| Description: |
Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway []. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [].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 (), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase () to charge a tRNA with glutamate, glutamyl-tRNA reductase () to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase () 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, ) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase, ) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase () 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 (). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen IIIdecarboxylase () [].This entry represents delta-aminolevulinic acid dehydratase (ALAD), also known as porphobilinogen (PBG) synthase (PBGS, or 5-aminoaevulinic acid dehydratase ), 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 []. 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 []. The lack of PBGS enzyme causes a rare porphyric disorder known as ALAD porphyria, which appears to involve conformational changes in the enzyme []. |
