Porphobilinogen deaminase

Porphobilinogen deaminase (EC 2.5.1.61, Older sources categorize it under ), also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase is an is_associated_with::enzyme that in humans is encoded by the HMBS is_associated_with::gene. Porphobilinogen deaminase is involved in the third step of the is_associated_with::heme biosynthetic pathway. It catalyzes the head to tail condensation of four is_associated_with::porphobilinogen molecules into the linear is_associated_with::hydroxymethylbilane while releasing four is_associated_with::ammonia molecules.

Structure and function
Functionally, porphobilinogen deaminase catalyzes the loss of ammonia from the porphobilinogen monomer (is_associated_with::deamination) and its subsequent polymerization to a linear tetrapyrrole, which is released as hydroxymethylbilane:



The structure of 40-42 kDa porphobilinogen deaminase, which is highly conserved amongst organisms, consists of three domains. Domains 1 and 2 are structurally very similar: each consisting of five beta-sheets and three alpha helices in humans. Domain 3 is positioned between the other two and has a flattened beta-sheet geometry. A dipyrrole, a cofactor of this enzyme consisting of two condensed porphobilinogen molecules, is covalently attached to domain 3 and extends into the active site, the cleft between domains 1 and 2. Several positively charged is_associated_with::arginine residues, positioned to face the active site from domains 1 and 2, have been shown to stabilize the carboxylate functionalities on the incoming porphobilinogen as well as the growing pyrrole chain. These structural features presumably favor the formation of the final hydroxymethylbilane product. Porphobilinogen deaminase usually exists in dimer units in the is_associated_with::cytoplasm of the cell.

Reaction mechanism


The first step is believed to involve an is_associated_with::E1 elimination of ammonia from porphobilinogen, generating a carbocation intermediate (1). This intermediate is then attacked by the dipyrrole cofactor of porphobilinogen deaminase, which after losing a proton yields a trimer covalently bound to the enzyme (2). This intermediate is then open to further reaction with porphobilinogen (1 and 2 repeated three more times). Once a hexamer is formed, hydrolysis allows hydroxymethylbilane to be released, as well as cofactor regeneration (3).

Pathology
The most well-known health issue involving porphobilinogen deaminase is is_associated_with::acute intermittent porphyria, an autosomal dominant genetic disorder where insufficient hydroxymethylbilane is produced, leading to a build-up of porphobilinogen in the cytoplasm. This is caused by a gene mutation that, in 90% of cases, causes decreased amounts of enzyme. However, mutations where less-active enzymes and/or different isoforms have been described.