Porphyrias and Heme Biosynthesis Overview

Porphyrias Overview

• Porphyrias are inherited genetic diseases
• They involve defects in heme synthesis
• These defects cause accumulation and increased excretion of porphyrins or porphyrin precursors

Porphyrin Structure

• Porphyrins are cyclic molecules
• Formed by the linkage of four pyrrole rings
• Connected via methenyl bridges
• Have side chains attached to the pyrrole rings
• Different porphyrins have different side chains (e.g., uroporphyrin with acetate and propionate chains, protoporphyrin IX with vinyl, methyl, and propionate groups)
• Heme is a metalloporphyrin
• Fe²⁺ is coordinated in the center of a protoporphyrin IX ring
• Heme is a prosthetic group for hemoglobin, myoglobin, and cytochromes

Heme Biosynthesis

• Synthesized in the liver and erythrocyte producing cells in bone marrow
• Liver synthesis varies depending on cellular heme pool
• Erythrocyte synthesis is constant, matching globin synthesis
• First reaction and last three steps occur in mitochondria, remaining steps in the cytosol

Porphyria Regulation

• End product inhibition by hemin: Heme production exceeds the availability of globin or other apoproteins, leading to heme accumulation and oxidation to hemin. Hepatic ALA synthase activity decreases. Erythropoiesis is affected by erythropoietin and intracellular iron.
• Effect of drugs on ALA synthase: Drugs like phenobarbital, griseofulvin, and hydantoins increase hepatic ALA synthase activity because they stimulate cytochrome P450 monoxygenase system activity, which uses heme. Heme concentration in liver cells decreases, stimulating ALA synthase.

Types of Porphyrias

Chronic Hepatic Porphyria (Porphyria cutanea tarda)

• Most common type
• Deficiency in uroporphyrinogen decarboxylase
• Uroporphyrin accumulates and is excreted in the urine
• Symptoms include photosensitivity (skin itching and burning due to porphyrin-mediated superoxide radicals) and red-to-brown urine

Acute Hepatic Porphyrias

Acute Intermittent Porphyria

• Deficiency in hydroxymethylbilane synthase
• ALA and porphobilinogen accumulate in the urine
• Urine darkens with exposure to air or light
• Patients are not photosensitive
• Symptoms include abdominal pain, and symptoms are aggravated by barbiturates

Hereditary Coproporphyria

• Deficiency in coproporphyrinogen oxidase
• Coproporphyrinogen III and preceding intermediates accumulate in the urine
• Patients are photosensitive

Variegate Porphyria

• Deficiency in protoporphyrinogen oxidase
• Protoporphyrinogen IX and preceding intermediates accumulate in the urine
• Patients are photosensitive

Erythropoietic Porphyrias

Erythropoietic Protoporphyria

• Deficiency in ferrochelatase
• Protoporphyrin IX cannot chelate with Fe²⁺ to form heme
• Protoporphyrin accumulates in erythrocytes, bone marrow, and plasma
• Patients are photosensitive

Congenital Erythropoietic Porphyria

• Deficiency in uroporphyrinogen III synthase
• Uroporphyrinogen I and coproporphyrinogen I accumulate in the urine (intermediates preceding the block)
• Patients are photosensitive

Porphyria Characteristics

• Porphyrias result in decreased heme synthesis
• Heme is a repressor of ALA synthase
• Absence of heme increases ALA synthase activity
• Synthesis of intermediates before the genetic block increases
• Accumulation of toxic intermediates causes porphyria pathology

Porphyria Treatment

• Treatment for pain and vomiting
• Intravenous hemin injection (decreases ALA synthase)
• Avoidance of sunlight for photosensitivity
• Ingestion of β-carotene (free radical scavenger)

Porphyria Diagnosis (Summary)

• A table summarizing the porphyria types, deficient enzymes, abnormal porphyrin concentrations, and photosensitivity status found for each.