Domain

Porphobilinogen deaminase, C-terminal (IPR022418)

Short name: Porphobilinogen_deaminase_C

Domain relationships

None.

Description

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [PMID: 16564539]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [PMID: 17227226].

  • The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (EC:2.3.1.37), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (EC:6.1.1.17) to charge a tRNA with glutamate, glutamyl-tRNA reductase (EC:1.2.1.70) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (EC:5.4.3.8) to catalyse a transamination reaction to produce ALA.

  • The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase, EC:4.2.1.24) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase, EC:2.5.1.61) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (EC:4.2.1.75) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.

  • Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (EC:2.1.1.107). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (EC:4.1.1.37) [PMID: 11215515].

Porphobilinogen deaminase (also known as hydroxymethylbilane synthase, EC:2.5.1.61) functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the polymerisation of four PBG molecules into the tetrapyrrole structure, preuroporphyrinogen, with the concomitant release of four molecules of ammonia. This enzyme uses a unique dipyrro-methane cofactor made from two molecules of PBG, which is covalently attached to a cysteine side chain. The tetrapyrrole product is synthesized in an ordered, sequential fashion, by initial attachment of the first pyrrole unit (ring A) to the cofactor, followed by subsequent additions of the remaining pyrrole units (rings B, C, D) to the growing pyrrole chain [PMID: 11215515]. The link between the pyrrole ring and the cofactor is broken once all the pyrroles have been added. This enzyme is folded into three distinct domains that enclose a single, large active site that makes use of an aspartic acid as its one essential catalytic residue, acting as a general acid/base during catalysis [PMID: 12555854, PMID: 1522882]. A deficiency of hydroxymethylbilane synthase is implicated in the neuropathic disease, Acute Intermittent Porphyria (AIP) [PMID: 16935474].

This entry represents the C-terminal domain of porphobilinogen deaminase, an enzyme involved in tetrapyrrole biosynthesis. The structure of this alpha/beta domain consists of alpha-beta(3)-alpha in two layers [PMID: 1522882]. Porphobilinogen deaminase has a three-domain structure. Domains 1 (N-terminal) and 2 are duplications with the same structure, resembling the transferrins and periplasmic binding proteins. The dipyrromethane cofactor is covalently linked to domain 3 (C-terminal), but is bound by extensive salt-bridges and hydrogen-bonds within the cleft between domains 1 and 2, at a position corresponding to the binding sites for small-molecule ligands in the analogous proteins [PMID: 1522882]. The enzyme has a single catalytic site, and the flexibility between domains is thought to aid elongation of the polypyrrole product in the active-site cleft of the enzyme.

GO terms

Biological Process

GO:0033014 tetrapyrrole biosynthetic process

Molecular Function

GO:0004418 hydroxymethylbilane synthase activity

Cellular Component

No terms assigned in this category.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
SUPERFAMILY
GENE3D
Pfam