Porphyrias PDF

# Porphyrias ## Structure of Porphyrins - Cyclic molecules formed by linkage of 4 pyrrole rings through methenyl bridges. - Side chains: different groups attached to the pyrrole rings. - Uroporphyrin: acetate, propionate side chains - Protoporphrin IX (and heme): vinyl, methyl and pro...

# Porphyrias ## Structure of Porphyrins - Cyclic molecules formed by linkage of 4 pyrrole rings through methenyl bridges. - Side chains: different groups attached to the pyrrole rings. - Uroporphyrin: acetate, propionate side chains - Protoporphrin IX (and heme): vinyl, methyl and propionate groups ## Heme - Metalloporphyrin: Fe²⁺ coordinated in the center of a protoporphyrin IX ring. - Prosthetic group for hemoglobin, myoglobin, cytochromes. ## Biosynthesis of Heme - Synthesized in the: - Liver: synthesizes several heme proteins, e.g. cytochrome P450 - Erythrocyte producing cells in bone marrow: hemoglobin synthesis - Synthesis in liver: variable rate, depends on cellular heme pool. - Synthesis in erythrocytes: constant rate, equal to the rate of globin synthesis. - Synthesis: first reaction and last three steps in mitochondria, remaining steps in the cytosol. ## Regulation of Heme Biosynthesis ### End product inhibition by hemin: - Heme production exceeds the availability of globin (or other apoproteins). - Heme accumulates and is oxidized (Fe²⁺ → Fe³⁺) to hemin (Hemin is oxidized heme with Fe³⁺). - Hemin decreases activity of hepatic ALA synthase by decreasing the synthesis of the enzyme ## Erythrocytes: heme synthesis affected by: - Erythropoietin - Availability of intracellular iron ### Effect of drugs on ALA synthase: - Phenobarbital, griseofulvin, hydantoins. - Cause increase in hepatic ALA synthase activity - Drugs are metabolized by microsomal cytochrome P450 monoxygenase system (present in liver, which requires heme). - In presence of drugs, synthesis of cytochrome P450 monoooxygenase system increases, heme consumption increases. - Concentration of heme in liver cells decreases. - Decrease in heme concentration increases synthesis of ALA synthase. ## Porphyrias - Inherited genetic diseases. - Defects in heme synthesis. - Result in accumulation and increased excretion of porphyrins or porphyrin precursors. - Porphyrias: - Erythropoietic (enzyme deficiency in erythropoietic cells of bone marrow) - Hepatic (enzyme deficiency in liver) ### Chronic Hepatic Porphyria: #### Porphyria cutanea tarda: - Most common porphyria. - Deficiency in uroporphyrinogen decarboxylase. - Uroporphyrin accumulates, excreted in urine - Symptoms: - Photosensitivity: exposure to light causes skin itches (pruritis) and burns (due to formation of porphyrin-mediated superoxide radicals). - Red to brown urine. ### Acute Hepatic Porphyrias: #### Acute intermittent porphyria: - Deficiency in hydroxymethylbilane synthase. - ALA and porphobilinogen accumulate in urine. - Urine darkens on exposure to air or light. - Patients are not photosensitive. - Patients have abdominal pain. - Symptoms aggravated by administration of 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 intermediates preceding block accumulate in 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 urine (intermediates preceding the block). - Patients are photosensitive. ## Characteristics of Porphyrias ### Increased δ-aminolevulinic acid (ALA) synthase activity - Porphyrias result in decreased synthesis of heme. - Since heme is a repressor of ALA synthase, absence of heme increases synthesis of ALA synthase enzyme. - Increases synthesis of intermediates occurring before genetic block. - Accumulation of toxic intermediates causes pathology of porphyrias. ## Treatment of Porphyrias - Treatment for pain and vomiting. - Intravenous injection of hemin (decreases synthesis of ALA synthase). - Avoidance of sunlight in cases of photosensitivity. - Ingestion of β‐carotene (free radical scavenger). ## Diagnosis of Porphyrias (summary) |Condition|Deficient Enzyme| Abnormal Porphyrin Concentrations|Photosensitivity| |:---|:---|:---|:---| |Porphyria cutanea tarda| Uroporphyringogen decarboxylase| Uroporphyrinogen in urine|Present| |Acute intermittent porphyria|Hydroxymethylbilane synthase|ALA & porphobilinogen in urine|Absent| |Hereditary coproporphyria|Coproporphyrinogen oxidase| Coproporphyrinogen III and preceding intermediates in urine.|Present| |Variegate porphyria | Protoporphyrinogen oxidase| Protoporphyrinogen IX and intermediates preceding block in urine. |Present| |Erythropoietic protoporphyria|Ferrochelatase|Protoporphyrin accumulates in erythrocytes, bone marrow and plasma.|Present| |Congenital erythropoietic porphyria |Uroporphyrinogen III synthase| Uroporphyrinogen I &c oproporphyrinogen I accumulate in urine and erythrocytes.|Present| ## Summary of Porphyrias - A diagram that summarizes the different porphyrias. - Diagram includes: - Lead poisoning - Acute intermittent porphyria - Porphyria cutanea tarda - Congenital erythropoietic porphyria - Hereditary coproporphyria - Variegate porphyria - Erythropoietic protoporphyria # Thanks for Your Attention