What are they?
• Porphyrin rings are biological molecules used in a variety of essential chemical processes
•The two most well-known porphyrins are heme and chlorophyll
Because of their large conjugated double bond system, porphyrins typically absorb visible light
Chlorophyll’s green color, heme’s red, and the blue blood of some sea creatures are all a result of this absorbance
Additionally, the 4 nitrogen atoms at the center of the ring are excellent at conjugating metals because of their lone pairs
As a result, porphyrins are a common way to attach metals to proteins
Heme
• Porphyrin synthesis is still poorly understood• Intermediates are known, but reaction
mechanisms are generally still speculative• Plants and animals follow different synthetic
pathways in the early stages of ring formation• Once delta-aminolevulinate is synthesized, the
synthetic pathways are identical• Delta-aminolevulinate is used only for porphyrin
synthesis, so its synthesis is tightly regulated—at least 6 enzymes or products are controlled
Beginning steps in plants
O
NH3
O
O
O
O
NH3
t RNA-Glu
O
O
ATP->AMP
NADPH
O
O
NH3
OH
O
O
O
NH3
Glutamate glutamyl-tRNA
glutamate 1-semialdehydedelta-aminolevulinate
O
NH3
GluANRt
O
O
NADPHO
O
NH3
OH
glutamyl-tRNA glutamate 1-semialdehyde
This reaction uses Glu tRNA as a leaving group, which is very unusual
Guu tRNA acts like a phosphate group, facilitating transformation of a carboxylic acid to an aldehyde
Because of the size of the tRNA molecule, the enzyme must be highly flexible
Structure of glutamate-1-semialdehyde 2,1-
aminomutase To limit access to the highly reactive PLP active site, the enzyme uses a “gating loop,” an alpha-helix that changes into a beta-sheet to expose the active site of the enzyme
This prevents a variety of side reactions from happening
What about people?
• For animals and some eukaryotes, synthesis of delta-aminolevulinate follows a different path
O
O
O
S-CoA
Succinyl-CoA
+O
NH3
O
Glycine
O
O
O
NH3
O
O
O
O
O
NH3
delta-aminolevulinate
What’s Next?The next step is the synthesis of Porphobilinogen
from 2 molecules of delta-aminolevulinate
O
O
O
NH3
delta-aminolevulinate
N
NH3
O
O
O
O
H
O
O
O
NH3
• Another cool thing about this enzyme is that it contains zinc, but the zinc does not react in any way
• Experiments determined that zinc is used to control reactivity and make the catalytic site more selective
N
NH3
O
O
O
O
H
4 NH HN
NHHN
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
This reaction mechanism is fairly complicated, but isotope experiments have confirmed which atoms come from which precursor molecules
The results of these studies are shown in blue and red
Steps after ring formation
Essentially all that is needed after these steps is insertion of the metal at the center of the ring
Additional covalent modification of the outside of the ring is often performed
Examples of this modification include siroheme and chlorophyll
Heme Iron Insertion
• Metal insertion in porphyrins is performed by a class of complexes called chelatases
Ferrochelatase
Ferrochelatase activity
To force iron (II) into the heme ring, ferrochelatase holds the ring in a bent conformation
This bending causes the ring to pop out of the enzyme once iron insertion is complete
What do you do with it once you’re done with it?
• Recycling the iron in heme is critical for survival
• To make sure iron is not unnecessarily wasted, a complex system for recycling the iron in heme is employed
• The ring itself is solubilized and eliminated—only the metal is reused
So what happens if you have a problem making or breaking down porphyrins?
A variety of medical conditions can occurBabies often suffer from jaundice, which is caused by an
accumulation of heme breakdown products in fatJaundice is typically harmless, and typically is cured with
exposure to lightThe condition fades once proper liver function develops in
the infantThere are some serious conditions that result from
accumulation of porphyrinsThe most severe of these is porphyria, which is caused by
a problem in one of the first 8 steps of synthesis
Porphyria• Porphyria is assumed to be the root of our myths about vampires
and werewolves• In all cases, the urine changes colors, typically to red, but
occasionally to pink or purple, and the teeth become reddish-brown, and the lack of heme means that sufferers are anemic
• In erythroid porphyrias, the skin becomes extremely sensitive to light, and will blister or scar if exposed, and hair will grow in unusual places
• Ulcers may also cause their hands to become deformed and paw-like and mutilate the nose, ears, eyelids, and fingers
• In hepatic porphyrias, damage to the central nervous system results, often leading to seizures or insanity
• Because of the wide variety of symptoms, porphyria has been associated with insane rulers like King George III