InterPro: IPR010961 Tetrapyrrole biosynthesis, 5-aminolevulinic acid synthase

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [1]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [2].

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) [3].

This entry represents 5-aminoaevulinic acid (ALA) synthase (EC:2.3.1.37), which catalyses the first stage of tetrapyrrole biosynthesis by the C4 pathway, namely the condensation of succinyl CoA and glycine. ALA synthase is a pyridoxal-phosphate-dependent enzyme. During catalysis, glycine initially binds to the enzyme cofactor, and after condensation with succinyl CoA, CoA, carbon dioxide and 5-aminolevulinic acid are produced [3].