Structures of fungal and plant acetohydroxyacid synthases

Lonhienne, Thierry; Low, Yu Shang; García, Mario D.; Croll, Tristan I.; Gao, Yan; Wang, Quan; Brillault, Lou; Williams, Craig M.; Fraser, James A.; McGeary, Ross P.; West, Nicholas P.; Landsberg, Michael J.; Rao, Zihe; Schenk, Gerhard; Guddat, Luke W.

doi:10.1038/s41586-020-2514-3

Cited by 43 publications

(40 citation statements)

References 23 publications

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“…ScALS (ID:6U9D) is composed of catalytic and regulatory subunits. Each subunit contains multiple chains (30). Other known amino acids such as LYS251 and ARG380 in ScALS for the binding of chlorimuron ethyl were not identi ed in this study.…”

Section: Discussionmentioning

confidence: 93%

“…The crystal structures of Arabidopsis thaliana ALS (AtALS) and Saccharomyces cerevisiae ALS (ScALS) binding with/without various inhibitors have been revealed (28, 29). Furthermore, the ALS complex of Mycobacterium tuberculosis shared a similar structure, suggesting that the overall ALS structure is conserved across kingdoms (30). These inhibitors of ALS were ultimately developed as herbicides or antimicrobials (31).…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that developed herbicides that impede ALS are not competitive inhibitors and have no shared binding sites with substrates, suggesting that they bind at a region distinct from the active site (26). Through the structure-based studies of the interaction of chain A, the catalytic subunit of ALS (30) with ve sulfonylurea derivatives (gliquidone, glisoxepide, metahexamide, tolbutamide, and chlorpropamide) that have been used for the treatment of diabetes mellitus type 2, we found that these ve sulfonylurea derivatives bind at amino acid residues that were different from the ones for the binding of substrates including magnesium, avin-adenine dinucleotide (FAD) and thiamine diphosphate (ThDP) (data not shown). The free energy of gliquidone or glisoxepide for ALS binding was lower than or equal to that of chlorimuron ethyl, illustrating gliquidone and glisoxepide as potential inhibitors of ALS in skin bacteria.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Huang

2021

Preprint

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“…Previous studies have shown that the catalytic subunits of Saccharomyces cerevisiae AHAS crystallize as dimer 17 , while A. thaliana and C. albicans AHAS catalytic subunits crystallize as tetramers 13 , 18 . However, in general AHAS complexes adopt the shape of a Maltese cross where the active form of the CSU is dimeric 19 . This suggests that the tetrameric form of the catalytic subunit observed at higher concentrations in A. thaliana and C. albicans crystal structures 12 , 13 , 18 , and here through SEC-MALS of Afu AHAS, may not represent a physiologically active form of the enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…The continuous spectrophotometric method (see above) was used to determine the K M of the substrate, pyruvate. The FAD of Afu AHAS was fully reduced to remove the lag phase prior to measuring the rates 19 . 100 µL of assay mixture was incubated at 30 °C at varying pyruvate concentrations (0.03–200 mM) containing 6.6 µM Afu AHAS.…”

Section: Methodsmentioning

confidence: 99%

Triazolopyrimidine herbicides are potent inhibitors of Aspergillus fumigatus acetohydroxyacid synthase and potential antifungal drug leads

Low

García

Lonhienne

et al. 2021

Sci Rep

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Aspergillus fumigatus is a fungal pathogen whose effects can be debilitating and potentially fatal in immunocompromised patients. Current drug treatment options for this infectious disease are limited to just a few choices (e.g. voriconazole and amphotericin B) and these themselves have limitations due to potentially adverse side effects. Furthermore, the likelihood of the development of resistance to these current drugs is ever present. Thus, new treatment options are needed for this infection. A new potential antifungal drug target is acetohydroxyacid synthase (AHAS; EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, and a target for many commercial herbicides. In this study, we have expressed, purified and characterised the catalytic subunit of AHAS from A. fumigatus and determined the inhibition constants for several known herbicides. The most potent of these, penoxsulam and metosulam, have Ki values of 1.8 ± 0.9 nM and 1.4 ± 0.2 nM, respectively. Molecular modelling shows that these compounds are likely to bind into the herbicide binding pocket in a mode similar to Candida albicans AHAS. We have also shown that these two compounds inhibit A. fumigatus growth at a concentration of 25 µg/mL. Thus, AHAS inhibitors are promising leads for the development of new anti-aspergillosis therapeutics.

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Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol–Acid Reductoisomerase

Lin

Kurz

Patel

et al. 2021

Chemistry A European J

Self Cite

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New drugs aimed at novel targets are urgently needed to combat the increasing rate of drug‐resistant tuberculosis (TB). Herein, the National Cancer Institute Developmental Therapeutic Program (NCI‐DTP) chemical library was screened against a promising new target, ketol–acid reductoisomerase (KARI), the second enzyme in the branched‐chain amino acid (BCAA) biosynthesis pathway. From this library, 6‐hydroxy‐2‐methylthiazolo[4,5‐d]pyrimidine‐5,7(4H,6H)‐dione (NSC116565) was identified as a potent time‐dependent inhibitor of Mycobacterium tuberculosis (Mt) KARI with a Ki of 95.4 nm. Isothermal titration calorimetry studies showed that this inhibitor bound to MtKARI in the presence and absence of the cofactor, nicotinamide adenine dinucleotide phosphate (NADPH), which was confirmed by crystal structures of the compound in complex with closely related Staphylococcus aureus KARI. It is also shown that NSC116565 inhibits the growth of H37Ra and H37Rv strains of Mt with MIC50 values of 2.93 and 6.06 μm, respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti‐TB drug development.

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Structures of fungal and plant acetohydroxyacid synthases

Cited by 43 publications

References 23 publications

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

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

Triazolopyrimidine herbicides are potent inhibitors of Aspergillus fumigatus acetohydroxyacid synthase and potential antifungal drug leads

Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol–Acid Reductoisomerase

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