Acetohydroxyacid synthase: a target for antimicrobial drug discovery

• Published in: Current pharmaceutical design Vol. 20; no. 5; p. 740
• Main Authors: Pue, Nason, Guddat, Luke W
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-02-2014
• Subjects: Acetolactate Synthase - antagonists & inhibitors; Acetolactate Synthase - chemistry; Acetolactate Synthase - genetics; Acetolactate Synthase - metabolism; Animals; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antifungal Agents - adverse effects; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biocatalysis; Disinfectants - chemistry; Disinfectants - pharmacology; Disinfectants - toxicity; Drug Discovery; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Fungal; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - chemistry; Fungal Proteins - genetics; Fungal Proteins - metabolism; Herbicides - chemistry; Herbicides - pharmacology; Herbicides - toxicity; Humans; Models, Molecular; Molecular Conformation; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Plant Proteins - antagonists & inhibitors; Plant Proteins - chemistry; Plant Proteins - genetics; Plant Proteins - metabolism
• ISSN: 1873-4286
• DOI: 10.2174/13816128113199990009

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 Ki values that can be in the low nM range. Such compounds also exhibit low application rates as herbicides (typically ~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.