Porphobilinogen synthase synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, porphobilinogen synthase is the prototype morpheein. The * represents a reorientation between two domains of each subunit that occurs in the state because it is sterically forbidden in the larger multimers. PBGS is encoded by a gene and each PBGS multimer is composed of multiple copies of the same protein. Each PBGS subunit consists of a ~300 residue αβ-barrel domain, which houses the enzymes active site in its center, allosteric regulation of PBGS can be described in terms of the orientation of the αβ-barrel domain with respect to the N-terminal arm domain. Each N-terminal arm has up to two interactions with subunits in a PBGS multimer. One of these interactions helps to stabilize a conformation of the active site lid. The other interaction restricts solvent access from the end of the αβ-barrel. As a nearly universal enzyme with a conserved active site. To the contrary, allosteric sites can be much more variable than active sites. Phylogenetic variation in PBGS allostery leads to the framing of discussion of PBGS allosteric regulation in terms of intrinsic and extrinsic factors, the allosteric magnesium ion lies at the highly hydrated interface of two pro-octamer dimers. It appears to be easily dissociable, and it has shown that hexamers accumulate when magnesium is removed in vitro. Inspection of the PBGS 6mer* reveals a surface cavity that is not present in the 8mer, small molecule binding to this phylogenetically variable cavity has been proposed to stabilize 6mer* of the targeted PBGS and consequently inhibit activity. Such allosteric regulators are known as morphlocks because they lock PBGS in a specific morpheein form, a deficiency of porphobilinogen synthase is usually acquired and can be caused by heavy metal poisoning, especially lead poisoning, as the enzyme is very susceptible to inhibition by heavy metals. Hereditary insufficiency of porphobilinogen synthase is called porphobilinogen synthase deficiency poprhyria and it is an extremely rare cause of porphyria, with less than 10 cases ever reported. All disease associated protein variants favor hexamer formation relative to the wild type human enzyme, lead poisoning works on the cellular level by binding to this enzyme, rendering it useless. Delta-Aminolevulinic Acid Dehydratase at the US National Library of Medicine Medical Subject Headings http, //www. omim. org/entry/125270. search=pbgs&highlight=pbgs
high resolution crystal structure of a mg2-dependent 5-aminolevulinic acid dehydratase
The PBGS quaternary structure equilibrium includes an inactive hexamer (PDB id 1PV8) that does not have subunit interactions necessary for an ordered active site lid. Dissociation to the pro-hexamer dimer can be followed by a conformational change that reorients the two αβ-barrel domains to form the pro-octamer dimer. Association of pro-octamer dimer to octamer (PDB id 1E51) includes formation of subunit interfaces that support order in the active site lid.