ArticleThe Journal of biological chemistry2014
The three Mycobacterium tuberculosis antigen 85 isoforms have unique substrates and activities determined by non-active site regions.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 68 citations in OpenAlex.
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- Trehalose catalytic shift inherently enhances phenotypic heterogeneity and multidrug resistance in Mycobacterium tuberculosis.Nature communications · 2025Article
- Intercepting a Mycobacterial Biosynthetic Pathway with Covalent Labeling.Journal of the American Chemical Society · 2025Article
- B Cell and Antibody Responses in Bovine Tuberculosis.Antibodies (Basel, Switzerland) · 2024Review
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- Molecular Mechanisms of MmpL3 Function and Inhibition.Microbial drug resistance (Larchmont, N.Y.) · 2023Review
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- Proton transfer activity of the reconstitutedProceedings of the National Academy of Sciences of the United States of America · 2022Article
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- Proteome characterization of the culture supernatant ofBiochemistry and biophysics reports · 2021Article
- Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes againstACS infectious diseases · 2021Article
- Structural basis of trehalose recycling by the ABC transporter LpqY-SugABC.Science advances · 2020Article
- Targeting MmpL3 for anti-tuberculosis drug development.Biochemical Society transactions · 2020Review
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Authors and funding
9 authors at 3 institutions in 6 countries.
Funding
Abstract
The three isoforms of antigen 85 (A, B, and C) are the most abundant secreted mycobacterial proteins and catalyze transesterification reactions that synthesize mycolated arabinogalactan, trehalose monomycolate (TMM), and trehalose dimycolate (TDM), important constituents of the outermost layer of the cellular envelope of Mycobacterium tuberculosis. These three enzymes are nearly identical at the active site and have therefore been postulated to exist to evade host immunity. Distal to the active site is a second putative carbohydrate-binding site of lower homology. Mutagenesis of the three isoforms at this second site affected both substrate selectivity and overall catalytic activity in vitro. Using synthetic and natural substrates, we show that these three enzymes exhibit unique selectivity; antigen 85A more efficiently mycolates TMM to form TDM, whereas C (and to a lesser extent B) has a higher rate of activity using free trehalose to form TMM. This difference in substrate selectivity extends to the hexasaccharide fragment of cell wall arabinan. Mutation of secondary site residues from the most active isoform (C) into those present in A or B partially interconverts this substrate selectivity. These experiments in combination with molecular dynamics simulations reveal that differences in the N-terminal helix α9, the adjacent Pro(216)-Phe(228) loop, and helix α5 are the likely cause of changes in activity and substrate selectivity. These differences explain the existence of three isoforms and will allow for future work in developing inhibitors.
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