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Amino Acids, Peptides & Proteins. a -amino acid:. Amino Acids. Are >500 naturally occurring amino acids identified in living organisms Humans synthesize 10 of the 20 they use. The other 10 are called essential amino acids. Amino Acids, Peptides & Proteins. Peptides & proteins: - PowerPoint PPT Presentation
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Amino Acids, Peptides & Proteins
-amino acid: H2N
O
OH
HR
carboxylic acid; acidic endamine; basic end
side chain
H3N
O
O
HR
zwitterionic form (internal acid/base reaction):overall neutralsaltH2O solublepH = 7.3 (within cell; isoelectric point depends on R)
(S) absolute stereochemistry
Amino Acids
• Are >500 naturally occurring amino acids identified in living organisms
• Humans synthesize 10 of the 20 they use. The other 10 are called essential amino acids.
H2N
O
OH
HH
H2N
O
OH
H
H2N
O
OH
HH2NH2CH2CH2CH2CH2N
O
OH
H
H2N
O
OH
H
O
OH
H
Glycine (achiral) Valine (hydrophobic, bulky)
Lysine (basic, nucleophilic, oftenused in catalysis)
CO2H
Aspartic acid (acidic, used incatalysis)
SH
Cysteine (nucleophilic, used incatalysis, controls shape of protein)
NH
Proline
Amino Acids, Peptides & Proteins
Peptides & proteins:
• Derived from amino acids through peptide or amide bonds.
• The amine and acid ends of amino acids couple to form amide (peptide) bonds in peptides/proteins/enzymes.
• Proteins fold into well-defined structures. The hydrophobic residues segregate to the water-free interior, while the polar/charged residues favor the exterior.
Peptides: Coupling AAs Together
• Peptides & Proteins: Linear oligomers of the 20 amino acids
• Peptides ≤ 20 amino acids; Proteins > 20 amino acids
Functions:1. Catalysis - enzymes2. Membrane channels3. Structural support (boundaries)4. Regulate metabolites (storage & transport)5. Antibodies; cellular signaling (recognition & binding)
Aspartame
Discovery story:• In 1965 by Jim Schlatterworking on discovering newtreatments for gastriculcers.• Made a dipeptide intermediate, which he spilled on his hand• Tested the dipeptide in coffee
H
HN
OO
CH3
O
H3NH
O O
Methyl ester
Phenylalanine
Aspartic acid
Aspartame• 4 calories per gram• 180 times sweeter than sugar
Aspartame: A Dipeptide
H
HN
OO
CH3
O
H3NH
O O
Methyl ester
Phenylalanine
Aspartic acid
Two main constituents:
PhenylalanineAspartic acid
Goal:1. Make the methylester of phenylalanine2. Make a peptide
(amide)bond between
phenylalanineand aspartic acid
Overall - two main steps to this synthesis
Dipeptides: Coupling of 2 AAs
H2N
O
NH
O
OH
CH3
valine alanine
C-terminusN-terminus
Consider the synthesis of the dipeptide val-ala (valine-alanine):
• Coupling of amino acids is an application of nucleophilic acyl substitution
• Issue of selectivity arises:val + ala val-ala + ala-val +
val-val + ala-ala
A mixture of 4 possible amideproducts
Merrifield’s Solid-Phase Synthesis
In order to get the desired peptide (val-ala), the appropriate NH2 and CO2units must be joined.
alanine's N-terminus
H2N
O
valine's C-terminus
OH H2N
O
OH
CH3
The selectivity is accomplished through the use of protecting groups.
Merrifield’s approach:1. Protect N-terminus of valine2. Protect C-terminus of alanine3. Couple valine and alanine4. Deprotect to get dipeptide
Merrifield’s Solid-Phase Synthesis1. Protection of valine’s N-terminus:
H2N
O
OH
O O
Cl
(FMOC-Cl)
HN
O
OH
O
O
Fmoc group
Merrifield’s Solid-Phase Synthesis2. Protection of alanine’s C-terminus:
Attach the C-terminus to a plastic bead (solid-phase synthesis!)
H2N
O
O
CH3
H2N
O
OH
CH3
Benefits of solid-phase:• Ease of attachment• Ease of removal; just filter away from product solution
Merrifield’s Solid-Phase Synthesis3. Couple valine and alanine:
H2N
O
O
CH3HN
O
OH
O
O
Fmoc group+
Coupling agentsuch as DCC(dicyclohexylcarbodiimide)
HN
O
O
ONH
O
O
CH3
N C N
DCC(Used to derivatize the CO2H to make it more reactive)
Merrifield’s Solid-Phase Synthesis3. Deprotection of Fmoc & bead:
HN
O
O
ONH
O
O
CH3
H2N
O
NH
O
OH
CH3
valine alanine
1. Piperidine (to remove Fmoc)
2. CF3CO2H (TFA, to remove bead)
Proteins• Amino acid polymers; when long enough, they fold back on themselves tocreate intricate, well-defined 3D structures• The structure of a protein specifies its function.• The AA sequence specifies its structure.• The AA chain typically adopts regional sub-structures which sum togetherto deliver the overall structure of the protein.
Forces/Factors that dictate protein folding:1. Planarity of amide bonds2. H-bonding3. Hydrophobic interactions4. Electrostatic Attraction5. Disulfide linkages
Proteins1. Planarity of amide bonds:
HN
O
NH
R O
R
O
HN
O
N
R O
R
O H
Barrier of rotation~20 kcal/mol
Proteins2. H-bonding:
HN
O
N
R O
R
O
N
O
NH
R O
R
O
H
H
H-bond worth ~ 5 kcal/mol
H-bonds orient the chain
Proteins3. Hydrophobic Interactions:
HN
O
N
O
HN
H
PhO
Fold
NH
O
NHO
NH
O
Hydrophobicpocket
Lots of hydrophobic interactions between Rs and H2O -unstable
Protein folds to “clump” Rgroups together in the interior of protein to avoidH2O - very energeticallyfavored
Proteins4. Electrostatic Attraction:
NH3 O
O
Proteins5. Disulfide Linkages:
HS
SH
S S
Mild oxidant
• Covalent S-S• Drastically alters shape• Worth ~ 50 kcal/mol
ProteinsOverall, these 5 structural/energetic features leads to the final 3D proteinstructure. However, predicting the structure from the amino acid sequenceis still a challenge.
Hierarchy of Structural Elements of Proteins
1. Primary structure: AA sequence
2. Secondary structure: discrete sub-structural elements (modules) -helix & -sheet
-helix: see board for depiction
Note:1. Internal H-bonding2. The way the side chains line up3. 3.6 AAs per turn
-sheet: see board for depiction
Note:1. Chain-to-chain H-bonding2. Alternating (up-down, up-down)Pattern of R groups
Proteins
Hierarchy of Structural Elements of Proteins
3. Teritary Structure: the individual secondary structural elements organizedin 3D.
See board for depiction.
4. Quaternary Structure: non-covalent complexation of different proteins.
Lipids• Structurally diverse, derived from living organisms• Functional theme is hydrophobicity - water avoiding due to long alkyl chains• Often found at the interface of aqueous compartments
3 Major Classes of Lipids:1. Fats and oils2. Phospholipids3. Cholesterol & derivatives (steroids)
Lipids1. Fats & Oils
Derived from glycerol and fatty acids:CH2OH
CH2OHH OH
Glycerol: a triol (3 nuc sites)
OH
O+
Palmitic acid (C16 fatty acid)
couple
O
O
O
O
O
O
Triacyl glyceride
Weak intra-molecular attractive forcesbetween chains
Lipids1. Fats & Oils
• In order for a fat to melt, these weak dispersive forces must be broken.• More contacts, the better the packing and the higher the m.p. of the fat• Less contacts, worse packing of chains, the lower the m.p.
Unsaturated Fats:O
O
O
O
O
O
No contacts heredue to Z-alkene
Oils are polyunsaturated - lots of alkenes & have low mp due to less packing
Butter has very little unsaturated & hashigher mp
LipidsSoaps & Detergents
• Hydrolyzed fats• A long chain carboxylate molecule:
O-Na+
O
Non-polar, hydrophobic endPolar, hydrophilic end
LipidsSoaps & Detergents
in H2O:
O-Na+O
+Na-OO
O-Na+O
O-Na+O
O-Na+OO-Na+
O
+Na-OO
+Na-OO
O-Na+
O
+Na-OO
+Na-OO
+Na-O O +Na-OO
O-Na+O
O-Na+O
+Na-OO
Hydrophobic Interior
Hydrophilic Exterior
H2O
H2O
H2O
H2O
Grease & dirt gettrapped in the interior.
Micelle is H2O solubleso can wash out dirt.
In H2O, formsa micelle.
Lipids2. Phospholipids:• Have hydrophobic and hydrophilic regions• Forms membranes• Precursors to prostaglandins
O
O
O
O
O P O
O
O
N
Phosphatidyl cholineHighly chargedH2O soluble
H2O insoluble
Lipids2. Phospholipids:• Forms membranes: self-organize at certain concentrations to form bilayers• Membranes are largely impermeable to charged species that exist in
biological environments.
OO
OO
OPO
OO
N
OO
OO
OPO
OO
N
OO
OO
OPO
OO
N
OO
OO
OPO
OO
N
OO
OO
OPO
O O
N
OO
OO
OPO
O O
N
OO
OO
OPO
O O
N
OO
OO
OPO
O O
N
Hydrophobic interior
H2O outside of cell
H2O inside of cell
Cell membrane
Lipids3. Cholesterol & Steroids
Cholesterol:
27 carbons4 rings8 stereocentersDerived from terpenes
Cholesterol is a precursor to several steroidal hormones:Testosterone (male hormone)Estrone (female hormone)
HO
H
H
H
polar non-polar
LipidsCholesterol is a precursor to several steroidal hormones:
Testosterone (male hormone)Estrone (female hormone)
O
H
H
OH
H
Testosterone
HO
H
H
O
H
Estrone
These hormones operate at the genetic level (turn genes on and off) to control biochemistry. They are recognized by specific protein receptors.
Antioxidants & ChocolateAntioxidants:• Protect against cardiovascular disease, cancer and cataracts• Thought to slow the effects of aging
Chocolate:• High levels of antioxidants - complex mixtures of phenolic comounds• By weight, has higher concentration of antioxidants than red wine or Green tea• 20x higher concentration of antioxidants than tomatoes
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Dark chocolate has more than 2x the level of antioxidants as milk chocolate.
Side note: The main fatty acid in chocolate, stearic acid, does not appear to raise blood cholesterol levels the way other saturated fatty acids do.
