olefin occurs, in spite of the fact that the bonds are non-linear about the metal ion.

Previously little work has been reported on uranium and vanadium complexes; however, this lack is now being rectified. The UIv-alanine system has been

l* 'Metal Ions in Biological Systems', Vol. 5. 'Reactivity of Coordination Compounds', ed. H. Sigel, Marcel Dekker, New York, 1976.

l7 'Porphyrins and Metalloporphyrins', ed. K. M. Smith, Elsevier, New York, 1975. 'An Introduction to Bio-inorganic Chemistry', ed. D. R. Williams, C. C. Thomas, Springfield, Illinois, 1976.

l@ J. M. McCord, Science 1974, 185, 529; see also Chem. Eng. News, 1974, 24 (19 Aug. issue).

2o I. Fridovich, Accounts Chem. Res., 1972, 5, 321; Ado. Enzymol., 1974, 41, 35. 21 L. R. de Alvare and T. Kimura, Abstracts XVII International Conference on Coordination

Chemistry, Hamburg, Sept. 1976 p. 292. 22 I.U.P.A.C., Critical Surveys of stability constants of Metal Complexes; see Coordination

Chern. Rev., 1975, 17, 358. 23 M. Israeli and L. D. Pettit, J. Inorg. NucZear Chem., 1975, 37, 999.

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496 Amino-acids, Peptides and Proteins studied,24 and a spectrophotometric investigation 25 carried out on the inter- action of dioxovanadium(v) with N-methyliminodiacetic acid, nitrolotriacetic acid, and ethylenediamine-NN'-diacetic acid.

Binary amino-acid-transition-metal ion systems for which stability constants have been reported are : DL-4-amino-3-hydroxybutanoic acid-Cu" ;2s

penicillamine- and cysteine-Co11;27 ~~-3,4-dihydroxyphenylalanine-C~" 28 (a system investigated because of its relationship to L-dopa and adrenaline in vivo); histidylhistidine-Cu" and -Zn" and mixed ligand complexes with h i ~ t i d i n e ; ~ ~ 2,3-diaminopropionic acid, 2,4diaminobutyric acid, ornithine, lysine, and arginine with Co", Ni", and CU";~O cysteine with Cd11;31 a range of potentially terdentate amino-acids with Nil1 and Zn1r;32 ~~-3-amino-2-hydroxypropanoic acid with Co", Ni", CuII, and adrenaline, L-dopa, and a catechol derivative with Fer11;34 NN-aminoethylglycine and diethylenetriamine-N-acetic acid with C O " ; ~ ~ L- and DL-serine and DL-threonine with Ni" and C U " ; ~ ~ alanine with Ni" and Cu" in dioxan-water and methanol-water 37 (in these latter two papers values of AHo and ASo were determined and the bonding discussed in terms of solvation effects); a variety of amino-acids with a range of first transition series

The introduction of improved glass electrode potentiometric techniques and the use of more sophisticated least-squares computational approaches for data analysis over recent years have allowed the study of ternary complex formation in solution to begin. In addition, there has been an increasing awareness of the pivotal role played by amino-acid complexes in uivo. It is becoming apparent that the most important complexes in biological systems are ternary and quaternary.

Formation constants have been reported for the N(3)-benzyl-~-histidine and N(a)N(3)-dibenzyl-~-histidine with CuI', Ni", and Zn" and D- and L-histidine. Stereoselective effects were Enthalpies of formation and formation constants are now available for the ternary systems, asparagine-glycine-Cu", asparagine-serine-Cu", and glufamine-serine-C~~~.~~ The enthalpy data suggest that above pH 9.5, the amide group of asparagine is deprotonated and bound to 24 G. Folcher, C. Neveu, and P. Rigny, J. Inorg. Nuclear Chem., 1975, 37, 1537. 25 S. Yamada, J. Nagase, S. Funahashi, and M. Tanaka, J. Inorg. Nuclear Chem., 1976, 38, 617. 26 A. Braibanti, G. Mori, F. Dallavalle, and E. Leporati, J.C.S. Dalton, 1975, 1319. 27 R. K. Boggess and R. B. Martin, J. Inorg. Nuclear Chem., 1975, 37, 359.

A. Gergely and T. Kiss, Inorg. Chim. Acta, 1976, 16, 51. 2n R. P. Agarwal and D. D. Perrin, J.C.S. Dalton, 1976, 89. 30 G. Brookes and L. D. Pettit, J.C.S. Dalton, 1976, 42. s1 G. D. Zegzhda, V. N. Kabanova, and F. M. Tulyupa, Zhur. neorg. Khim., 1975, 20, 2325

(Russ.) (Chem. A h . , 1975,). 32 A. Gergely and E. Farkas, Magyar Kdm. Folyoirat, 1975, 81,471 (Hung.) (Chem. Abs., 1975

84, 35 947). 33 A. Braibanti, G. Mori, and F. Dallevalle, J.S.C. Dalton, 1976, 826. 34 E. Mentasti, E. Pelizzeti, and G. Saini, J. Inorg. Nuclear Chem., 1976, 38, 785. s5 G. McLendon, D. T. MacMillan, M. Hariharan, and A. E. Martell, Inorg. Chem., 1975, 14,

2322. aa L. D. Pettit and J. L. M. Swash, J.C.S. Dalton, 1976, 2416. 37 A. Gergely and T. Kiss, J. Inorg. Nuclear Chem., 1977, 39, 109. 38 H. Guntner and K. E. Schwarzhans, Anorg. Chem. Org. Chem., 1976, 31, 198. an T. Sakurai, 0. Yamauchi, and A. Nakahara, Bull. Chem. Soc. Japan, 1976, 49, 169. 40 P. V. Selvaraj and M. Santappa, J. Inorg. Nuclear Chem., 1977, 39, 119. 41 G. Brooks and L. D. Pettit, J.C.S. Dalton, 1976, 1224. 43 A. Gergely, I. Nagypal, and E. Farkas, J. Znorg. Nuclear Chern., 1975,37, 551.

mixed amino-acid iystems with C U " ; ~ ~ amino-acids with UOi+.40

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Metal Complexes of Amino-acids, Peptides, and Proteins 497 copper(I1). A pH-titration study has been reported for the ligands (considered as pairs or triplets) cysteine, orthophosphoric acid, and either citric or nitrilo- triacetic acid with AIttt, Ca", or Cd". The means by which such mixed complexes are introduced into the roots of plants is also The mixed complexes of 5-sulphosalicylic acid and an a-amino-acid with Cu" have been studied and values of AH* and ASo dete~mined.~~ Two papers have appeared concerning mixed amino-acid complexes of Ni" and CU".~~, 46

The concentrations of the individual complexes formed by trace elements and amino-acids in vivo are too low to be detectable by current analytical techniques. If one accepts the caveat that biological solutions approximate to equilibrium conditions, formation constants determined in vitro can be used to calculate the relative concentrations of species present in vivo. An approach of this type was used to assess agents for oral iron and zinc administration (a neutral complex which is membrane transmittable at pH 6.5 is 48

Similar investigations have revealed the salient complexes formed between asparagine, threonine, and histidine and C U " . ~ ~ Possible structures for these ternary complexes were suggested on the basis of the AHo and ASo values obtained.

Some essential elements and polluting metal ions can be removed from blood plasma by carefully choosing the ligand to sequester selectively the metal ion in question. Thus, treatment with calcium diethylenetriaminepenta-acetate encourages the excretion of zinc(i~).~O As a result of a study of the binding of amino-acids to Cd" and Pb" it was concluded that glutathione deserves investi- gation as a ligand for mobilizing Pb" and Cd" in plasma.61 Thermodynamic studies of the binding of glycine, glycylglycine, triglycine, cysteine, and glutathione to Pb" have been reported and possible structures suggested.6a

Ternary complexes of glutathione containing two dissimilar metal ions, e.g. Ca" and ZnlI or Latr1 and Zn", have been reported.63 It is noteworthy that such complexes increase the concentrations of neutral lipophilic complexes. A discussion of the principles of metal-metal stimulation phenomena in vivo has been pre~ented .~~

It should be noted that these highly complex systems require extremely precise data for their solution and the use of least-square assessments. In order to confirm that a minor complex occurs, normalized curve graphical analysis is advisable. A computerized curve comparison treatment which takes the tedium out of normalized curve analysis has been developed and used in studies of the binding of glycine to Zn" and Pbxt.56 43 S. Ramamoorthy and P. G. Manning, J. Inorg. Nuclear Chem., 1975, 37, 363. 44 P. I. Migal, A. P. Gerbeleu, and G. G. Muntyanu, Zhur. neorg. Khim., 1975,20, 1975 (Russ.)

(Chern. Abs., 1975,84,36 011). 45 M. Kodama, Bull. Chem. SOC. Japan, 1975,48, 2961. 48 0. Yamauchi, Y. Nakao, and A. Nakahara, Bull. Chem. SOC. Japan, 1975,48,2572. 47 J. N. Cape, D. H. Cook, and D. R. Williams, J.C.S. Dalton, 1974, 1849. 48 G. K. R. Makar, M. L. D. Touche, and D. R. Williams, J.C.S. Dalton, 1976, 1016. 49 A. C. Baxter and D. R. Williams, J.C.S. Dalton, 1975, 1757. 5 0 N. Cohen and R. Guilmette, Bioinorg. Chem. 1976, 5,203. s1 A. M. Corrie, M. D. Walker, and D. R. Williams, J.C.S. Dalton, 1976, 1012. 62 A. M. Corrie and D. R. Williams, J.C.S. Dalton, 1976, 1068. K1 E. Friedheim and C. Corvi, J. Pharm. Pharmacol, 1975, 27, 624. 54 M. L. D. Touche and D. R. Williams, J.C.S. Dalton, 1976, 1355. 55 A. M. Corrie, G. K. R. Makar, M. L. D. Touche, and D. R. Williams, J.C.S. Dalton, 1975, 105.

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498 Amino-acids, Peptides and Proteins Spectroscopic Studies.-1.r. spectroscopic studies of metal complexes of amino- acids are increasing in popularity. Band assignments are often a contentious topic. Although there is general agreement on the frequency ranges in which ligand vibrations occur, the assignment of metal-ligand stretching vibrations is often a matter for debate. Isotopic substitution of ligand atoms with 13C, l5N, and l 8 0

provides a suitable method for verifying band assignments. This technique has been used successfully with trans-~i(Gly)2(OH2)2].66 Similar studies have been reported for the Ni" and Cu" complexes with L- and /3-alanine.57 The i.r. spectra of Mo"' complexes of iminodiacetic acid, N-methyliminodiacetic acid, nitrilotri- acetic acid, aspartic acid, and histidine indicate that they act as terdentate ligands, the complexes containing either a core of MOO, or di-p-oxo-dioxo Mo204.s8

Raman and i.r. studies of mercury(I1) complexes of cysteine, cysteine methyl ester and methionine, have shown that in the solid state, bis(methionat0)- mercury(1r) has predominantly amino N- and carboxyl O-mercury bonds, whereas in solution sulphur-mercury bonding is preferred.5g An i.r. investigation (with band assignments) of Hg", Zn", and Cd" complexes of N-acetylglycine has also been published.s0

Magnetic and i.r. measurements have been used to investigate Ni(L-arginine)" ClO,,nH,O complexes in which pressure induces ionic perchlorate to become a bidentate ligand.61 The Faraday method has been used to estimate the molar magnetic susceptibilities of a1 kali-metal amino-acid salts. Magnetic and e. p .r . studies have also been reported for bis(p-hippurato-0)-bis(hippurato-0)- dicopper(I1) tetrahydrateYg3 copper(@ complexes of hippurate and a~etylglycine,~~ and bis(glycinato)copper(r~).~~ Thermal stability and i.r. data for some edda-type polyaminocarboxylate complexes of nickel(I1) have also been reported.66

Various n.m.r. studies have been carried out on amino-acid complexes. [Co(acac),(L)]"+ (L = amino-acid or its ester) has been considered as a possible new type of N-terminal peptide bond-cleaving Cobalt(r1r) complexes of L-aspartic acid and L-glutamic acid have been investigated using d-d spectra and c.d. and n.m.r. techniques.6s N.m.r. techniques have been used to study (using D20 solvent over a range of pD) nickel@) complexes of alanine, valine, threonine, histidine, and ~ y s t e i n e . ~ ~ A series of papers aimed at the reinterpretation of paramagnetic line broadening in the n.m.r. spectra of complexes of amino- acids and peptides has begun with studies of the copper(I1) complexes of glycine and s a r c ~ s i n e . ~ ~ Co-ordination sites of acetylhistamine and acetylhistidine in s6 G. C. Percy and H. S. Stenton, J.C.S. Dalton, 1976, 1466. s7 G. C. Percy and H. S. Stenton, J.C.S. Dalton, 1977, 2429. s8 R. J. Butcher, H. K. J. Powell, C. J. Wilkins, and S. H. Yong, J.C.S. DaZton, 1976, 356.

Y. K. Sze, A. R. Davis and G. A. Neville, Inorg. Chem., 1975, 14, 1969. 6o G. Marcotrigiano, L. Menabue, and G. C. Pellacani, J. Inorg. Nuclear Chem., 1975,37,2344. 61 S . T. Chow and C. A. McAuliffe, J. Inorg. Nuclear Chem., 1975, 37, 1059. 62 M. A. Bernard, N. Bois, and M. Daireaux, Canad. J . Chem., 1975, 53, 3167. 63 E. D. Estes, W. E. Estes, R. P. Scaringe, W. E. Hatfield, and D. J. Hodgson, Inorg. Chem.,

1975,14,2564. 64 R. Gaura, G. Kokoszka, K. E. Hyde, and R. Lancione, J. Coordination Chem., 1976, 5, 105. 66 V. G. Krishnan and G. S. Sastry, Bioinorg. Chem., 1976, 6, 179. 66 I. Hirako, T. Murakami, and M. Hatano, Bull. Chem. SOC. Japan, 1976, 49, 147. 67 T. L. Hall and S. H. Laurie, J. Inorg. Nuclear Chem., 1976, 38, 349. 68 T. Yasui, H. Kawaguchi, Z . Kanda, and T. Ama, Bull. Chem. SOC. Japan, 1974,47, 2393. 69 L. Gelbaum and R. Engel, J. Inorg. Nuclear Chem., 1975, 37, 793. 7 0 J. K. Beattie, D. J. Fenson, and H. C. Freeman, J. Amer. Chem. Soc., 1976, 98, 500.

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Metal Complexes of Amino-acids, Peptides, and Proteins 499

complexes with copper(r1) are suggested as a result of n.m.r. Gergely and his co-workers 72 have studied the rates of proton exchange for 13 amino- acids with copper(n) using n.m.r. and equilibrium techniques. The rate- determining step in complex formation often appears to be ring closure.

The lability of the metal-nitrogen bonds in complexes of polyaminocarboxylic acids, (HO,CCH,),N(CH,).N(CH,CO,H), (n = 2, 3, or 4), with Cd", Zn", and Hg" has been studied by n.m.r.73 Various physical techniques, including n.m.r., have been used to investigate complexes of S-methyl-L-cysteine and 2-aminoethanethiol with Mo"'. There is a greater tendency to form sulphur- bridged species with Mo"' than with MoXV, the bridges being less labile than oxygen bridges.74 Papers have also appeared dealing with the binding of methyl- mercury to methionine 75 and the effect of paramagnetic metal ion impurities on the lH spin-lattice relaxation times of L-histidine. The impurities can be removed by treatment with a chelating resin.76 A spectroscopic investigation of ternary complexes of L- and D-aspartic acid, glutamic acid and arginine, lysine or ornithine with copper(@ has also been p~blished.~'

Some unusual octahedral complexes of nickel(r1) with thioether derivatives of cysteine ethyl ester have been characterized; novel features arise due to steric interactions of bulky groups.78 A number of new dinuclear and trinuclear complexes of p-aminocarboxylates with cobalt(II1) have been chara~terized.~~ Mixed ligand complexes of a wide range of amino-acids and related ligands with copper(II) have been investigated.80 A particular aim of this work was to gain an insight into interactions between charged groups such as -Cog, -&H3, and guanidium.

The interaction of D-penicillamine with methylmercury and phenylmercury has been studied by a variety of physical techniques and the degree of a-covalent and .rr-back bonding investigated.s1 The characteristic red-violet chromophore formed when D-penicillamine interacts with copper(1r) in aqueous solution has been attributed to a polymeric anion of mixed oxidation states with [Cu,(~-penicillarnine),]~ repeating units.82 It is intriguing that formation of this polymer is halide-ion dependent. The interaction of cysteine with silver(1) has also been studied.85 Diffraction Studies.-Several crystallographic investigations have been carried out, particularly of cobalt(m) and copper(r1) complexes. The X-ray structure of the red (+)-cis-(O)trans(N,)cis(N~)bis(L-ornithinato)cobalt(~rr) complex has been

71 P. A. Temussi and A. Vitagliano, J. Amer. Chem. SOC., 1975, 97, 1572. 78 I. Nagypal, E. Farkas, and A. Gergely, J. Znorg. Nucl. Chem., 1975, 37, 2145. 73 D. L. Rabenstein, G. Blakney and B. J. Fuhr, Canad. J. Chem., 1975,6,787. 7 p P. C. H. Mitchell and R. D. Scarle, J.C.S. Dalton, 1975, 110. 76 M. T. Fairhurst and D. L. Rabenstein, Znorg. Chem., 1975, 14, 1413. 70 A. Nakano, F. Inagaki, M. Tasumi, and T. Miyazawa, J.C.S. Chem. Comm., 1976, 232. 77 T. Sakakurai, 0. Yamauchi, and A. Nakahara, Bull. Chem. SOC. Japan, 1976, 49, 169. 73 R. E. Wagner and J. C. Bailar, jun., J. Amer. Chem. SOC., 1975, 97, 533. 7B T. Yasui, T. Ama, H. Morio, M. Okabayashi, and Y. Shimura, Bull. Chem. SOC. Japan, 1974,

47, 2801. 8o 0. Yamauchi, Y. Nakao, and A. Nakahara, Bull. Chem. SOC. Japan, 1975,48,2572.

Y . Hojo, Y . Sugiura, and H. Tanaka, J . Inorg. Nuclear Chem., 1976, 38, 641. J. R. Wright and E. Frieden, Bioinorg. Chem. 1975, 4, 163. G. D. Zegzhda, S. I. Neikovskii, and F. M. Tulyupa, Koord. Khim., 1976, 2, 162.

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500 Amino-acids, Peptides and Proteins reported in conjunction with c.d. Buckingham, Sargeson, and co-workers have determined crystal structures for A-R-[Co(ethylenediamine),(N-methyl-(S)- alaninato}]I, 85 and [Co(trien)(gly~inato)]Cl~,H~O,~~ and correlated the results to strain-energy minimization calculations.

The crystal structure of DL-(ethylvalinate-NN-diacetato)diaquocopper(rr) has been determined in order to investigate the feasibility of hydrolysis mechanisms involving quadridentate bonding of the ligand (1). The structure is a distorted

octahedron, where the equatorial co-ordination consists of the tertiary nitrogen, the two acetate oxygens, and a water The second water molecule occupies an axial position at a greater distance from the metal, while the ether oxygen of the ester group occupies the other axial position lying 2.84 A from the metal. The ester carbonyl group is not involved in bonding.

Crystallographic, spectral, and magnetic studies of Cu(L-asparaginate), and Cu(L-glutaminate), have also been reported.88

Complexes of D-penicillamine have attracted the attention of crystallographers in both America 89 and A ~ s t r a l i a . ~ ~ ~ 91 The synthesis and X-ray structures of L-histidinyl-D-penicilIaminatocobaIt(rII) and L-histidinyl-D-penicillamino- chromium(n1) have been described.89 The central metal ion is approximately octahedral, the ligating atoms being N (imidazole), N (terminal), 0 (histidine), and N, 0, and S (penicillamine). The stereochemical selectivity observed in these reactions is quite striking; reaction of [M(~-His),l (M = Co or Cr) with DL-penicillamine (pen) gave only [M(~-His)(~-pen)] and no diastereoisomeric [M(~-His)(~-pen)]. D-Penicillamine is used in chelation therapy for lead(I1) and mercury(rI), but not for cadmium(r1) because it redistributes the metal to other tissues. The crystal structure of D-penicillaminatocadmium(II) establishes octahedral stereochemistry around cadmium with two S atoms, three 0 (carboxylate), and one N (amino) atoms from four ligand m01ecules.~~ This relatively weak and non-specific interaction is in contrast with the strong terdentate chelation of the analogous lead ~ys te rns .~~

X-Ray crystallography has been carried out on the highly hydrated purple thallium(1) salt of the anion [Cu1,Cu116-~-penicillaminato,,C115-. Eight S,- co-ordinated Cu' atoms surround a central chloride ion and each of the six 84 Y. Nakayama, S. Ooi, and H. Kuroya, Bull. Chem. SOC. Japan, 1976,49, 151. 85 B. F. Anderson, D. A. Buckingham, G. J. Gainsford, G. B. Robertson, and A. M. Sargeson,

Inorg. Chem., 1975, 14, 1658. 86 D. A. Buckingham, M. Dwyer, G. J. Gainsford, V. J. Ho. L. G. Marzilli, W. T. Robinson,

A. M. Sargeson, and K. R. Turnbull, Inorg. Chem., 1975, 14, 1739. R 7 J. Rodgers and R. A. Jacobson, Inorg. Chim. Acta, 1975, 13, 163. s3 M. N. Srivastava, R. C. Tewari, U. C. Srivastava, G. B. Bhargava, and A. N. Vishnoi, J .

Inorg. Nuclear Chem., 1976, 38, 1897. P. de Meester and D. J. Hodgson, J.C.S. Chem. Comm., 1976, 280. H. C. Freeman, F. Huq, and G. N. Stevens, J.C.S. Chem. Comm., 1976, 90. P. J. M. W. L. Birker and H. C. Freeman, J.C.S. Chem. Comm., 1976, 312.

9 2 H. C. Freeman, G. N. Stevens, and I. F. Taylor, J.C.S. Chem. Comm., 1974, 366.

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Metal Complexes of Amino-acids, Peptides, and Proteins 501

Cull atoms are N,S,-co-ordinated from two ligand~.~l Although when administered intravenously the half-life of the complex is sufficiently long to permit a significant proportion to be excreted through the kidneys,8a it is unlikely that such mixed oxidation state cluster complexes are formed in vivo during therapy with D-penicillamine because of the relatively low concentrations of copper in blood plasma.

The stability of the dimolybdenum(I1) unit, Mot+, has been noted in the structure of tetrakis(g1ycine)dimolybdenum disulphate te t rah~dra te .~~ The structures of three Hg" complexes of sulphur-containing amino-acids, (HgCI2)%- (~~-peniciI~arnine),2H~O, HgC1,(~~-penicillamke),,H,O, and Hg(C1OJ2- (methionine),,2H20 reveal polar, polymeric arrangement with chloride, sulphur, and carboxylate bridges which are absent in the corresponding methylmercury der i~at ives .~~ Trimethyltin glycinate has been found to be a linear polymer with amino-bridged, trigonal-bipyramidal structural Two structural papers of general interest concern the crystal structures of imidazolium sulphate dihydrate 98 and tetraimidazolezinc(I1) perchl~ra te .~~ Stereochemistry and Stereose1ectivity.-A novel optical resolution of racemic a-amino-acids by formation of mixed ligand copper(I1) complexes with electro- static ligand-ligand interactions has been Resolution of DL-aspartic acid and DL-glutamic acid (A) was achieved via the stereospecific formation of ternary copper(I1) complexes composed of one of these amino-acids and a basic L-a-amino-acid (B = arginine, lysine, or ornithine). A trans structure (2) is suggested for CU(L-A)(L-B) and a cis structure (3) for CU(D-A)(L-B). The

+-7 7-+- oc- ,f,,".I- -0 TH

HC-NH1 0-CO CU(L-A)(L-B)

(2) CU(D-A)(L-B)

(3)

resolution of DL-(A) implies that the resolution of DL-(B) is feasible by this method. Fujiinn has continued his work on the determination of the optical purity of

amino-acids by complex formation. The method uses the fact that when an optically active amino-acid is added to a basic solution of K[Co(acac,en)(Gly),] the solution shows a much larger optical rotation than that of the free amino-acid in the visible region. About 0.1-0.05 g (ca. 1/50 to l/lOO of the usual amount) suffices to determine the optical purity of the amino-acid.

Copper(1) oxide has been reported to be an excellent initiator for the racemization of alanine in basic The metal-ion catalysed racemization O3 F. A. Cotton and T. R. Webb, Inorg. Chem., 1976, 15, 68. 94 A. J. Carthy and N. J. Taylor, J.C.S. Chem. Comm., 1976, 214. g6 B. Y . K. Ho, J. A. Zubieta, and J. J. Zuckerman, J.C.S. Chem. Comm., 1975, 88. g6 H. C. Freeman, F. Huq, J. M. Rosalky, and I. F. Taylor, jun., Actu Cryst., 1975, B31,2833. @' C. A. Bear, K. A. Duggan, and H. C. Freeman, Actu Cryst., 1975, B31, 2713.

T. Sakurai, 0. Yamauchi, and A. Nakahara, J.C.S. Chem. Comm., 1976, 553. Y . Fujii, Bull. Chem. SOC. Japan, 1974, 47, 2856.

loo A. Tai, K. Okada, T. Masuda, and Y. Izumi, Bull. Chem. SOC. *Japan, 1976, 49, 310.

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502 Amino-acids, Peptides and Proteins and a-proton exchange of NN-dicarboxymethyl-D-phenylglycine have been studied kinetically.lol When bound to metal ions, Pb", CuII, and Ni", the ligand undergoes racemization at rates up to 5000 times faster than for the free ligand.

A number of papers have appeared dealing with stereoselective effects in the formation of metal complexes of amino-acids. In the biological pH range marked stereoselectivity is present in the formation of ternary histidinato- copper(1r) complexes containing ligands (A) with positively charged protonated side-chains,lo2 with preferential formation of the complex containing ligands of the same chirality, e.g. Cu(L-His)@-HA). Stereoselectivity in formation of mononuclear complexes of histidine with some bivalent metal ions has been observed.lo3 Stereoselective binding of copper(n), zinc(Ir), cobalt(n), and nickel(r1) to the optically active amino-acids p-(2-pyridyl)- and p-(6-methyl-2-pyridyI)- a-alanine, which can be regarded as analogues of histidine and phenylalanine, has also been observed.lo4

The meso-complex [Ni(~-Met)(~-Met)] is more thermodynamically stable than [Ni(~-Met)(~-Met)]. The stereoselectivity is attributed to terdentate binding of the methionine and indicates a weak interaction between nickel(r1) and the thioether sulphur atom of the ligand.los It has been reportedlo6 that for the ligand N-benzyl-DL-valine (A), CU(D-A), and CU(L-A)~ are more stable than the meso-complex CU(L-A)(D-A). Crystallographic results suggest that the observa- tions can be rationalized in terms of steric hindrance to co-ordination of solvent water molecules in the axial positions of the meso-complex. The results of a study on the effect of solvent on stereoselective effects in copper(rr) complexes of N-alkyl derivatives of bifunctional a-amino-acids have been pub1i~hed.l~~ A number of theoretical investigations on the optical activity of copper(1r) complexes of amino- acids have appeared.lo8-l10

Several investigations with cobalt(m) complexes of amino-acids have been published. C.d. spectra of the tmsym-cis(0) isomers of (L-alaninate-N-mono- acetato)(diethylenetriamine)cobalt(uI) have been reported,lll and stereoselectivity in formation of oxalato-L-aspartato-ethylenediaminecobalt(rrr), i.e. [Co(Ox)- (L-AspH)(en)], has been studied.l12 Stereoselectivity (> 80%) was found in the mer-A and fac-A isomers. Biguanide-amino-acid complexes of the type [Co(arn)(Hbg),l3+, where am is the anion of glycine, sarcosine, L-alanine, L-valine, L-isoleucine, or L-proline, have been prepared and res01ved.l~~ 101 L. G. Stadtherr and R. J. Angelici, Znorg. Chem., 1975, 14, 925. lo8 G. Brookes and L. D. Pettit, J.C.S. Chem. Comm., 1975, 385. lo3 L. D. Pettit and J. L. M. Swash, J.C.S. Dalton, 1976, 588. lo* P. R. Rechani, R. Nakon, and R. J. Angelici, Bioinorg. Chem., 1976, 5, 329. lo5 J. L. M. Swash and L. D. Pettit, Znorg. Chim. A d a , 1976, 19, 19. lo6 V. A. Davankov, S. V. Rogozhin, Y. T. Struchkov, G. G. Alexandrov, and A. A. Kurganov,

J. Znorg. Nuclear Chem., 1976, 38, 631. lU7 V. A. Davankov, S. V. Rogozhin, A. A. Kurganov, and L. Y . Zhuchkova, J. Inorg. Nuclear

Chem., 1975, 37, 369. lo8 C.-Y. Yeh and F. S. Richardson, Inorg. Chem., 1976, 15, 682. loS A. Decinti and G. Larrazabal, Inorg. Chim. Acta, 1976, 18, 121. 'lo L. Gil, E. Moraga, H. Bobadill, S. Bunel, and C. A. Bunton, J. Inorg. Nuclear Chem., 1975,

37, 2509. 111 K. Okamoto, J. Hidaka, and Y. Shimura, Bull. Chem. SOC. Japan, 1975, 48, 2456. 112 M. Takeuchi and M. Shibata, Bull. Chem. SOC. Japan, 1974, 47, 2797. 113 H, Kawaguchi and B. Douglas, J. Coordination Chem., 1976, 5, 115.

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Metal Complexes of Amino-acids, Peptides, and Proteins 503

Reactivity and Kinetics.-A number of interesting papers have appeared in this area, and the topic of synthetic oxygen carriers of biological interest reviewed.ll* The two isomers of NN-bis-(2-aminoethyl)glycine react with cobalt(@ in the absence of dioxygen (0,) to give a complex CoL+ which, when exposed to dioxygen, forms a stable dimeric oxygen adduct [COLO,OHCOL]+.~~ The complex does not react further with oxygen or rearrange to give a kinetically inert cobalt(II1) complex. Purging at low pH with N, results in complete reversal of the reaction, giving CoL+ and 02. The oxygenation of the bis complexes of cobalt(I1) with ~~-2,3-diaminopropionate and L-ornithinate has also been studied. Equilibrium data for oxygenation were obtained using polarographic techniques.lls

Chloroauric acid oxidizes methionine stereospecifically to methionine sulphoxide.lls Condensation of formaldehyde with [C~(en)~(Gly)]~+ gives as the initial product [cll-hydroxymethylserinebis(ethylenediamine)cobalt(r~r)]~+, which is subsequently converted into the [a-hydroxymethylserine-l,4,8,1 l-tetra- aza-6,13-dioxacyclotetradecanecobalt(111)]~+ ion containing the new macrocyclic ligand (4) which is co-ordinated via the nitrogen donors as in (5).l17 The acidity

of the CH, group of co-ordinated glycine has been recognized for many years; thus Cu(Gly), reacts with acetaldehyde to give complexes of threonine and allothreonine. Cooke and Dabrowiak 118 have studied the reaction of acetaldehyde with optically active [C~(en),(Gly)]~+. The isolated threonine and allothreonine contain an excess of the S-enantiomer, indicating that the aldehyde prefers to attack the S 'side' of the co-ordinated glycine.

A number of studies of metal derivatives of amino-acid esters have appeared and the metal-ion promoted hydrolysis of amino-acid esters and peptides has been reviewed.llsa The polymerization of the methyl esters of amino-acids via their copper(I1) complexes has been reported.ll9 The co-ordination of optically active amino-acids and their methyl esters to nickel(I1) complexes of 1 ,2-bis- [2(S)-aminomethyl-l-pyrrolidinyl]ethane (6 ; R = H) and 1,2-bis-[2(S)-N-methyI-

114 F. Basolo, B. M. Hoffman, and J. A. Ibers, Accounts Chem. Res., 1976, 384. 116 K. T. Sew and H. K. J. Powell, J.C.S. Dalton, 1975, 2023.

G. Natile, E. Bordignon, and L. Cattalini, Inorg. Chem., 1976, 15, 246. 11' R. J. Geue, M. R. Snow, J. Springborg, A. J. Herlt, A. M. Sargeson, and D. Taylor, J.C.S.

Chem. Comm., 1976,285. 118 J. C. Dabrowiak and D. W. Cooke, Inorg. Chem., 1975,14, 1305. lleCr R. W. Hay and P. J. Morris, in ref. 16. 119 A. Brack, D. Louembe, and G. Spach, Origins Life, 1975, 6,407.

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504 Amino-acids, Peptides and Proteins aminomethyl-l-pyrrolidinyllethane ( 6 ; R = Me) has been studied.120 Some amino-acidate ions co-ordinate stereoselectively, as do their methyl esters, so that base hydrolysis of the esters proceeds stereoselectively. The reactions of cis- [MC12(PPh2C1)2] (M = Pd or Pt) with a-amino-acid ester have been studied.121 Complexes such as cis-[MC12(PPh2),NCH2C02Me] and frans-[MCl,(PPh,- NHCH,CO,Me),] were prepared which may be useful catalysts for asymmetric induction.

The potential antitumour activity of some amino-acid complexes has been studied.122 A number of copper(I1) complexes of a-amino-acids have pronounced antiarthritic activity which is a function of their copper content.l*

Efforts continue to be directed towards the simulation of the action of nitrogenase using systems containing a dimeric molybdenum(v) cysteine complex (7) and a reducing agent, and the area has been reviewed.123 Such systems reduce acetylene to ethylene and dinitrogen (N,) to ammonia in low yields. Ferredoxin model compounds such as [Fe,S,(SR),]*- (n = 2 4 ) apparently accelerate the transfer of electrons from reductant to molybdenum and improve ethylene ~ i e 1 d s . l ~ ~ Electrochemical reduction of the Mo" cysteine dimer (7) shows that it undergoes a single four-electron reduction to Mo"' products, and it is suggested that a monomeric Mo"' species is the catalytically active complex.125 A dextran-bound cysteine polymer (1.05 mmol cysteine per g dextran) forms a molybdenum complex analogous to (7) which does not appear to dissociate into a monomer analogous to (8) under basic conditions.12s In the presence of borohydride the polymer-complex reduces acetylene 30 times faster than (7) possibly because the inert polymer support acts to keep apart reduced catalytically active species analogous to (9), thus preventing formation of inactive oxo-bridged dimers.

The metal-complex catalysed /I-decarboxylation of L-aspartic acid has been ~ep0rted.l~' Various other kinetic investigations have been carried out. The nitrogen to oxygen isomerization of the penta-ammineruthenium(m)glycine ion has been investigated,12* as have the Cr" reductions of amino-acid substituted

'-0,CCHNHz 0 0 Gs_\Jo/o\&2J CN" = I

CH2S- c*/ '0' '01 (0 (7)

(8) (9) lZo S. Kitagawa, T. Murakami, and M. Hatano, Inorg. Chem., 1976, 15, 1378. lZ1 P. W. Lednor, W. Beck, and G. Thiel, Inorg. Chim. Actu, 1976, 20, L11. lz2 A. J. Charlson, K. E. Trainor, and E. D. Watton, J. Proc. Roy. SOC. N.S.W., 1975, 108,

123 G. N. Schrauzer, Angew. Chem. Internat. Edn., 1975, 14, 514. 12d K. Kano and G. N. Schrauzer, J. Amer. Chem. SOC., 1975,97, 3404. lZ5 D. A. Ledwith and F. A. Schultz, J. Amer. Chem. SOC., 1975,97,6591. lZ8 €I. Susuki, S. Meshitsuka, T. Tabashima, and M. Ichikawa, Chem. Letters, 1975, 4, 285. 12' N. Y. Sakkab and A. E. Martell, Bioinorg. Chem., 1975, 5, 67. lZ8 S. E. Diamond and H. Taube, J. Amer. Chem. SOC., 1975,97,5921.

Pt 1-2, 6.

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Metal Complexes of Amino-acids, Peptides, and Proteins 505

penta-amminecobalt(m) ions, i.e. [CO(NH~)~OOCCHR&H~]C~~.~~~ The reaction of [HCrOJ- with L-cysteine (HzL) has been studied by stopped-flow methods.lso The transient orange species observed at 420 nm is the 1:l chromate ester [(HL)CrO,]-. Oxygen-18 exchange studies of the trans(fac)-bis(N-methylimino- diacetato)chromate(m) anion have been carried and studies made of the kinetics and mechanism of the elimination of chloride from cis-chlorobis- (ethylenediamine)(glycinato-N)cobalt(m). 132

The kinetics of complexing of nickel(I1) by methionine, cysteine, penicillamine, cysteine ethyl ester, glycylmethionine, glutathionine, tyrosine, m-tyrosine, and o-tyrosine have been measured by stopped-flow methods. Initial complexing is at the carboxylate 133 group of the zwitterion; however, for methionine, peni- cillamine, and cysteine ethyl ester, a reaction path involving initial complexing at the thiol group occurs.

Schiff Bases.-Compared with previous years there has been some resurgence of interest in the general field of Schiff base complexes of amino-acids. The oxidative deamination of alanine by atmospheric dioxygen in bis(N-salicylidene- alaninato)cobaltate(m) has been as has the asymmetric synthesis of threonine and allothreonine by the condensation of acetaldehyde at pH 11 with dissymmetric bis(N-salicylideneglycinato)cobaltate(rII) complexes.136 A novel threonine aldolase model has been described.136 The Al"' pyridoxal-catalysed threonine aldolase model reactions of threonine and a new substrate, /3-hydroxy- valine, were followed by quantitative n.m.r. in D,O solution. Formation of acetone in the /3-hydroxyvaline reaction provides the first quantitative evidence for C-C bond fission of an a-amino-acid having an at-proton in the presence of pyridoxal and metal ions. The reaction of acrylonitrile with N-salicylidene- glycinatocopper(i1) gives the copper(1r) complex of N-(2-cyanoethyl)-4-cyano- 5-o-hydroxyphenylproline

The crystal and molecular structures of iron(rx1) complexes of the sexadentate ligand NN'-ethylenebis-(o-hydroxyphenylglycine) have been reported.13* Struc- tures of the metal complexes of N-salicylidenecysteine have also been

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iaa

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132

133

134

135

136

137

138

(10) R. Bembi and W. U. Malik, J. Inorg. Nuclear Chem., 1975,37, 570. J. P. McCann and A. McAuley, J.C.S. Dalton, 1975, 783. S . Dutta-Chaudhuri, C. J. O'Connor, and A. L. Odell, J.C.S. Dalton, 1975, 1921. A. C. Dash, R. K. Nanda, and S. K. Mohapatra, J.C.S. Dalton, 1975, 897. J. E. Letter and R. B. Jordan, J. Amer. Chem. Soc., 1975, 97, 2381. N. G. Faleev, Y. N. Belokon, V. M. Belikov, and L. M. Mel'nikova, J.C.S. Chem. Comm., 1975, 85. Y. N. Belokon, V. M. Belikov, S. V. Vitt, M. M. Dolgaya, and T. F. Savel'eva, J.C.S. Chem. Comm., 1975, 86. J. A. Marcello, A. E. Martell, and E. H. Abbott, J.C.S. Chern. Comm., 1975, 16. L. Casella, M. Gullotti, A. Pasini, G. Ciani, M. Manassero, M. Sansoni, and A. Swoni, Inorg. Chim. Acta, 1976, 20, L31. N. A. Bailey, D. Cummins, E. D. McKenzie, and J. M. Worthington, Inorg. Chim. Acta, 1976, 18, L13.

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506 Amino-acids, Peptides and Proteins described.135 Various spectroscopic investigations have been carried out on Schiff-base derivatives. The absorption and c.d. spectra of pyridoxylidenalanato- aluminium(I1i) have been studied,140 as have the i.r. spectra of nickel(r1) and cobalt(ii) N-sali~ylideneglycinates.~~~ A series of Cu" and CuI1-Zn1I complexes of X-salicylaldehyde-amino-acid Schiff bases (X = 4-OH, H, 5-OH, 5-Cl) with glycine, alanine, and phenylglycine have been prepared and their magnetic and spectral properties investigated.142 The condensation of salicylaldehyde or acetylacetone with S-( + )-cysteine esters in the presence of nickel(ir) gives diamagnetic, dinuclear, planar Schiff-base complexes. Their c.d. spectra show negative Cotton effects due to the stereospecific co-ordination of the chiral ligand.143 Stereoselective interactions between amino-acids and optically active diketones in copper(rr) complexes of their Schiff bases have been described.144 The structures of some transition-metal complexes of N-glycyl-a-picolylamine have been studied, and their mechanism of formation was inve~t iga ted .~~~ Karube and Matsuschima 146 have carried out work on non-enzymatic pyridoxal catalysis and describe a species absorbing at 467 nm which they suggest to be the Al"' complex of the Schiff base N-methylpyridoxylidene-a-aminoacrylate (1 1). The

species is considered as a possible model for an intermediate in pyridoxal- catalysed a&elirnination and /3-replacement reactions of amino-acids.

A review dealing with Schiff base complexes of copper(r1) has appeared.147

3 Peptides Structural Aspects.-There appears to have been an increase in activity in this area, particularly in using metal-peptides as models for metalloproteins. Thus Lau and Sarkar 148 have studied the copper(1i) complexes of diglycyl-L-histidine as a peptide mimicking the copper(i1)-transport site of albumin. In addition there has been a significant increase in the volume of work dealing with the formation constants of metal complexes of simple peptides. 13m F. Baykut, A. Aydin, and A. Uren, Chim. Acfa Turc., 1975, 3, 105. 140 A. E. Martell and A. F. Eidson, Bioinorg. Chem., 1975, 4, 277. 141 G. C. Percy, J. Inorg. Nuclear Chem., 1975, 37, 2071. 142 L. A. Zyzyck, H. Frummer, and J. F. Villa, J. Inorg. Nuclear Chem., 1975, 37, 1653. 143 F. Jursik and B. Hajek, Inorg. Chim. Acfa, 1975, 13, 169. 144 L. Casella, M. Gullotti, A. Pasini, and M. Visca, Inorg. Chim. Acfa, 1976, 19, L9. 146 0. Bekaroglu, Chim. Acta Turc., 1975, 3, 23. l46 Y. Karube and Y . Matsushima, J. Amer. Chem. Soc., 1976, 98, 3725. 14' H. S. Maslen and T. M. Waters, Coordination Chem. Rev., 1975, 17, 137. 148 S. Lau and B. Sarkar, Canad. J. Chem., 1975, 53, 710.

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Metal Complexes of Amino-acids, Peptides, and Proteins 507 The thermodynamics of formation of complexes of copper(I1) and nickel(I1)

with glycylhistidine, B-alanylhistidine, and histidylglycine have been studied potentiometrically at 25 "C and I = 0.10 mol dm-3 (KN03).149 The equilibria are very complicated but polynuclear species are insignificant below pH 10 in dilute solution. Suggestions are made as to the probable co-ordination sites as a function of pH. A further paper by the same group 160 deals with the formation constants of nickel(n) and copper(r1) complexes of dipeptides containing non- co-ordinating substituent groups. The structures of the complexes are discussed and the possible equilibria in the nickel-dipeptide systems considered. Several metallo-proteins contain more than one copper ion per protein molecule, and in some cases a pair of copper ions may be close enough to interact with each other. Model amino-acid and peptide complexes containing two or more neighbouring copper(rr) ions are rare. Carnosine (p-alanyl-L-histidine) forms a dimer in equimolar solutions of copper(I1) and ligand at pH 6.161 L-Histidylglycine is also reported to form a dimer in equimolar solutions with copper(I1) at pH 7,162 and this conclusion has now been confirmed by Boggess and Martin163 who carried out a spectrophotometric-pH study over an eight-fold concentration range.

A considerable number of potentiometric studies have been carried out on copper(@ and nickel(11) complexes of peptides, although it is now becoming more common for a variety of other physical techniques to be employed to study these problems. Thus Scheinblatt 164 has investigated the interaction of copper(r1) with acetylglycine using potentiometric titration, e.s.r., n.m.r., and spectro- photometric techniques. At pH < 6.5 the copper is bound to the carboxylate group to give a 'blue' complex. Precipitation of copper occurs at pH ca. 7, but at pH > 9 in the presence of excess ligand, soluble complexes are formed due to binding via deprotonated amide groups.

Sige1166 has carried out a detailed investigation of the influence of alkyl side- chains on the stability of binary and ternary copper(I1)-dipeptide complexes. Protonation constants and formation constants have been determined for the dipeptides: glycylglycine, glycyl-L-alanine, L-alanylglycine, L-alanyl-L-alanine, glycyl-L-leucine, L-leucylglycine, glycyl-L-isoleucine, L-isoleucylglycine, glycyl- sarcosine, sarcosylglycine, glycyl-L-proline, and L-prolylglycine. Besides the binary complexes CuL+ and Cu(L - H) the mixed ligand complexes with 2,2'-dipyridyl Cu(dipy)L+ and Cu(dipy)(L - H) were also investigated. Depend- ing upon the position of the alkyl group either the stability or the acidity of the complexes is altered.

Highly polynuclear species are formed in equilibrium solutions of copper(n) and glycyl-L-histidylglycine.166 Histidine-containing peptides have received considerable attention. Formation constants have been determined 167 for zinc@) and cobalt(r1) complexes of glycyl-L-histidine, glycyl-L-histidylglycine, 14@ G. Brookes and L. D. Pettit, J.C.S. Dalton, 1976, 2112. 160 G. Brookes and L. D. Pettit, J.C.S. Dalton, 1976, 2106. 151 E. W. Wilson, M. H. Kasperian, and R. B. Martin, J . Amer. Chem. Sue., 1970, 92, 5365. Ib2 H. Aiba, A. Yokoyama, and H. Tanaka, Bull. Chem. SOC. Japan, 1974,47, 136. lbS R. K. Boggess and R. B. Martin, J. Inorg. Nuclear Chem., 1975, 37, 1097. lb4 M. Scheinblatt, Bioinorg. Chem., 1975, 5, 95. lb6 H. Sigel, Znorg. Chem., 1975, 14, 1535.

R. Osterberg and B. Sjoberg, J. Inorg. Nuclear Chem., 1975,37, 815. 16' R. P. Agarwal and D. D. Perrin, J.C.S. Dalton, 1975, 1045.

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508 Amino-acids, Peptides and Proteins and L-histidylglycine from pH-titration data, using a range of metal ion and ligand concentrations. Dinuclear complexes are the predominant species in solutions of zinc(r1) and glycylhistidine. Mixed-ligand complexes of the type MAL are also formed by zinc(I1) and cobalt(r1) with histidine (HA) and the peptides. Comparisons are made of the zinc@)-complexing abilities of the peptides in competition with a-amino-acids under physiological conditions. Formation constants have also been determined 158 for the copper(r1) complexes of glycylhistidine, glycylhistidylglycine, histidylglycine, and carnosine by pH- titration, and comparisons made with the copper-complexing abilities of these peptides in competition with a-amino-acids under physiological conditions.

Diglycyl-L-histidine is a peptide molecule designed to mimic the specific copper(I1)-transport site of human albumin. The equilibria and structures of the complexes formed in the ternary system of L-histidine, copper(n), and diglycyl- L-histidine have been studied by Kruck and S a r k a ~ . l ~ ~ In addition, kinetic studies of the copper(@-exchange from L-histidine to human serum albumin and diglycyl-L-histidine have been made.148 The exchange rates from L-histidine to albumin and the tripeptide are 0.67 and 0.42 s-l at pH 7.53, respectively. Possible mechanisms for these reactions are considered.

Only limited work has been carried out on stereoselective effects in the co- ordination of peptides to metal ions. For complexes of copper(n) with Gly-Val, Gly-Phe, and Leu-Leu there is no stereoselectivity when only one of the amino- acids is optically active.160 When both residues contain chiral centres there is no stereoselectivity in the complexes formed prior to ionization of the amide hydrogen, but after ionization occurs, dipeptide complexes containing amino- acid residues of the same chirality (e.g. [Cu(~-Leu-~-Leu]) are more thermo- dynamically stable than those of mixed chirality (e.g. [Cu(~-Leu-~-Leu]).

Probably the most significant development in the area of copper-peptide complexes has been the characterization of a readily accessible copper(n1)- peptide complex by Margerum and his co-workers.lS1 Copper(r1) occurs in a number of compounds, many of which are not stable in aqueous solution. Thus, crystalline NaCuO, can be prepared but it decomposes in solution in a few seconds. Cu"-tetraglycine can be oxidized quantitatively to [CU*~'(H-,G,)]- (12) by IrCli-. If the other species are removed by anion exchange, the resulting

0

CH, I c0,-

(12) 15& R. P. Agarwal and D. D. Perrin, J.C.S. Dalton, 1975, 268. 159 T. P. A. Kruck and B. Sarkar, Inorg. Chern., 1975, 14, 2383. 160 G . Brookes and L. D. Pettit, J.C.S. Dalton, 1975, 2302. 161 D. W. Margerum, K. L. Chellappa, F. P. BOSSU, and G. L. Burce, J. Amer. Chem. SOC., 1975,

97, 6894.

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Metal Complexes of Amino-acids, Peptides, and Proteins 509

solutions of [CU~~'(H_,G,)]- are slow to decompose in weakly acidic media. Visible spectra, e.p.r. measurements, and substitution kinetics (d8-square planar complex) are consistent with the presence of copper(rrr). The Eo value of the complex is 0.892 V at 25 "C and I = O.1M-NaCIO,. The low potential and relatively high stability of the complex are of special interest in biological redox reactions. Molecular oxygen reacts with Cu"-tetraglycine in neutral solution to give [CU~~'(H_,G,)]-, provided photochemical inhibition is avoided.162 This reaction provides a pathway for the activation of molecular oxygen in its oxidation of peptides. In addition, the attractive possibility of two electron transfer reactions between Cul and Cu"' is of interest as a biological redox pathway which would avoid high-energy free radical intermediates. Hamilton has proposed a Cu1I1/CU1 couple in the reactions of the copper enzyme galactose 0 x i d a ~ e . l ~ ~

In view of the importance of thiol groups of cysteine residues in the active sites of metalloproteins, it is surprising that only a few studies have been reported concerning the interaction of the thiol-containing peptides with biologically interesting metal ions. Thiol co-ordination has been suggested by p-mercuri- benzoate binding studies on azurin, plastocyanin, and stellacyanin. There is now evidence that this lack is being rectified. Sugiura and Hirayama 184 have investi- gated the copper(r1) and nickel(rr) complexes of a variety of thiol peptides using potentiometric and visible spectral measurements. The formation constants increase in the order 6-6 < 6-5 < 5-6 < 5-5 for the chelate rings. The nickel(1r) complex of a-mercaptopropionylglycine has also been studied by visible spectra, potentiometric, and 13C n.m.r. techniques.les The co-ordination sites are sulphur, the peptide nitrogen, and the carboxylate group. Unlike the glycylglycine-nickel(11) system, ionization of the peptide proton occurs in the neutral pH region with the formation of a diamagnetic square-planar complex.

Complexes of a-gl u t am ylc ys tein ylgl ycine (glut at hione) with some transition- metal ions have been isolated and characferized.lB6 Glutathione (GluH,) is an extremely versatile ligand complexing as the mononegative GluH; species in Pd(GluH2)C1,3H20, the dinegative GluH2- species in Cu(GluH),4H20 and the trinegative species in Li[Ni(Glu)],2H20 and Li[Co(Glu)],2H20. The mercapto- group ionizes most readily, and subsequent ionizations involve the carboxylate groups.

The iron complexes of several sulphur-containing peptides such as mercapto- propionylglycine, glycylcysteine, and glutathione have similar absorption spectra to those of 2Fe2S ferredoxins and show a dramatic e.p.r. signal change from g = 4.4 to g = 2.0 upon addition of sulphide.la7

Various investigations have been carried out using glycyl peptides. Formation constants obtained using PSEUDOPLOT are reported for zinc(rr) and lead(r1) 162

169

164

166

160

107

G. L. Burce, E. €3. Paniago, and D. W. Margerum, J.C.S. Chem. Comm., 1975,241. G. A. Hamilton, R. D. Libby, and C. R. Hartzell, Biochem. Biophys. Res. Comm., 1973,55, 333. Y. Sugiura and Y. Hirayama, Inorg. Chem., 1976, 15, 679. Y. Sugiura, Y. Hirayama, H. Tanaka, and H. Sakurai, J. Inorg. Nuclear Chem., 1975, 37, 2367. S. T. Chow, C. A. McAuliffe and B. J. Sayle, J. Inorg. Nuclear Chem., 1975,37, 451. Y. Sugiura, M. Kunishima, H. Tanaka, and H. H. Dearman, J. Inorg. Nuclear Chem., 1975, 37, 1511.

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510 Amino-acids, Peptides arid Proteins complexes of gl ycine, glycylglycine, and triglycine.lss Kaneka and Martell have studied the solution equilibria of copper(@ and nickel(r1) polyglycine complexes by magnetic susceptibility, optical spectra, and ~H-titrati0n.l~~ 0.r.d. and c.d. measurements have been used to investigate the copper(r1) complexes of various optically active di- and tri-peptides.170 The aqueous solution equilibria of the copper(n) and nickel(I1) complexes of glycinamide, glycylglycinamide, and glycylglycylglycinamide have been determined by pH-titration at 25 OC.171 Protons are ionized from terminal amide nitrogens in addition to peptide hydrogens. The nickel(@ complex of glycylglycinamide has two amide proton ionizations with pK, values of 8.52 and 9.34. A third ionization, pK, 10.5, is attributed to a co-ordinated water molecule.

The polarographic behaviour of nickel(r1) complexes of di- and tri-glycine has been as have the formation constants of biuret with a variety of bivalent metal ions.173

Wilson's disease is a genetic defect resulting in an excessive accumulation of copper(I1) ions in the liver, kidney, and brain. Several metal-binding reagents have been studied for their effectiveness in removing the excess copper, notably 2,3-dimercaptopropanol (BAL) and D-penicillamine. Laurie and co-workers 17*

have investigated the ternary systems Cu"-Gly-Gly-D-penicillamine and Culr-L-His-D-penicillamine in aqueous solution by electronic spectra and e.s.r. Evidence is presented indicating the formation of dimeric ternary complexes. The possible role of ternary complexes in the mobilization of the excess copper in Wilson's disease is discussed.

Iron@) and cobalt(n) complexes of Boc-(Gly-~-Cys-Gly),-NH, have been synthesized in dimethyl sulphoxide s01ution.l~~ It is suggested that the iron complex is the first rubredoxin model incorporating a polypeptide backbone which has a tetrahedral FeS, core. Adenochrome, the iron(rI1)-containing pigment from the bronchial heart of Octopus vulgaris, has been characterized and shown to consist of a group of closely related peptides derived from novel iron-binding amino-acids, adenochromines A (1 3) and B arise biologically from L-dopa and ~-histidine-5-thiol.

p H p; SR

HZN COzH H,N CO,H

' SR

(13) (14)

glycine and two (14), which may

16* A. M. Corrie, G. K. R. Makar, M. L. D. Touche, and D. R. Williams, J.C.S. Dalton, 1975, 105. lo* A. Kaneda and A. E. Martell, J. Coordination Chem., 1975, 4, 137. 170 A. E. Martell, M. K. Kim, and A. Kaneda, J. Coordination Chem., 1975, 4, 159. 171 T. F. Dorigatti and E. J. Billo, J. Inorg. Nuclear Chem., 1975, 37, 1515. 172 K. Nag and P. Bannerjee, J. Inorg. Nuclear Chem., 1975, 37, 1521. 173 R. M. Sanyal, P. C. Srivastava, and B. K. Banerjee, J. Inorg. Nuclear Chem., 1975, 37, 343. 174 S. H. Laurie, T. Lund, and J. B. Raynor, J.C.S. Dalton, 1975, 1389. 176 J. R. Anglin and A. Davidson, Inorg. Chem., 1975, 14, 234. 176 S. Ito, G. Nardi, and G. Prota, J.C.S. Chem. Comm., 1976, 1042; see also G. Nardi and H.

Steinberg, Comp. Biochem. Physiol., 1974, 48B, 453.

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Metal Complexes of Amino-acids, Peptides, and Proteins 51 1 Sites of copper(1r) binding to molecules such as histidine and peptides have

often been characterized by selective broadening in lH n.m.r. spectra of ligand hydrogens located nearest to copper(1:). TypicalIy the ligand is present in a 100-fold excess over copper(::). Martin and co-workers 177 have suggested that two criteria must be met before this method can be applied, (i) there must be rapid exchange of copper(@ among all sites and (ii) there must be no scalar coupling to contribute to line-broadening. An interesting dinuclear copper(:r) complex of oxidized glutathione has been ~haracterized.~~~ The suggested structure (1 5 ) involves metal-metal interaction via the disulphide bridge, and it

4 --

may be regarded as a model for the non-e.p.r.-detectable copper in the 'blue oxidases'. The reaction of a variety of di- and tri-peptides with Zeise's salt, K[PtC2H4C1JH20, has been studied.17@ Uni-, and bi-, and ter-dentate complexes involving the amino N, peptide N or 0, and the carboxylate O-donor atoms have been characterized and their i.r. spectra studied.

Several interesting crystal structures have been published. In glycylglycinato- (1, lO-phenanthroline)copper(1:)trihydrate,lso glycylglycine acts as a terdentate ligand via amino N-ionized amide and carboxylate O-donors. The fourth tetragonal position about copper(r1) is occupied by one phen N, while the other 177 W. G. Espersen, W. C. Hutton, S. T. Chow, and R. B. Martin, J. Amer. Chem. SOC., 1974,

96, 8111. 178 P. Kroneck, J. Amer. Chem. SOC., 1975, 97, 3839.

L. E. Nance and H. G. Frye, J. Inorg. Nuclear Chem., 1976,38,637. lR0 M. C. Lim, E. Sinn, and R. B. Martin, Znorg. Chem., 1976, 15, 807.

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512 Amino-acids, Peptides and Proteins N-donor occupies a tilted apical position resulting in a distorted square-pyramidal geometry about copper(I1). Visible spectra suggest that the structure found in the solid persists in aqueous solution near pH 9. The crystal structure of aqua- (glycy1)-L-tryptophanatocopper(I1) dihydrate has been established.lS1 The peptide ligand behaves as a terdentate ligand oia the terminal amino-group, deprotonated peptide nitrogen, and the carboxylate group; a single water molecule completes an approximate square (four-co-ordinate copper). The crystal structure lS2 of the orange isomer of [Co(tren)(gly)]Cl,C10, [tren = tris-(2-aminoethyl)amine] establishes that the glycine is co-ordinated with its nitrogen atom trans to the tertiary amino-group of tren, and that the tren chelate rings have two k and one k‘ conformations. This result is important since the hydroxoaquotris-(2-aminoethyl)aminocobalt(111) ion (1 6) promotes the hydrolysis of glycylphenylalanine to give the orange glycinato complex (17), which is also

H,

I

OH c1

(16) (17) (18)

obtained in the Hg”-promoted reaction of [C~(tren)(glyOR)CI]~+ (1 8). It is probable that the red isomer lS3 has the oxygen trans to the tertiary nitrogen of tren. Reactivity.-There seems to have been some decline in the amount of work carried out in this area. The interaction of dioxygen with cobalt(1r) complexes of glycylglycine in solution has been investigated.ls4 It has previously been generally assumed that only the bis-glycylglycine complex interacted with dioxygen, since it has been accepted 1s6s lS6 that only complexes which contain three nitrogens in the co-ordination sphere interact with dioxygen. The ‘3” rule has been questioned as a result of studies on the oxygenation of cobalt complexes of the ethylenediaminediacetic acids.lS7 The oxygenation equilibria of a large variety of cobalt(1r) complexes of amino-acids and dipeptides have been investigated.lsS The stoicheiometries of the oxygenation complexes have been determined and thermodynamic equilibrium constants obtained. The actual oxygenated species is the ‘brown intermediate’ observed by some early investi- gators at high pH. This intermediate eventually loses the bridging peroxo-group to form red, unoxygenated mononuclear cobalt(Ir1) complexes.

The binding of zincb) to L-aspartyl-L-phenylalanine methyl ester has been studied.lS9 Hydrolysis of the ester is promoted by the zinc. N.m.r. (100-MHz) lS1 M. B. Hursthouse, S. A. A. Jayaweera, H. Milburn, and A. Quick, J.C.S. Dalton, 1975, 2569.

Y. Mitsui, J. Watanabe, Y. Iitaka, and E. Kimura, J.C.S. Chem. Comm., 1975, 280. lS3 E. Kimura, S. Young, and J. P. Collman, Znorg. Chem., 1970, 9, 1183. la* G. McLendon and A. E. Martell, Znorg. Chem., 1975, 14, 1423. lg5 M. S. Michailidis and R. €3. Martin, J. Amer. Chem. Sac., 1969, 91, 4683. lY6 S. Fallab, Angew. Chem. Znternat. Edn., 1967, 6, 496. 18’ R. G. Wilkins, in ‘Bioinorganic Chemistry’ (Advances in Chemistry Series No. 100). The

American Chemical Society, Washington, 1971, p. 100. laa W. R. Harris, G. McLendon, and A. E. Martell, J. Amer. Chem. Soc., 1976, 98, 8378. lS9 M. L. D. Touche and D. R. Williams, J.C.S. Dalton, 1976, 2001.

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Metal Complexes of Amino-acids, Peptides, and Proteins 513 measurements were used to identify the binding sites. A detailed investigation of the metal-promoted hydrolysis of glycylglycine has appeared,lsO in conjunction with an i.r. investigation of the structures of the copper(r1) and zinc@) complexes in D,O The results confirm the earlier observationsls2 that in the presence of copper(n) the pH-rate profile has a maximum at pH4.4 (the rate decrease at high pH being associated with ionization of the amide proton), whereas this effect is not observed with zinc(@.

Several kinetic investigations have dealt with metal-peptide complexes. The proton-transfer kinetics of cyano(glycylglycinato)nickelate(~~) and cyano- (glycylglycinamido)nickelate(II) have been studied.lg3 Margerum and co- workerslB4 have established that the rates of proton transfer at the nitrogen atom in metal peptide complexes are several orders of magnitude slower than the reaction rates of typical nitrogen acids with similar pK, values. The Bronsted plots for the metal-peptides undergo a relatively rapid transition from a values of unity to zero without reaching the diffusion-limiting rates. The acid decomposition and proton-assisted nucleophilic displacement by triethylene- tetramine of copper(1r)-glycylglycyl-L-histidine has been studied kineti~al1y.l~~ The presence of histidine as the third amino-acid residue in tripeptide complexes of copper(x1) drastically decreases their susceptibility to nucleophilic attack.

4 Proteins Interest in this area increases from year to year. One point of considerable importance is that jackbean urease (the first enzyme to be crystallized) has been established to be a nickel metalloenzyme.las Until now nickel(rr) metalloenzymes were unknown, with the exception of procarboxypeptidase A. Study of copper- sulphur interactions in relation to copper-containing proteins such as oxidases has been an active field. The results of an X-ray photoelectron spectroscopic study of bean plastocyanin have been interpreted in terms of delocalized Cu'I- cysteine-sulphur binding.lg7

Freeman's lB8 group in Sydney have reported preliminary crystallographic data for plastocyanin from poplar leaves. The metalloprotein was crystallized in the oxidized (i.e. Cu") state. The deep-blue crystals are rhombic prisms with space group P212121 and cell dimensions a = 29.6, b = 46.9, c = 57.6 A. The molecular weight is 10 500 with four molecules of protein in the unit cell. An n.m.r. study (at 270 MHz) of oxidized and reduced French bean plastocyanin has appeared.lss Copper complexes of cyclic or linear poly-thioethers show an l90 T. Nakata, M. Tasumi, and T. Miyazawa, Bull. Chem. SOC. Japan, 1975,48, 1599.

M. Tasumi, S. Takahashi, T. Nakata, and T. Miyazawa, Bull. Chem. Soc. Japan, 1975,48,1595. lU2 1. J. Grant and R. W. Hay, Austral. J. Chem., 1965, 18, 1189. lU3 G. K. Pagenkopf and V. T. Brice, Inorg. Chern., 1975,14,3119. lB4 C. E. Bannister, D. W. Margerum, J. M. T. Raycheba, and L. F. Wong, 'Proton Transfer'

Faraday Society Symposium No. 10, The Chemical Society, London, 1975. L. F. Wong, J. C. Cooper, and D. W. Margerum. J. Amer. Chem. SOC., 1976, 98, 7268.

Ig6 N. E. Dixon, C. Gazzola, R. L. Blakeley, and B. Zerner, J. Amer. Chem. Soc., 1975, 97, 4131. lQ7 P. J. Clendening, H. B. Gray, F. J. Grunthaner, and E. I. SoIomon, J. Amer. Chem. Soc.,

1975,97, 3878. IQ8 G. V. Chapman, P. M. Colman, H. C. Freeman, J. M, GUSS, M. Murata, J. A. M. Ramshaw,

and M. P. Venkatappa, J. Mol. Biol., in press. lQ9 J. K. Beattie, D. J. Fensom, H. C. Freeman, E. Woodcock, H. A. 0. Hill, and A. M. Stokes,

Biochim. Biophys. Acta, 1975, 405, 109.

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514 Amino-acids, Peptides and Proteins absorption band (600nm) similar to that of ‘blue’ proteins, assigned in both complexes and proteins to an S + Cu” charge-transfer band.200 The complex of the macrocyclic thioether ligand (19) has a planar arrangement about copper,

suggesting that distorted site symmetry about copper need not occur in the proteins. A further extrapolation from this work is that thioether sulphurs of methionine groups could be the copper-binding site of ‘blue’ proteins. A kinetic study of the reduction of ‘blue’ proteins by [Fe(edta)12- has been discussed in terms of an outer-sphere mechanism for all such proteins but laccase, which requires a specific protein activation to accept the reductant.201 McLendon and Martell 202 have examined the sequence data for the ‘blue’ proteins plastocyanine and azurin, and suggested a copper binding site of one cysteine, one methionine, and one or two histidine residues.

Sigel 203 has presented a very useful summary of metal binding sites in naturally occurring metal complexes of 3d ions (see Table, p. 5 18). Various investigations of carboxypeptidase A have appeared. Cobalt(m) carboxypeptidase A has been prepared by oxidation of cobalt(1r) carboxypeptidase A with hydrogen peroxide at pH 7.5.204 The new derivative has a band at 503 nm ( E 500) and its catalytic activity was investigated. W l N.m.r. linewidth measurements have been used to probe the active site zinc chemistry of carboxypeptidase A.205 The arsanilazotyrosine-248 zinc complex of carboxypeptidase A has been used to monitor the catalytic events at the active site.206 Cobalt(m) complexes of azo- phenols have been synthesized and their relevance to azotyrosine-modified enzymes, which may form exchange-inert cobalt(m) complexes, has been

Electronic spectra and magnetic susceptibility studies of nickel(r1) and cobalt(I1) carboxypeptidase A have been reported.208 Comparison with known complexes suggests an N20, or NO6 donor set in the nickel derivative. Spectral studies of copper(r1) carboxypeptidase A and related model complexes have also been Oxidase activity is displayed by the copper(I1)

a o o T. E. Jones, D. B. Rorabacher, and L. A. Ochrymowycz, J. Amer. Chem. Soc., 1975, 97, 7485; L. C. Zimmer and L. L. Diaddario, ibid., p. 7163, and references therein.

201 S. Wherland, R. A. Holmerda, R. C. Rosenberg, and H. B. Gray, J. Amer. Chem. Soc., 1975,97, 5260.

202 G. McLendon and A. E. Martell, J. Inorg. Nuclear Chem., 1977, 39, 191. 203 H. Sigel, B. E. Fischer, and B. Prijs, J. Amer. Chem. Soc., in press. 204 E. P. Kang, C. B. Storm, and F. W. Carson, J. Amer. Chem. Soc., 1975, 97, 6723. 206 R. S. Stephens, J. E. Jentoft, and R. G. Bryant, J. Amer. Chem. SOC., 1975, 97, 8041.

L. W. Harrison, D. S. Auld, and B. L. Vallee, Proc. Nat. Acad. Sci. U.S.A., 1975, 72, 3930.

207 W. I. White and J. I. Legg, J. Amer. Chem. Soc., 1975, 97, 3937. 2 0 8 R. C. Rosenberg, C. A. Root, and H. B. Gray, J. Amer. Chem. SOC., 1975, 97,21. *09 R. C. Rosenberg, C. A. Root, P, K. Bernstein, and H. B. Gray, J . Amer. Chern. SOC., 1975,

97, 2092.

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Metal Complexes of Amino-acids, Peptides, and Proteins 515

enzyme.210 Breslow and co-workers 211 have studied the very fast zinc(I1)- promoted hydrolysis of an anhydride which provides a model for the rate and mechanism of carboxypeptidase A catalysis.

Non-haem iron-sulphur proteins are implicated in biological processes as diverse as photosynthesis and nitrogen fixation. They can be classified according to the number of iron atoms present: Fey 2Fe, 4Fe, and 8Fe proteins. X-Ray crystal structures of the 4Fe protein from Chromatiurn and the 8Fe protein from P. aerogenes show them to contain one and two [Fe,S,(S-Cys),] clusters, respec- tively. The complexes [Fe,S4(SR),l2- (R = alkyl or aryl), containing structurally and spectrally analogous clusters, were synthesized some time ago, and work in this area up to the end of 1974 has been reviewed.212 The general area of electron-transfer proteins is the subject of a current review by Moore and William~.~

The synthetic clusters are prepared in high yields from FeCI,, thiol, and NaHS in the presence of base, and an X-ray crystal structure (20) indicates that they are somewhat distorted from cubic symmetry.213 Polarography shows that the [Fe,S,(SR),I2- clusters are members of the electron-transfer series [Fe4S,(SR),In- (n = l---4).213 The structural unit of the Fe-S moiety of the 2Fe proteins has not been established by X-ray diffraction, but the synthetic model (21) has similar spectroscopic properties to the biological Critical assessment of the physicochemical data and further structural work on synthetic analogues 21s suggests (22) as the minimal formulation of the 2Fe proteins.

R

I R

CYS-s, ;s.. s-cys ~ e ‘ ke’

cys-s’ ‘s‘ ‘s-cys

The [Fe,S,(SR),l2- clusters undergo ready thiol exchange reactions, and these reactions have now been studied kinetically.216 This reaction provides the basis for a method for the removal of intact iron-sulphur clusters from the active sites of ferredoxin Any subtle distortions within the clusters caused by a variation of the peripheral ligands should be reflected in the Fe-S stretching 210 K. Yamamura and E. T. Kaiser, J.C.S. Chem. Comm., 1976, 830. 211 R. Breslow, D. E. McClure, R. S. Brown, and J. Eisenach, J. Amer. Chem. SOC., 1975,97,194. 212 R. H. Holm, Endeaoour, 1975, 34, 1. 213 B. V. Pamphilis, B. A. Averill, T. Herskovitz, L. Aue, and R. H. Holm, J. Amer. Chem. SOC.,

1974, 96, 4159. 214 J. J. Mayerle, R. B. Frankel, R. H. Holm, J. A. Ibers, W. D. Phillips, and J. F. Weiker,

Proc. Nat. Acad. Sci. U.S.A., 1973,70,2429. a16 J. J. Mayerle, S. E. Denmark, B. V. De Pamphilis, J. A. Ibers, and R. H. Holm, J. Amer.

Chem. SOC., 1975,97, 1032. 218 G. R. Dukes and R. H. Holm, J. Amer. Chem. SOC., 1975, 97, 528. 217 L. Que, R. H. Holm, and L. E. Mortenson, J . Amer. Chem. SOC., 1975,97,463.

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51 6 Amino-acids, Peptides and Proteins frequencies within the cluster. These vibrations can be enhanced in intensity by use of resonance Raman spectroscopy, and some recent results218 suggest that the overall symmetry of the biological clusters is lower than that of the models. A number of dit hiol-iron-sulphur and -selenium complexes have been prepared and compared with iron-sulphur

Various investigations dealing with carbonic anhydrase have been made, The three-dimensional crystal structure of human erythrocyte carbonic anhydrase B to 2.2A resolution has been announced.220 The essential metal ion, zinc, is firmly bound to the enzyme via three histidyl ligands and is located at the bottom of a 12 A deep conical cavity. Several mechanistic studies of the action of the enzyme have been 222 The preparation of an Fe" bovine carbonic and human carbonic anhydrase has been Mossbauer spectroscopy indicates that Fe" (low spin) is bound at the enzymatically active site. The interaction of cobalt(I1) complexes 224 and metal-directed inhibitors 225 with the enzyme have been investigated.

Many other investigations have been carried out. A discussion of albumin as the major metal transport agent in blood has appeared,22e and the copper(r1)- induced polymerization of human albumin The lH n.m.r. spectra of peroxidases from turnip and horseradish have been studied,228 and the function and mechanism of peroxidases reviewed.229 Gadolinium and calcium binding to bovine serum albumin has been studied by temperature-jump For the reaction of CaOH+ and bovine serum albumin the formation rate constant is 1 x lo8 mol-l dm3 s-l and the dissociation rate 9.3 s-l at 7 "C. The kinetics of oxidation of horse heart ferrocytochrome c by tris-(1,lO-phen- anthroline)cobalt(m) have been investigated.231 Inhibition of leucine amino- peptidase by platinum complexes has been and iron-sulphur bonding in cytochrome c studied by X-ray photoelectron

A polarographic study of the interaction of copper(I1) and cadmium(r1) with poIy(a,L-g1utamic)glutamic acid has appeared 234 and the interaction of Agl with

218 S.-P. W. Tang, T. G. Spiro, C. Antaraitis, T. H. Moss, R. H. Holm, T. Herskovitz, and L. E. Mortenson, Biochem. Biophys. Res. Comm., 1975, 62, 1.

218 Y. Sugiura, K. Ishizu, T. Kimura, and H. Tanaka, Bioinorg. Chem., 1975, 4, 291. K. K. Kannan, B. Notstrand, K. Friborg, S. Lovgren, A. Ohlsson, and M. Peter, Proc. Nut. Acad. Sci. U.S.A., 1975, 72, 51.

221 C. K. Tu and D. N. Silverman, J. Amer. Chem. Soc., 1975,97,5935. 22a D. E. Tallman, G. Graf, T. J. McNeese, and M. M. Wilson, J. Amer. Chem. SOC., 1975, 97,

173. 223 B. J. Zabransky, D. Lawless, D. Basile, V, Ploplis, and C. A. Hoenich, J. Inorg. Nuclear

Chem., 1976,38, 1413. 224 K. Gerber, I?. T. T. Ng, and R. G. Wilkins, Bioinorg. Chem., 1975,4, 153. a2s D. W. Appleton and B. Sarkar, Bioinorg. Chem., 1975, 4, 309.

F. Friedberg, F.E.B.S. Letters, 1975, 59, 140. 227 R. Osterberg, B. Branegard, and R. Ligaarden, Bioinorg. Chem., 1975, 5, 149. 228 R. J. P. Williams, P. E. Wright, G. Mazza, and J. R. Ricard, Biochim. Biophys. Acta, 1975,

412, 127. 228 H. B. Dunford and J. S. Stillman, Coordination Chem. Rev., 1976, 19, 187. 230 H. B. Silber and J. Rosen, J. Inorg. Nuclear Chem., 1976, 38, 1415. 231 B. S. Brunschwig and N. Sutin, Inorg. Chem., 1976, 15, 631. 232 P. Melius and C. A. McAuliffe, J. Medicin. Chem., 1975, 18, 1150. 233 Y. A. Isaacson, 2. Majik, M. A. Brisk, M. E. Gellender, and A. D. Baker, J. Amer. Chem.

SOC., 1975, 97, 6603. z34 S. Inoue, J. Sci. Hiroshima Univ. Ser. A., Phys. Chent., 1975,39, 259.

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Metal Complexes of Amino-acids, Peptides, and Proteins 517

polypeptides Oxygen binding to iron porphyrins has been investi- gated 2369 237 and the topic of inorganic oxygen carriers reviewed.l0S 238 The kinetics of reduction of Rhus vernicifera laccase by Fe(CN)t- have been studied,239 and the reversible uncoupling of the copper and cobalt spin systems of cobalt bovine superoxide dismutase at low pH investigated.240 Conversion of the exchange labile cobalt(n) in E. coli alkaline phosphatase into exchange-inert cobalt(n1) has been carried out by Hz02 Oxidation leads to a single absorption band at 530nm and loss of the characteristic e.p.r. signal and of enzymatic activity. A zinc(I1) protein has been isolated from human parotid saliva (mol. wt. 37000) and contains two moles of zinc per mole of Zinc plays an important role in taste perception and patients with hypogeusia (decreased taste acuity) exhibit lower than normal zinc in parotid saliva. A calcium-binding protein has been identified as a calcium-dependent regulator of brain adenylate c ~ c l a s e . ~ * ~ Selenium appears to induce redistribution of calcium binding to tissue proteins and may provide a possible mechanism against cadmium The single polypeptide chain of conalbumin strongly binds two iron(II1) or two copper(n) to give intense absorption in the visible region similar to that of the related protein t r a n ~ f e r r i n , ~ ~ ~ The inter- action between uranyl ion (UO$+) and cocarboxylase (thiamine pyrophosphate) leads to 1 : 1 or 3 : 2 UOi+/TPP complexes which may be related to the uranyl inhibition of TPP-catalysed reactions.246 236 K. Burger, G. Farsang, L. Ladanyi, B. Noszal, M. Pekli, and G. Takasci Nagy, Magyar

Kdm. Folydirat, 1975, 81, 457. za6 C. J. Weschler, D. L. Anderson, and F. Basolo, J. Amer. Chem. SOC., 1975, 97, 6707. 237 J. P. Collman, J. I. Brauman, and K. S. Suslick, J. Amer. Chem. Soc., 1975, 97, 7185. 238 F. Basolo, B. M. Hoffman, and J. A. Ibers, Accounts Chem. Res., 1976, 384. z39 R. A. Holwerda and H. B. Gray, J. Amer. Chem. SOC., 1975,97,6036. z40 L. Calabrese, D. Cocco, L, Morpurgo, B. Mondovi, and G. Rotilio, F.E.B.S. Letters, 1975,

59, 29. R. A. Anderson and B. L. Vallee, Proc. Nat. Acad. Sci. US.A., 1975, 72, 394.

242 R. I. Henkin, R. E. Lippoldt, J. Bilstad, and H. Edelhoch, Proc. Nat. Acad. Sci. U.S.A., 1975, 72, 488.

z43 C. 0. Brostrom, Y.-C. Huang, B. M. Breckenridge, and D. J. Wolff, Proc. Nat. Acad. Sci. U.S.A., 1975,72, 64.

244 R. W. Chen, P. D. Whanger, and P. S. Weswig, Bioinorg. Chem., 1975,4, 125. 246 R. Prados, R. K. Boggess, R. B. Martin, and R. C. Woodworth, Bioinorg. Chem., 1975, 4,

135. 2 r s A. Marzotto, J. Inorg. Nuclear Chem., 1975, 37, 1329.

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Tab

le

Com

pila

tion

of b

indi

ng s

ites

in n

atur

ally

occ

urrin

g m

etal

-ion

com

plex

es of 3

d-io

ns a

A m

ino-

acid

Mn+

1 2

3 4

5 6

Con

cana

valin

A

Mn2

+ O

(G1u

) O

(Asp

) O

(Asp

) N

(Im

) H

20

H2

0

Enz

ymel

pro t

ein

Bind

ing

site

s

N(I

m)

N(I

m)?

Pyru

vate

kin

ase

Mn2

+ (M

g2+

?) N

(Im

) 0 (p

hosp

hate

/sub

stra

te)

Hem

eryt

hrin

Fe

2+]F

e2+

four

N Im

) and

two

0 (T

yr) a

re b

ound

to

two

Fe

Tran

sfer

rin

Fe3+

O

(Tyr

) 0 (T

yr)

O(T

yr)

N(1

m)

N(I

m)

HC

O;

(con

albu

min

is

clos

ely

rela

ted)

63

Ure

ase

(jack

bea

n)

Ni2

+ S(

CYS)

C

erul

opla

smin

CU

"/CU

2+

N (Im) m

oiet

ies a

nd th

iol g

roup

s H

aem

ocya

nin f

cu

2+

Cur

l-O~-

-Cul

*,

and

Cu-

N

(Im) -

bond

s Pl

asto

cyan

in (b

ean)

C

u2+

N (I

m)

S (C

ys)

N (I

m)

N (d

epro

t. am

ide)

L-

His

tidin

ate a

nd

cu2+

N

(Im

) N

H,

(His

) 0 (T

hr)

NH

, (Thr) 0

(His

) HgO

L-th

reon

inat

e

Alb

umin

(hum

an)

Cu2

+

Gal

acto

se o

xida

se

Cu2

+

Supe

roxi

de d

ism

utas

e J

Cu2

+ Z

n2+

Insu

lin

Zn2

+ Th

erm

olys

in

Zn2

+ A

lkal

ine

phos

phat

ase

Zn2+

(E

, col

i)

-

NH

, N

(am

ide,

w

(am

ide,

N

(Im

)

N,0

2 sq

uare

-pla

nar s

yste

m w

ith a

pro

tein

sul

phur

in o

ne a

xial

(A

SP)

Ma)

H

is)

site

/N (I

m) s

eem

s to

be in

volv

ed

N(I

@

NO

m)

N(I

d

N(I

m)

NO

m)

N(I

m)

O(A

SP)

N(I

m)

N(I

m)

N(I

m)

H2O

H

20

H2O

N

(Im

) N

(Im

) O

(G1u

) H

20

thre

e N

(Im

) app

ear

to b

e in

volv

ed a

nd

0 (p

hosp

hate

lsub

stra

te)

Met

hods

/ Com

men

ts

Ref

. X

-ray

247

titra

t./ch

em. m

odif.

/ 24

8, 2

49

n.m

.r./c

hem

. mod

if.

250,

251

X

-ray

(5.5

A

252

chem

. mod

if.

253

chem

. stu

dies

(Tyr

24

9, 2

54,

role

mor

e 25

5 em

phas

ized

, His

in

volv

emen

t mor

e un

certa

in)

dial

ys.

reso

lutio

n)

chem

. mod

if.

256

chem

. mod

if./ti

trat.

249,

257

sp

ectro

scop

ic ex

per.

258

spec

trosc

opic

expe

r. 25

9

rath

er s

tabl

e in

24

9, 2

61,

aq. s

ol.

262

$ ch

em. s

tudi

es

249,

262

, R

263

& sp

ectra

l stu

dies

, 26

4 ';a s

X-ra

y 26

0 b

chem

. mod

if.

X-ra

y 26

5 s

X-ra

y 26

6 2

31P

n.m

.r.

s 5

267,

268

X

-ray

phot

o-ox

idat

ion

269

e.p.

r. of

Cu2

+ enz

yme

268,

270

*cr

-

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‘07

J. W

einz

ierl

and

A. J

. Kal

b, F

.E.B

.S. L

ette

rs, 1

971,

18,

268;

K. D

. Har

dman

and

C. F

. Ain

swor

th, B

ioch

emis

try

1972

,11,

49

10; N

atw

e, N

ew B

iol.,

197

2,23

7,54

; G

. M. E

delm

an, B

. A. C

unni

ngha

m, G

. N. R

eeke

, jun.

, J. W.

Bec

ker,

M. J

. Wax

dal,

and

J. L.

Wan

g, P

roc.

Nat

. Aca

d. S

ci.

U.S

.A.,

1972

, 69,

258

0.

248

G. G

ache

lin, L

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dste

in, D

. Hof

nung

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A. J

. Kal

b, E

urop

eanJ

. Bio

chem

., 19

72,3

0,15

5; M

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ham

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b, a

nd

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cht,

Bio

chem

istr

y, 1

973,

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191

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248

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dber

g an

d R

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Mar

tin, C

hem

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4,47

1.

2so

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l. C

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40,2

38;

ibid

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41,1

178;

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van,

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nd M. C

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261

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S. M

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d C.

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truc

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1.

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dric

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pens

tein

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d, P

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1975

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216

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2s8

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ioph

ys. A

cta,

197

6, 4

20,

265;

G.

McL

endo

n, W

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arri

s, a

nd A

. E.

Mar

tell,

C

ente

nnia

l A.C

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Mee

ting,

New

Yor

k, I

NO

R 4

4 (1

976)

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den,

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6,1,

149

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utku

s, J

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nd R

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ney,

Bio

chem

istr

y, 1

965,

4,

998;

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n, R

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asa,

B.

G.

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mst

rom

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T.

Van

ngar

d, J.

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242,

248

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d P. A

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1968

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9; P

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nd A

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bid.

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9,24

4,46

28;

A. T

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nd R

C. W

oodw

orth

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chem

istr

y, 1

969,

8, 3

711.

2s

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ixon

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la, R

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y, a

nd B

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91, 1

144;

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mer

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1963

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d, E

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179

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D. G

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and

E.

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den,

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iol.

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34,

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n J. B

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1972

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ts of

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ompl

ex F

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n in

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oduc

tion

to B

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soni

us, K

. Tita

ni, K

. A. W

alsh

, and

H. N

eura

th, N

atur

e New

Bio

l., 1

972,

238,

41;

B. W

. M

atth

ews

and

L. H

. W

eave

r, B

ioch

emis

try,

197

4, 1

3, 1

719.

J.

F. C

hleb

owsk

i and

J. E

, Col

eman

, in

‘Met

al Io

ns in

Bio

logi

cal S

yste

ms’

, Vol

. 6, e

d. H

. Sig

el, M

arce

l Dek

ker,

New

Yor

k 19

76, p

. 1.

G

. H

. Tai

t and

B.

L. V

alle

e, P

roc.

Nat

. Aca

d. S

ci. U

.S.A

., 19

66, 5

6, 1

247.

2

70

J.

S. T

aylo

r and

J. E

. C

olem

an, P

roc.

Nut

. Aca

d. S

ci. U.S.A.,

1972

, 69,

859

.

Syst

ems;

ed. H

. Si

gel,

Mar

cel D

ekke

r, N

ew Y

ork,

197

3.

Dow

nloa

ded

by S

tanf

ord

Uni

vers

ity o

n 27

Sep

tem

ber

2012

Publ

ishe

d on

31

Oct

ober

200

7 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/9

7818

4755

7339

-004

94

View Online

Tab

le

(con

t.)

Enz

ymel

prot

ein

Bind

ing

site

s A

min

o-ac

id

M”+

1

2 3

4 5

6 M

etho

ds1 C

omm

ents

R

ef:

Car

boni

c an

hydr

ase

Zn2+

N

CIm

) N

m-0

N

Clm

) H

a0

X-r

ay

268,

27

1 C

arbo

xype

ptid

ase A

Z

n2+

N(1

m)

O(G

1u)

N(X

m)

H20

X

-ray

26

8,27

2 0 (c

arbo

nyl/s

ubst

rate

) X

-ray

26

8, 2

72

0 (p

heno

late

of T

yr) c

o-or

d. to

Zn2

+ in

solu

tion

chem

., sp

ect.,

kin

et.

273

Alc

ohol

deh

ydro

- Zn

2+

S(C

ys)

S(C

ys)

N(I

m)

H2

01

X

-ray

27

4 da

ta

gena

se

Zn2+

s (

CY

d s (

CYS)

s (

CYS)

s K

YS)

“Im

= im

idaz

ole m

oiet

y of

a h

istid

yl re

sidu

e; th

e ab

brev

iatio

ns o

f the

am

ino-

acid

resi

dues

are t

hose

gen

eral

ly us

ed.

Ca2

+ is

also

pre

sent

, co-

ordi

nale

d to

0 d

onor

s.

6 O

xyge

n-ca

rryi

ng n

on-h

aem

pr0

tein

.2~~

H

alf

of t

he c

oppe

r at

oms

are

copp

er(n

) an

d th

e ot

her

half

copp

er(I

).ean

f O

xyge

n-ca

rryi

ng ‘

Cu”

‘H

n.m

.r.

stud

ies

of p

last

ocya

nins

fro

m s

pina

ch a

nd a

bl

ue-g

reen

alga

‘sug

gests

that

the

imid

azol

e gro

ups o

f tw

o hi

stid

ine r

esid

ues a

re li

gand

ed d

irect

ly to

the

copp

er. . .

. The

sing

le co

pper

of p

last

ocya

nin

may

ex

ist i

n ei

ther

the

oxid

ized

Cu” o

r re

duce

d C

u fo

rm’.

The

dis

tanc

e of t

he

0 (c

arbo

nyl)

atom

of L

-hist

idin

e fr

om C

ue+ i

s 2.

58 A

, com

pare

d w

ith o

nly

1.97

A fo

r th

e 0 (c

arbo

nyl)

atom

of

L-th

reon

ine;

mor

eove

r, th

e 0

(car

bony

l) at

om o

f his

tidin

e is i

n an

irre

gula

r axi

al po

sitio

n [a

ngle

N (

amin

o)-C

u-0

(car

boxy

l) =

68.3

’1. Thus, i

t see

ms t

hat t

his l

atte

r bon

d is

not

ver

y st

rong

, and

in

aqu

eous

sol

utio

n th

e ax

ial p

ositi

on (a

t lea

st in

equ

ilibr

ium

) may

wel

l be

occu

pied

by

wat

er.

3 T

he a

ctiv

e site

con

tain

s an

imid

azol

ate-

brid

ged C

u”-

Zna

+ moi

ety;

one

of

the

axia

l di

rect

ions

of t

he C

u is

ope

n to

sol

vent

acc

ess.

eo8

Hum

an c

arbo

nic

anhy

dras

e B

and

C a

re tw

o is

oenz

ymes

whi

ch d

iffer

in

the

posi

tion

of th

e th

ird h

istid

ine r

esid

ue.*

ss

Ther

e is

evi

denc

e th

at t

his

(i.e

. the

firs

t) Z

n2+ w

ith it

s co

-ord

inat

ion

sphe

re is

at t

he a

ctiv

e si

te a

nd th

at b

HaO

is re

plac

ed b

y an

0 of

alc

ohol

/ald

ehyd

e in

the

activ

e enz

yme.

268 T

he fu

nctio

n of

the

sec

ond

Zn2

+ is n

ot c

lear

, it a

ppea

rs th

ere

is n

o di

rect

func

tiona

l

Con

albu

min

is

clos

ely

rela

ted

in i

ts b

indi

ng s

ites w

ith t

rans

ferr

i~~

.~*~

Pres

ent i

n hu

man

ser

um a

nd in

equ

ilibr

ium

with

alb

umin

bou

nd C

u2+.

zs3

role

in c

atal

ysis

, or

in m

aint

aini

ng th

e se

cond

ary

or q

uate

rnar

y st

ruct

ure.

e68

g g %

The

auth

ors

than

k D

r. H

. Si

gel f

or th

e pr

epub

licat

ion

info

rmat

ion

used

in th

e Ta

ble.

Q

27

1 A

. Li

ljas,

K. K

. Kan

nan,

P.-C

. B

ergs

ten,

I. W

arra

, K

. Fr

idbo

rg, B

. St

rand

berg

, U.

Car

lbor

n, L

. Jm

p, S.

Lovg

ren,

and

Exp

. Med

. Bio

l., 1

972,

28,

169;

B.

And

erss

on, P

. 0. N

yman

, and

L.

Strid

, Bio

chem

. Bio

phys

. Res

. Com

m.,

1972

,48,

670

; L.

E.

Hen

ders

on, D

. H

enrik

sson

, and

P. 0.

Nym

an, i

bid.

, 19

73, 5

2, 1

388;

K. K

. K

anna

n, B

. N

ords

trand

, K

. Fr

idbo

rg,

S. Lo

vgre

n, A

. O

hlso

n, a

nd M

. Pet

er, P

roc.

Nat

. Aca

d. S

ci. U

.S.A

., 19

75, 7

2, 5

1.

27

2 F.

A.

Qui

ocho

and

W.

N.

Lips

com

b, A

d. P

rote

in C

hem

., 19

71,

25,

1 ; W

. N

. Li

psco

mb,

Acc

ount

s C

hem

. Res

., 19

78, 3

,

M.

Pete

f, N

atur

e N

ew B

iol.,

197

2, 2

35,

131;

I.

War

ra,

S. L

ovgr

en, A

. Li

ljas,

K.

K.

Kan

nan,

and

P.-C

. B

ergs

ten,

Ado

. *a

e $

2 ca a s E’

81;

Che

m. S

OC

. Rev

., 19

72,1

, 31

9.

B. L

. V

alle

e, P

ure

App

l. C

hem

., 19

75, 4

4, 1

. 27

4 (2

.4.

BrSi

nden

, H. E

klun

d, B

. Nor

dstro

m, T

. Boi

we,

G. S

oder

lund

, E. Z

eppe

zaue

r, I.

Ohl

sson

, and

A. A

keso

n, P

roc.

Nat

. A

cad.

Sci

. U.S

.A.,

1973

,70,

2439

; H

. Ekl

und,

B. N

ords

trom

, E. Z

eppe

zaue

r, G

. Sod

erlu

nd, I

. Ohl

sson

, T. B

oiw

e, a

nd C

. -I.

Bra

nden

, F.E

.B.S

.Let

ters

, 19

74, 4

4,20

0.

Dow

nloa

ded

by S

tanf

ord

Uni

vers

ity o

n 27

Sep

tem

ber

2012

Publ

ishe

d on

31

Oct

ober

200

7 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/9

7818

4755

7339

-004

94

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