Porphyrins and PorphyriasPorphyrins and Porphyrias

Dr. Zeyad El-Akawi Jreisat, M.D, M.A, Ph.DDr. Zeyad El-Akawi Jreisat, M.D, M.A, Ph.D

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

HemeHeme

• Is the prosthetic group for:Is the prosthetic group for:

– HemoglobinHemoglobin

– MyoglobinMyoglobin

– CytochromesCytochromes

– CatalaseCatalase

– Tryptophan pyrrolaseTryptophan pyrrolase

• The major sites of heme biosynthesis are the liver The major sites of heme biosynthesis are the liver (cytochrom P450) and the erythrocyte-producing cells of (cytochrom P450) and the erythrocyte-producing cells of the bone marrow which are active in hemoglobin synthesisthe bone marrow which are active in hemoglobin synthesis

Regulation of Heme Biosynthesis Regulation of Heme Biosynthesis

• In hepatocytes: In hepatocytes:

– Heme is required for incorporation into the Heme is required for incorporation into the cytochromes, in particular P450.cytochromes, in particular P450.

– The rate-limiting step in hepatic heme biosynthesis is The rate-limiting step in hepatic heme biosynthesis is the ALA synthase catalyzed stepthe ALA synthase catalyzed step

– Regulation of the heme synthesis is by the effect of Regulation of the heme synthesis is by the effect of hemin ashemin as

• Feed-back inhibitor on ALA synthaseFeed-back inhibitor on ALA synthase

• Inhibits transport of ALA synthase from the cytosol Inhibits transport of ALA synthase from the cytosol (site of synthesis) into the mitochondria (site of (site of synthesis) into the mitochondria (site of action)action)

• Repress the synthesis of the enzymeRepress the synthesis of the enzyme

Regulation of Heme BiosynthesisRegulation of Heme Biosynthesis

• In erythroid cells:In erythroid cells:– Heme is synthesized for incorporation into hemoglobinHeme is synthesized for incorporation into hemoglobin

– Control of heme biposynthesis in erythrocytes occurs at Control of heme biposynthesis in erythrocytes occurs at numerous sites other than at the level of ALA synthasenumerous sites other than at the level of ALA synthase

– Heme synthesis is under the control of erythropoitin Heme synthesis is under the control of erythropoitin and the availability of intracellular ironand the availability of intracellular iron

– Control has been shown to be exerted on ferrochelatase, Control has been shown to be exerted on ferrochelatase, and porphobilinogen deaminase and porphobilinogen deaminase

PorphyriasPorphyrias

• Porphyrias are a group of disorders due to abnormalities Porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of hemein the pathway of biosynthesis of heme

• They can be genetics or acquiredThey can be genetics or acquired

• They can be hepatic or erythroidThey can be hepatic or erythroid

• In general the porphyrias are inherited in an autosomal In general the porphyrias are inherited in an autosomal dominant manner, with the exception of congenital dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive erythropoietic porphyria, which is inherited in a recessive modemode

PorphyriasPorphyrias

• The clinical signs and symptoms of porphyria result from The clinical signs and symptoms of porphyria result from either a deficiency of metabolic products beyond the either a deficiency of metabolic products beyond the enzymatic block or from an accumulation of metabolites enzymatic block or from an accumulation of metabolites behind the blockbehind the block

• General main disorders:General main disorders:

– Skin diseases

– Neurological disorders

Erythroid ClassErythroid Class

– X-linked sideroblastic anemiaX-linked sideroblastic anemia• δ-aminolevulinic acid synthase 2δ-aminolevulinic acid synthase 2• progressive iron accumulation, fatal if not treatedprogressive iron accumulation, fatal if not treated

– Congenital erythropoietic porphyriaCongenital erythropoietic porphyria• uroporphyrinogen III synthaseuroporphyrinogen III synthase• photosensitivity photosensitivity

– Erythropoietic protoporphyriaErythropoietic protoporphyria• ferrochelataseferrochelatase• photosensitivityphotosensitivity

Hepatic Class Hepatic Class

• ALA ALA dehydratasedehydratase deficient deficient porphyriaporphyria

– ALA dehydratase: also called porphobilinogen synthaseALA dehydratase: also called porphobilinogen synthase

– neurovisceralneurovisceral

• Acute intermittent Acute intermittent porphyriaporphyria

– hydroxymethylbilane synthasehydroxymethylbilane synthase

– neurovisceralneurovisceral

• Hereditary Hereditary coproporphyriacoproporphyria

– coproporphyrinogen oxidasecoproporphyrinogen oxidase

– neurovisceral, some photosensitivityneurovisceral, some photosensitivity

Hepatic ClassHepatic Class

• Variegate porphyriaVariegate porphyria– protoporphyrinogen oxidaseprotoporphyrinogen oxidase– neurovisceral, some photosensitivityneurovisceral, some photosensitivity

• Porphyria cutanea tarda type IPorphyria cutanea tarda type I– hepatic uroporphyrinogen decarboxylasehepatic uroporphyrinogen decarboxylase– photosensitivityphotosensitivity

• Porphyria cutanea tarda type II, may also be referred to as Porphyria cutanea tarda type II, may also be referred to as hepatoerythropoietic porphyria, uroporphyrinogen hepatoerythropoietic porphyria, uroporphyrinogen decarboxylase in non-hepatic tissues, photosensitivity, decarboxylase in non-hepatic tissues, photosensitivity, some neurovisceralsome neurovisceral