Porphyrin Metabolism

Porphyrin Metabolism • Biosynthesis of heme: • Hemoglobin is synthesized mainly in the liver & bone marrow. • Mature RBC’s lack mitochondria and are unable to synthesize heme. • There are eight enzymes in the heme biosynthetic pathway, four of which(the first one and the last three)are in the mitochondria , while the other four are in the cytosol.

1)Formation of δ-aminolevulinic acid (ALA): • Synthesis of ALA occurs in mitochondria. • ALA synthase is the rate-controlling enzyme in porphyrin biosynthesis

2) Formation of porphobilinogen (PBG): • In the cytosol, two molecules of ALA are condensed by the enzyme ALA dehydratase to form one molecule of porphobilinogen (PBG).

3) Formation of uroporphyrinogen III:

4) Formation of coproporphyrinogen III:

5) Formation of protoporohyrin IX:

6) Formation of heme:

ALA dehydratase

Regulation of heme biosynthesis: • The rate limiting reaction in heme biosynthesis is that catalyzed by ALA synthase enzyme . • ALA synthase enzyme is strictly regulated by intracellular iron levels and heme concentration. • A low-iron level, e.g., in iron deficiency, leads to decreased porphyrin synthesis. • Heme acts as a negative regulator ( feedback inhibitor) for the synthesis of ALA synthase enzyme.

When heme biosynthesis exceeds the synthesis of globin part, heme Fe2+ Oxidized to hemin (Fe3+). • The resulted hemin acts as a positive regulator for the biosynthesis of globin part

Porphyria • Porphyrias are a group of disorders caused by defects in heme biosynthesis, whichresult in accumulation and increased excretion of porphyrins or its precursors. • Examples of porphyrias are :

Porphyrin Metabolism