Acetohydroxyacid Synthase: A Target for Antimicrobial Drug Discovery
Acetohydroxyacid Synthase: A Target for Antimicrobial Drug Discovery
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DOI：
10.2174/13816128113199990009
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发表时间：
2014-02-01
影响因子：
3.1
通讯作者：
Guddat, Luke W.
中科院分区：
文献类型：
--
作者：
Pue, Nason;Guddat, Luke W.
乙酰羟酸合酶（AHAS）（EC 2.2.1.6）（也称为乙酰乳酸合酶）是支链氨基酸（BCAA）生物合成途径中的第一个常见酶。这种途径存在于微生物和植物中，但不存在于动物中，使其成为药物和除草剂发现的有吸引力的目标。AHAS的功能是催化两个丙酮酸分子转化为2-乙酰乳酸或将一个丙酮酸分子和一个2-酮丁酸分子转化为2-乙酰基-2-羟基丁酸。AHAS的活性需要三种辅因子：二磷酸硫胺素（ThDP）、Mg 2+和黄素腺嘌呤二核苷酸（FAD）。AHAS是几类商业除草剂的靶标，包括磺酰脲和咪唑啉酮家族。这些除草剂是AHAS的有效和选择性抑制剂，Ki值可以在低nM范围内。此类化合物作为除草剂的施用率也较低（通常类似于3 g ha（-1）），并且具有较低的哺乳动物毒性（LD 50值通常>4g/kg），从而突出了它们作为杀菌剂的实用性和有效性。然而，考虑到AHAS在微生物代谢中的核心重要性，有些令人惊讶的是，没有这种酶的抑制剂被商业化为抗微生物剂。本文综述了细菌和真菌来源的AHAS的生化特性，分析了这些对催化作用至关重要的酶的结构特征，并提供了关于AHAS抑制剂的最新数据，这些抑制剂有可能被开发成抗菌治疗剂。
Acetohydroxyacid synthase (AHAS) (EC 2.2.1.6) (also known as acetolactate synthase) is the first common enzyme in the branched chain amino acid (BCAA) biosynthesis pathway. This pathway is present in microorganisms and in plants but not in animals, making it an attractive target for both drug and herbicide discovery. The function of AHAS is to catalyze the conversion of two molecules of pyruvate to 2-acetolactate or to convert one molecule of pyruvate and a molecule of 2-ketobutyrate into 2-aceto-2-hydroxybutyrate. Three cofactors are required for the activity of AHAS: thiamine diphosphate (ThDP), Mg2+ and flavin-adenine dinucleotide (FAD). AHAS is the target for several classes of commercial herbicides that include the sulfonylurea and imidazolinone families. These herbicides are potent and selective inhibitors of AHAS with K-i values that can be in the low nM range. Such compounds also exhibit low application rates as herbicides (typically similar to 3 g ha(-1)) and have low mammalian toxicity (LD50 values typically >4g/kg), thereby highlighting their utility and effectiveness as biocidal agents. However, somewhat surprisingly given the central importance of AHAS in the metabolism of microorganisms, no inhibitors of this enzyme have been commercialized into antimicrobial agents. Here we provide an overview of the biochemical characterization of AHASs from bacterial and fungal sources, analyse the structural features of these enzymes that are criticial to catalysis andprovide the current data on AHAS inhibitors that have potential to be developed into antimicrobial therapeutics.