Porphyrins and Porphyrias

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: • 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

8. Regulation of Heme Biosynthesis • 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 • Inhibits transport of ALA synthase from the cytosol (site of synthesis) into the mitochondria (site of action) • Repress the synthesis of the enzyme

9. Regulation of Heme Biosynthesis • 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 • They can be genetics or acquired • 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

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 • General main disorders: • Skin diseases • Neurological disorders

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

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

14. Hepatic Class • Variegate porphyria • protoporphyrinogen oxidase • neurovisceral, some photosensitivity • Porphyria cutanea tarda type I • 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