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Publication Abstract from PubMed

Lysine varepsilon-aminotransferase (LAT) converts lysine to alpha-aminoadipate-delta-semialdehyde in a PLP-mediated reaction. We mutated active-site T330, N328 and E243, and structurally rationalized their properties. T330A and T330S mutants cannot bind PLP and are inactive. N328A although inactive, binds to PLP. E243A retains activity, but binds alpha-ketoglutarate in a different conformation. We had earlier identified 2-aminomethyl piperidine derivative as a LAT inhibitor. The co-crystal structure reveals that it mimics binding of C5 substrates and exhibits two binding modes. E243, that shields R422 in the apo enzyme, exhibits conformational changes to permit the binding of the inhibitor in one of the binding modes. Structure-based analysis of bound water in the active site suggests optimization strategies for synthesis of improved inhibitors.

Mutational analysis of Mycobacterium tuberculosis lysine varepsilon-aminotransferase and inhibitor co-crystal structures, reveals distinct binding modes.,Tripathi SM, Agarwal A, Ramachandran R Biochem Biophys Res Commun. 2015 Jul 17-24;463(1-2):154-60. doi:, 10.1016/j.bbrc.2015.05.055. Epub 2015 May 20. PMID:26003725^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.