Functional evaluation of residues in the herbicide-binding site of Mycobacterium tuberculosis acetohydroxyacid synthase by site-directed mutagenesis

Jung, In-Pil; Cho, Jun‐Haeng; Koo, Bon‐Sung; Yoon, Moon‐Young

doi:10.1016/j.enzmictec.2015.06.009

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…Branched‐chain amino acid synthesis can be blocked by AHAS inhibition, which can result in an influence on protein synthesis. Hence the plant will eventually undergo necrosis and death . Since the first launch of DPX‐4189 by DuPont in 1978, the discovery of novel AHAS inhibitors has been the hot topic in new agrochemical discovery.…”

Section: Introductionmentioning

confidence: 99%

Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant

Yang

Liu

et al. 2016

Pest. Manag. Sci.

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Section: Introductionmentioning

confidence: 99%

Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant

Yang

Liu

et al. 2016

Pest. Manag. Sci.

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“…Site‐directed mutations of this arginine residue in E. coli AHAS II failed in accepting the second substrate (Engel et al., ). In addition, this residue mutations in Mycobacterium tuberculosis AHAS all led to a complete loss of AHAS activity (Jung, Cho, Koo, & Yoon, ). The conserved sites shown in Figure are important for the catalytic activity.…”

Section: Resultsmentioning

confidence: 99%

Molecular evolution of acetohydroxyacid synthase in bacteria

Liu

Wang

2017

MicrobiologyOpen

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Acetohydroxyacid synthase (AHAS) is the key enzyme in the biosynthetic pathways of branched chain amino acids in bacteria. Since it does not exist in animal and plant cells, AHAS is an attractive target for developing antimicrobials and herbicides. In some bacteria, there is a single copy of AHAS, while in others there are multiple copies. Therefore, it is necessary to investigate the origin and evolutionary pathway of various AHASs in bacteria. In this study, all the available protein sequences of AHAS in bacteria were investigated, and an evolutionary model of AHAS in bacteria is proposed, according to gene structure, organization and phylogeny. Multiple copies of AHAS in some bacteria might be evolved from the single copy of AHAS, the ancestor. Gene duplication, domain deletion and horizontal gene transfer might occur during the evolution of this enzyme. The results show the biological significance of AHAS, help to understand the functions of various AHASs in bacteria, and would be useful for developing industrial production strains of branched chain amino acids or novel antimicrobials.

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“…It has been reported that six residues [ARG199, methionine (MET)200, lysin (KLS)256, aspartic acid (ASP)376, ARG377, and tryptophan (TRP)574)] in AtALS are vital for directly interacting with the sulfonylurea herbicides (43). Mutations at amino acid residues [ARG318, alanine (ALA)146, GLN148, MET512, and valine (VAL)513)] in Mycobacterium tuberculosis ALS led to signi cant herbicide resistance against chlorimuron ethyl (44). The structure of ScALS co-crystallized with chlorimuron ethyl has been revealed (32).…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Analysis of Skin Malodor-Associated Compounds and Structure-based Prediction of Acetolactate Synthase Selective Sulfonylurea Inhibitors

Huang

2021

Preprint

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Bromhidrosis is characterized as a chronic condition related to malodor from the skin. The underlying etiology is from bacterial decompositions of glandular secretion products. However, specific pathways and metabolites for the disease are yet to be investigated. Here, twenty-eight metabolites, including fifteen major sweat constituents and thirteen compounds emitted from malodor-producing skin bacteria, were subjected to the metabometric analysis using Metaboanalyst. Different pathways in the butanoate metabolism revealed that acetolactate synthase (ALS) in skin Staphylococcus epidermidis (S. epidermidis) bacteria are catalyzing pyruvate to several malodor compounds like diacetyl. In the docking studies of the sulfonylurea-ALS interaction, five selected sulfonylureas, which originally were developed for the treatment of diabetes mellitus type 2, showed different binding free energies (ΔG) from chlorimuron ethyl - a well-known ALS sulfonylurea inhibitor. Amongst five sulfonylureas, gliquidone and glisoxepide were found to have free energy differences that were lower than or equal to chlorimuron ethyl, revealing their high affinities to ALS. In the future, further investigations of gliquidone and glisoxepide against ALS in skin bacteria would be crucial in repurposing these two sulfonylureas as new anti-bromhidrosis drugs.

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Functional evaluation of residues in the herbicide-binding site of Mycobacterium tuberculosis acetohydroxyacid synthase by site-directed mutagenesis

Cited by 9 publications

References 21 publications

Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant

Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant

Molecular evolution of acetohydroxyacid synthase in bacteria

Metabolomic Analysis of Skin Malodor-Associated Compounds and Structure-based Prediction of Acetolactate Synthase Selective Sulfonylurea Inhibitors

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