1. Porphyrins and bile pigment

2. 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

3. 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.

4. 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.

5. 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.

6. (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.

7. (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 reticulo- endothelial (RE) system, particularly in the liver and spleen.

8. 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)

9. 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.

10. 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) ,
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)