Hydroxymethylbilane

Hydroxymethylbilane is an intermediate in heme biosynthesis. It is a linear tetrapyrrole produced in the cytosol by the deamination and linking of four porphobilinogen molecules, a reaction catalyzed by porphobilinogen deaminase (also known as hydroxymethylbilane synthase). The enzyme adds successive porphobilinogen units to form the extended linear chain that constitutes hydroxymethylbilane.

In the normal pathway, hydroxymethylbilane is cyclized by the action of uroporphyrinogen III synthase to form uroporphyrinogen III, a cyclic tetrapyrrole that is further processed through decarboxylation and oxidation steps to eventually yield heme. If the enzyme uroporphyrinogen III synthase is deficient or nonfunctional, hydroxymethylbilane can cyclize nonenzymatically to form uroporphyrinogen I, leading to the accumulation of type I porphyrinogens and porphyrins and contributing to porphyria symptoms.

Clinical relevance is most evident in disorders of the heme pathway. Defects in porphobilinogen deaminase, the enzyme that forms hydroxymethylbilane, cause acute porphyrias, whereas deficiency of uroporphyrinogen III synthase results in congenital erythropoietic porphyria due to abnormal accumulation of type I porphyrins. Hydroxymethylbilane itself is typically an unstable intermediate and is rapidly converted to downstream products under normal physiological conditions.

References to laboratories often focus on the downstream products and enzyme activities in the heme biosynthesis pathway, with hydroxymethylbilane serving as a key transient substrate connecting early and later steps.