Characterization of the N-acetyl-α-d-glucosaminyll-malate synthase and deacetylase functions for bacillithiol biosynthesis in Bacillus anthracis

Parsonage, Derek, Newton, Gerald L., Holder, Robert C., Wallace, Bret D., Paige, Carleitta, Hamilton, Christopher, Dos Santos, Patricia C., Redinbo, Matthew R., Reid, Sean D. and Claiborne, Al (2010) Characterization of the N-acetyl-α-d-glucosaminyll-malate synthase and deacetylase functions for bacillithiol biosynthesis in Bacillus anthracis. Biochemistry, 49 (38). pp. 8398-8414.

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Abstract

Bacillithiol (Cys-GlcN-malate, BSH) has recently been identified as a novel low-molecular weight thiol in Bacillus anthracis, Staphylococcus aureus, and several other Gram-positive bacteria lacking glutathione and mycothiol. We have now characterized the first two enzymes for the BSH biosynthetic pathway in B. anthracis, which combine to produce a-d-glucosaminyl l-malate (GlcN-malate) from UDP-GlcNAc and l-malate. The structure of the GlcNAc-malate intermediate has been determined, as have the kinetic parameters for the BaBshA glycosyltransferase (?GlcNAc-malate) and the BaBshB deacetylase (?GlcN-malate). BSH is one of only two natural products reported to contain a malyl glycoside, and the crystal structure of the BaBshA-UDP-malate ternary complex, determined in this work at 3.3 Å resolution, identifies several active-site interactions important for the specific recognition of l-malate, but not other a-hydroxy acids, as the acceptor substrate. In sharp contrast to the structures reported for the GlcNAc-1-d-myo-inositol-3-phosphate synthase (MshA) apo and ternary complex forms, there is no major conformational change observed in the structures of the corresponding BaBshA forms. A mutant strain of B. anthracis deficient in the BshA glycosyltransferase fails to produce BSH, as predicted. This B. anthracis bshA locus (BA1558) has been identified in a transposon-site hybridization study as required for growth, sporulation, or germination [Day, W. A., Jr., Rasmussen, S. L., Carpenter, B. M., Peterson, S. N., and Friedlander, A. M. (2007) J. Bacteriol. 189, 3296-3301], suggesting that the biosynthesis of BSH could represent a target for the development of novel antimicrobials with broad-spectrum activity against Gram-positive pathogens like B. anthracis. The metabolites that function in thiol redox buffering and homeostasis in Bacillus are not well understood, and we present a composite picture based on this and other recent work.

Item Type:	Article
Uncontrolled Keywords:	escherichia-coli,molecular-weight thiol,iii pantothenate kinase,substrate-specificity,mycothiol biosynthesis,mycobacterium-tuberculosis,a-disulfide reductase,staphylococcus-aureus,crystal-structure,transcriptional responses,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Depositing User:	Rachel Smith
Date Deposited:	17 Mar 2011 11:12
Last Modified:	24 Sep 2024 09:08
URI:	https://ueaeprints.uea.ac.uk/id/eprint/26476
DOI:	10.1021/bi100698n

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