Uroporphyrinogens

Uroporphyrinogens are a pair of porphyrinogen intermediates in the biosynthesis of heme (and related tetrapyrroles). They are tetrapyrrole compounds that carry four carboxylate-containing side chains and exist in two stereoisomeric forms: uroporphyrinogen I and uroporphyrinogen III. The physiologically important pathway proceeds through the III isomer; the I form is considered non-physiological.

Biosynthesis and role

Four porphobilinogen molecules are linked by hydroxymethylbilane synthase to form hydroxymethylbilane. This linear tetrapyrrole can cyclize to the corresponding uroporphyrinogen. If the cyclization occurs in the absence of the enzyme uroporphyrinogen III synthase, it yields uroporphyrinogen I; with the enzyme, hydroxymethylbilane is converted into uroporphyrinogen III, the substrate for subsequent steps. Uroporphyrinogen decarboxylase then decarboxylates the four carboxyl groups to produce coproporphyrinogen III, which continues through the heme biosynthetic pathway via coproporphyrinogen oxidase, protoporphyrinogen oxidase, and ferrochelatase to form heme.

Clinical relevance

Disorders affecting the enzymes that channel uroporphyrinogens toward heme can lead to porphyrias. For example, deficiency of uroporphyrinogen III synthase causes congenital erythropoietic porphyria (Gunther disease), with accumulation of uroporphyrinogen I and related porphyrins and symptoms such as photosensitivity and erythrodontia. In normal physiology, uroporphyrinogens are rapidly oxidized to colored porphyrins, which can appear in urine during porphyrinurias.

Notes

Porphyrinogens are colorless and readily oxidized to colored porphyrins; the I isomer is non-physiological and not used for heme production.