| Defects in the heme synthetic pathway lead to rare disorders known as porphyrias. Different forms of porphyrias are caused by defects in enzymes starting from 5-ALA synthase and ending with ferrochelatase. Porphyrias are classified as hepatic or erythropoietic depending on the primary organ affected. |
| Three porphyrias are known as acute porphyrias and can be a cause of emergency admissions with abdominal pain (which needs to be differentiated from various surgical causes). They also cause neuro-psychiatric symptoms. Acute intermittent porphyria (AIC) is caused by the deficiency of hydroxymethylbilane synthase: an enzyme converting PBG to a linear tetrapyrrole: in this disorder the concentrations of 5-ALA and PBG increase in plasma and urine. |
| Hereditary coproporphyria is due to the defect in the conversion of coproporphyrinogen III to protoporphyrinogen III (copro-oxidase). The third form of acute porphyria is the variegate porphyria, the clinical manifestations of which are very similar to AIC. Other porphyrias, such as porphyria cutanea tarda, present clinically as the sensitivity of skin to light (photosensitivity) which may cause disfiguration and scarring. Also, the pathway is inhibited by lead at the stage of porphobilinogen synthase. |
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Heme, a constituent of hemoglobin, myoglobin, and cytochromes is synthesized in most cells of the body. The liver is the main nonerythrocyte source of its synthesis. Heme is a porphyrin, a cyclic compound which contains four pyrrole rings linked together by methenyl bridges. It is synthesized
from glycine and succinyl-Coenzyme A, which condense to form 5-aminolevulinate (5-ALA). This reaction is catalyzed by 5-ALA synthase, located in mitochondria and is the rate-limiting step in heme synthesis. Subsequently, in the cytosol, two molecules of 5-ALA condense to form a molecule containing a pyrrole ring, porphobilinogen (PBG). Then, four PBG molecules combine to form a linear tetrapyrrole compound which cyclizes to yield uroporphyrinogen III and then coproporphyrinogen III. Final stages of the pathway occur again in the mitochondria where a series of decarboxylation and oxidation of side chains in uroporphyrinogen III yield protoporphyrin IX. At the final stage, iron (Fe2+) is added by ferrochelatase to protoporphyrin IX to form heme. Heme controls the rate of its synthesis by inhibiting 5-ALA synthase (Fig. 28.3).
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