Porphyrins and bile pigment
Porphyrins (Structure of Porphyrins)
• Objective:
• In addition to serving as building blocks for proteins, amino acids are
precursor of many nitrogen-containing compounds that have important
physiologic functions, these molecules include porphyrin.
• Porphyrins are cyclic compounds that readily bind metal ions, usually
Fe2+, Fe3+.
• The most prevalent metallopophyrin in human is heme, which consists of
one Fe2+ coordinated in the center of tetrapyrrol ring protoporphyrin lX
through methenyl bridges.
• Heme is the prothetic group for hemoglopin, myoglopin, the
cytochromes, catalase and tryptophane pyrrolase
Structure of Porphyrins
• (1) Side chains :Ex., uroporphyrin contains acetate (-ch2-coo-), and
propionate (-ch2-ch2-coo-). while coproporphyrin is substituted with methyle
(-ch3) and propionate group.
• Distribution of side chains: The side chains of porphyrins can be ordered
around the tetrapyrrol nucleus in four different ways designated by Roman
numerals I & IV.
• Only type III Porphyrins which contains asymmetric substitution on ring D are
physiologically important in humans.
Biosynthesis of heme
• Liver is the major site of heme biosynthesis.
• Liver synthesizes a number of heme proteins, cytochrome P 450,
and the erythrocyte-producing cells of the bone marrow which are
active in hemoglobin synthesis.
• In the liver: The rate of heme synthesis is highly variable, responding
to alterations in the cellular heme pool caused by fluctuating
demands for heme proteins.
• In contrast, heme synthesis in erythroid cells is relatively constant ,
and is matched to globin synthesis
• The initial reaction and the last three steps occur in the
mitochondria, whereas the intermediate steps occur in the cytosol.
Biosynthesis of heme
(1) Formation of δ-aminolevulinic acid (ALA).
• All the carbon of the porphyrin molecule are
provided by by two simple blocks: (glycine and
succinyl CoA ).
• glycine and succinyl CoA condense to form ALA
in a reaction catalyzed by ALA synthase.
• This reaction requires pyridoxal phosphate as a
coenzyme.
• It is a rate limiting steps.
(2) Formation of porphobilinogen
In this reaction: The dehydration of two molecules of ALA to form
porphobilinogen by ALA dehydratase ( this enzyme is extremely
sensitive to inhibition by heavy metal ions).
(3) Formation of uroporphybilinogen
• The condensation of four molecules of porphobilinogen results in
the formation of uroporphybilinogen lll
• This reaction requires hydroxymethybilane synthase and
uroporphybilinogen lll synthase.
(4) Formation of heme.
• uroporphybilinogen lll is converted to heme by a series
of decarboxylation and oxidation reactions
• The introducing of Fe+2 into protoporphyrin
spontaneously, but the rate is enhanced by
ferrochelatase ( an enzyme inhibited by lead.
Degradation of heme.
• After approximately 120 days in the circulation, red
blood cells are taken up and degraded by the reticuloendothelial (RE) system, particularly in the liver and
spleen.
Degradation of heme.
(1) Formation of bilirubin:
• Microsomal heme oxygenase (HO) system of the
RE cells responsible for the first step of heme
degradation.
(a) In presence of NADH & O2, the enzyme adds
hydroxyl group to the methenyl bridge between
two pyrrole rings with a concomitant oxidation of
Fe+2 to Fe+3
(b) by the same enzyme system a second oxidation
results in cleavage of porphyrin ring, Fe+3 & Co is
released in addition to production of green pigment
Biliverdin.( c) Biliverdin is reduced by biliverdin
reductase forming bilirubin ( red-orange pigment,
bile pigment)
Degradation of heme.
(2) Uptake of bilirubin by the liver. Bilirubin is slightly soluble in plasma, so it
transported to the liver by binding non-covalently to albumin.
• Bilirubin dissociated from albumin and enter hepatocyte, where it binds to
intracellular proteins (ligandin)
(3)Formation of bilirubin diglucuronide: In hepatocytes bilirubin is conjugated
to 2 molecules of glucuronic acid in presence of bilirubin glucuronyltransferas
using UDP-glucuroic acid (as a glucuronate donor)
(4) Excretion of bilirubin into bile: Bilirubin diglucuronide is actively
transported against concentration gradient into the bile canaliculi and then
into the bile.
• This energy –dependant, rate limiting step is susceptible to impairment in
the liver disease
• Unconjugated bilirubin is normally not excreted.
Degradation of heme
(5)Formation of urobilins in the intestine.
In the gut, bilirubin diglucuronide is
hydrolyzed by bacteria to yield
urobilinogen ( a colourless compound) ,
(a) Most urobilinogen is oxidized to
sterbilin( brown color & excreted in
feces).
(b) Some is reabsorbed from the gut and
enter portal blood to participate in the
enterohepatic urobilinogen cycle.
(c ) The remainder urobilinogen is
transported by the blood to the kidney
where it is converted to yellow
urobilinogen (give urine its characteristic
color)