Hurtado-Guerrero Ramon, Raimi Olawale, Shepherd Sharon, van Aalten Daan M F
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
FEBS Lett. 2007 Dec 11;581(29):5597-600. doi: 10.1016/j.febslet.2007.10.065. Epub 2007 Nov 20.
Glucosamine-6-phosphate N-acetyltransferase (GNA1) catalyses the N-acetylation of d-glucosamine-6-phosphate (GlcN-6P), using acetyl-CoA as an acetyl donor. The product GlcNAc-6P is an intermediate in the biosynthesis UDP-GlcNAc. GNA1 is part of the GCN5-related acetyl transferase family (GNATs), which employ a wide range of acceptor substrates. GNA1 has been genetically validated as an antifungal drug target. Detailed knowledge of the Michaelis complex and trajectory towards the transition state would facilitate rational design of inhibitors of GNA1 and other GNAT enzymes. Using the pseudo-substrate glucose-6-phosphate (Glc-6P) as a probe with GNA1 crystals, we have trapped the first GNAT (pseudo-)Michaelis complex, providing direct evidence for the nucleophilic attack of the substrate amine, and giving insight into the protonation of the thiolate leaving group.
6-磷酸葡萄糖氨基N-乙酰基转移酶（GNA1）以乙酰辅酶A作为乙酰供体，催化6-磷酸-D-葡萄糖胺（GlcN-6P）的N-乙酰化反应。产物N-乙酰葡糖胺-6-磷酸（GlcNAc-6P）是生物合成尿苷二磷酸-N-乙酰葡糖胺（UDP-GlcNAc）的中间体。GNA1是与GCN5相关的乙酰转移酶家族（GNATs）的成员之一，该家族使用多种受体底物。GNA1已被基因验证为抗真菌药物靶点。深入了解米氏复合物以及向过渡态的反应轨迹将有助于合理设计GNA1和其他GNAT酶的抑制剂。通过使用6-磷酸葡萄糖（Glc-6P）作为伪底物与GNA1晶体进行研究，我们捕获了首个GNAT（伪）米氏复合物，为底物胺的亲核攻击提供了直接证据，并深入了解了硫醇盐离去基团的质子化情况。
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