<p>Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [<cite idref="PUB00035498"/>]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [<cite idref="PUB00035496"/>].</p><p> <ul> <li>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 (<db_xref db="EC" dbkey="2.3.1.37"/>), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (<db_xref db="EC" dbkey="6.1.1.17"/>) to charge a tRNA with glutamate, glutamyl-tRNA reductase (<db_xref db="EC" dbkey="1.2.1.70"/>) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (<db_xref db="EC" dbkey="5.4.3.8"/>) to catalyse a transamination reaction to produce ALA.</li> </ul> </p><p> <ul> <li>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, <db_xref db="EC" dbkey="4.2.1.24"/>) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase, <db_xref db="EC" dbkey="2.5.1.61"/>) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (<db_xref db="EC" dbkey="4.2.1.75"/>) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.</li> </ul> </p><p> <ul> <li>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 (<db_xref db="EC" dbkey="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 (<db_xref db="EC" dbkey="4.1.1.37"/>) [<cite idref="PUB00009744"/>].</li> </ul> </p><p>This entry represents porphobilinogen (PBG) synthase (PBGS, or 5-aminoaevulinic acid dehydratase, or ALAD, <db_xref db="EC" dbkey="4.2.1.24"/>), which functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses a Knorr-type condensation reaction between two molecules of ALA to generate porphobilinogen, the pyrrolic building block used in later steps [<cite idref="PUB00035500"/>]. The structure of the enzyme is based on a TIM barrel topology made up of eight identical subunits, where each subunit binds to a metal ion that is essential for activity, usually zinc (in yeast, mammals and certain bacteria) or magnesium (in plants and other bacteria). A lysine has been implicated in the catalytic mechanism [<cite idref="PUB00000460"/>]. The lack of PBGS enzyme causes a rare porphyric disorder known as ALAD porphyria, which appears to involve conformational changes in the enzyme [<cite idref="PUB00035501"/>.</p>