Porphyrin Ring Synthesis and
Breakdown
Daniel Wellman
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
Heme
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
• 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
Glutamate
glutamyl-tRNA
O
ATP->AMP
O
NH3
NH3
O
O
O
NADPH
O
t RNA-Glu
O
glutamate 1-semialdehyde
delta-aminolevulinate
O
O
NH3
O
O
H
O
NH3
O
glutamyl-tRNA
glutamate 1-semialdehyde
O
O
NH 3
O
GluANRt
O
NADPH
NH3
O
H
O
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
The only well-understood mechanism is the
last step
Structure of glutamate-1-semialdehyde 2,1aminomutase
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?
Glycine
Succinyl-CoA
O
O
+
S-CoA
NH3
O
O
O
O
delta-aminolevulinate
O
O
O
O
NH3
O
O
NH3
O
• For animals and some eukaryotes, synthesis of
delta-aminolevulinate follows a different path
What’s Next?
The next step is the synthesis of Porphobilinogen
from 2 molecules of delta-aminolevulinate
delta-aminolevulinate
O
O
O
NH3
O
O
O
O
O
O
N
NH3
O
NH3
H
Proposed mechanism for Porphobilinogen synthesis
• 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
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
O
O
O
O
O
O
O
O
O
O
O
O
4
HN
NH
HO
HN
NH
N
NH3
H
O
O
O
O
O
O
O
O
Ring closure
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
O
HN
NH
HN
NH
H
HN
NH
O
HN
NH
O
O
O
O
O
O
O
O
O
O
O
O
O
Mechanism for ring
closure
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
Heme Breakdown
Followed By…
• Reaction with 2 molecules of sugar to
yield:
Bilirubin diglucuronide
So what happens if you have a problem making or breaking
down porphyrins?
A variety of medical conditions can occur
Babies often suffer from jaundice, which is caused by an
accumulation of heme breakdown products in fat
Jaundice is typically harmless, and typically is cured with
exposure to light
The condition fades once proper liver function develops in
the infant
There are some serious conditions that result from
accumulation of porphyrins
The 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 pawlike 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