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Although PBGD appears to have hydrogen bonding capabilities between two identical PBGD units, at physiological pH, these interactions account for a dimer interface of approximately 5% while average dimer interface between subunits is 16%<ref name="Raj">PMID: 19207107</ref>. Therefore, it is generally assumed that this protein is active naturally as a monomeric enzyme, while the crystalline form is a homo-dimeric structure of two identical PBGD subunits<ref name="Raj">PMID: 19207107</ref>. | Although PBGD appears to have hydrogen bonding capabilities between two identical PBGD units, at physiological pH, these interactions account for a dimer interface of approximately 5% while average dimer interface between subunits is 16%<ref name="Raj">PMID: 19207107</ref>. Therefore, it is generally assumed that this protein is active naturally as a monomeric enzyme, while the crystalline form is a homo-dimeric structure of two identical PBGD subunits<ref name="Raj">PMID: 19207107</ref>. | ||
==Mechanism== | ==Mechanism== | ||
PBGD is responsible for the formation of hydroxymethylbilane (HMB) from four porphobilinogen (PBG) subunits<ref name="Peter">PMID:3079571</ref>. The enzyme is loaded with a single porphobilinogen that is covalently linked to the dipyrromethane cofactor<ref name="Lander">PMID: 2025226</ref>. The remaining three PBG units are attached in a head-to-tail fashion to yield an early, linear, HMB precursor that is covalently linked to PBGD<ref name="Lander">PMID: 2025226</ref>. The six pyrole unit compound is cleaved at the second pyrole to yield the final product, hydroxymethylbilane<ref> A.R. Battersby, F.J. Leeper. Biosynthesis of the pigments of life: mechanistic studies on the conversion of porphobilinogen to uroporphyrinogen III. Chern. Rev. 1990 Nov;90(7):1261-1274</ref>. | PBGD is responsible for the formation of hydroxymethylbilane (HMB) from four porphobilinogen (PBG) subunits<ref name="Peter">PMID:3079571</ref>. The enzyme is loaded with a single porphobilinogen that is covalently linked to the dipyrromethane cofactor<ref name="Lander">PMID: 2025226</ref>. The remaining three PBG units are attached in a head-to-tail fashion to yield an early, linear, HMB precursor that is covalently linked to PBGD<ref name="Lander">PMID: 2025226</ref>. The six pyrole unit compound is cleaved at the second pyrole, by water, to yield the final product, hydroxymethylbilane<ref> A.R. Battersby, F.J. Leeper. Biosynthesis of the pigments of life: mechanistic studies on the conversion of porphobilinogen to uroporphyrinogen III. Chern. Rev. 1990 Nov;90(7):1261-1274</ref>. | ||
==Importance of hPBGD== | ==Importance of hPBGD== | ||
===Acute Intermittent Porphyria=== | ===Acute Intermittent Porphyria=== | ||
Acute intermittent porphyria (AIP) is an autosomal dominant disorder (0.06% incidence rate in population) caused by a mutation in the hydroxymethylbilane synthase gene (HMBS)<ref name="Whatley">Whatley S.D., Roberts A.G., Llewellyn D.H., Bennett C.P., Garrett C, Elder G.H. (2000). Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene. Hum. Genet. 107 (3): 243–248.</ref>. The protein, responsible for the conversion of porphobilinogen (PBG) to hydroxymethylbilane (HMB) is less active in most affected individuals by approximately one-half normal activity<ref name="Whatley" />. Defective PBGD, AIP, and can be diagnosed through the detection of increased concentrations of porphobilinogen (PBG) in urine as it remains unincorporated by the defective enzyme<ref name="Aarsand">PMID: 16595824</ref>. | |||
==References== | ==References== | ||
<references/> | <references/> | ||
