School of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
J Mol Biol. 2010 Jul 16;400(3):379-92. doi: 10.1016/j.jmb.2010.04.058. Epub 2010 May 4.
Heptoses are found in the surface polysaccharides of most bacteria, contributing to structures that are essential for virulence and antibiotic resistance. Consequently, the biosynthetic enzymes for these sugars are attractive targets for novel antibiotics. The best characterized biosynthetic enzyme is GmhA, which catalyzes the conversion of sedoheptulose-7-phosphate into D-glycero-D-manno-heptopyranose-7-phosphate, the first step in the biosynthesis of heptose. Here, the structure of GmhA from Burkholderia pseudomallei is reported. This enzyme contains a zinc ion at the heart of its active site: this ion stabilizes the active, closed form of the enzyme and presents coordinating side chains as a potential acid and base to drive catalysis. A complex with the product demonstrates that the enzyme retains activity in the crystal and thus suggests that the closed conformation is catalytically relevant and is an excellent target for the development of therapeutics. A revised mechanism for the action of GmhA is postulated on the basis of this structure and the activity of B. pseudomallei GmhA mutants.
庚糖存在于大多数细菌的表面多糖中，有助于形成与毒力和抗生素耐药性相关的结构。因此，这些糖的生物合成酶是新型抗生素的有吸引力的靶标。研究最充分的生物合成酶是 GmhA，它催化 sedoheptulose-7-phosphate 转化为 D-glycero-D-manno-heptopyranose-7-phosphate，这是庚糖生物合成的第一步。本文报道了来自伯克霍尔德氏菌的 GmhA 的结构。该酶的活性中心含有一个锌离子：该离子稳定酶的活性、封闭构象，并呈现出配位侧链，作为潜在的酸和碱来驱动催化。与产物的复合物表明，该酶在晶体中保持活性，因此表明封闭构象与催化相关，是开发治疗药物的极好靶标。基于该结构和伯克霍尔德氏菌 GmhA 突变体的活性，提出了 GmhA 作用的修订机制。
