1. Porphyrins and Porphyrias Dr. Zeyad El-Akawi Jreisat, M.D, M.A, Ph.D

2. Porphyrins are cyclic compounds formed by the linkage of four pyrrole rings through methenyl bridges (-HC=)

4. Heme Is the prosthetic group for: Is the prosthetic group for: – Hemoglobin – Myoglobin – Cytochromes – Catalase – Tryptophan pyrrolase The major sites of heme biosynthesis are the liver (cytochrom P450) and the erythrocyte-producing cells of the bone marrow which are active in hemoglobin synthesis The major sites of heme biosynthesis are the liver (cytochrom P450) and the erythrocyte-producing cells of the bone marrow which are active in hemoglobin synthesis

8. Regulation of Heme Biosynthesis In hepatocytes: In hepatocytes: – Heme is required for incorporation into the cytochromes, in particular P450. – The rate-limiting step in hepatic heme biosynthesis is the ALA synthase catalyzed step – Regulation of the heme synthesis is by the effect of hemin as Feed-back inhibitor on ALA synthase Feed-back inhibitor on ALA synthase Inhibits transport of ALA synthase from the cytosol (site of synthesis) into the mitochondria (site of action) Inhibits transport of ALA synthase from the cytosol (site of synthesis) into the mitochondria (site of action) Repress the synthesis of the enzyme Repress the synthesis of the enzyme

9. Regulation of Heme Biosynthesis In erythroid cells: In erythroid cells: – Heme is synthesized for incorporation into hemoglobin – Control of heme biposynthesis in erythrocytes occurs at numerous sites other than at the level of ALA synthase – Heme synthesis is under the control of erythropoitin and the availability of intracellular iron – Control has been shown to be exerted on ferrochelatase, and porphobilinogen deaminase

10. Porphyrias Porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme Porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme They can be genetics or acquired They can be genetics or acquired They can be hepatic or erythroid They can be hepatic or erythroid In general the porphyrias are inherited in an autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive mode In general the porphyrias are inherited in an autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive mode

11. Porphyrias The clinical signs and symptoms of porphyria result from either a deficiency of metabolic products beyond the enzymatic block or from an accumulation of metabolites behind the block The clinical signs and symptoms of porphyria result from either a deficiency of metabolic products beyond the enzymatic block or from an accumulation of metabolites behind the block General main disorders: General main disorders: – – Skin diseases – – Neurological disorders

12. Erythroid Class – X-linked sideroblastic anemia X-linked sideroblastic anemia X-linked sideroblastic anemia δ-aminolevulinic acid synthase 2 δ-aminolevulinic acid synthase 2 progressive iron accumulation, fatal if not treated progressive iron accumulation, fatal if not treated – Congenital erythropoietic porphyria Congenital erythropoietic porphyria Congenital erythropoietic porphyria uroporphyrinogen III synthase uroporphyrinogen III synthase photosensitivity photosensitivity – Erythropoietic protoporphyria Erythropoietic protoporphyria Erythropoietic protoporphyria ferrochelatase ferrochelatase photosensitivity photosensitivity

13. Hepatic Class ALA dehydratase deficient porphyria ALA dehydratase deficient porphyria ALA dehydratase deficient porphyria ALA dehydratase deficient porphyria – ALA dehydratase: also called porphobilinogen synthase – neurovisceral Acute intermittent porphyria Acute intermittent porphyria Acute intermittent porphyria Acute intermittent porphyria – hydroxymethylbilane synthase – neurovisceral Hereditary coproporphyria Hereditary coproporphyria Hereditary coproporphyria Hereditary coproporphyria – coproporphyrinogen oxidase – neurovisceral, some photosensitivity

14. Hepatic Class Variegate porphyria Variegate porphyria Variegate porphyria Variegate porphyria – protoporphyrinogen oxidase – neurovisceral, some photosensitivity Porphyria cutanea tarda type I Porphyria cutanea tarda type I Porphyria cutanea tarda Porphyria cutanea tarda – hepatic uroporphyrinogen decarboxylase – photosensitivity Porphyria cutanea tarda type II, may also be referred to as hepatoerythropoietic porphyria, uroporphyrinogen decarboxylase in non-hepatic tissues, photosensitivity, some neurovisceral Porphyria cutanea tarda type II, may also be referred to as hepatoerythropoietic porphyria, uroporphyrinogen decarboxylase in non-hepatic tissues, photosensitivity, some neurovisceral Porphyria cutanea tarda Porphyria cutanea tarda