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Structure, interactions and action of Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase

Srikalaivani, Rajapiramuthu and Singh, Amrita and Vijayan, Mamannamana and Surolia, Avadhesha (2018) Structure, interactions and action of Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase. In: BIOCHEMICAL JOURNAL, 475 (15). pp. 2457-2471.

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Official URL: http://dx.doi.org/10.1042/BCJ20180271


Biochemical and crystallographic studies on Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase (MtHIBADH), a member of the 3-hydroxyacid dehydrogenase superfamily, have been carried out. Gel filtration and blue native PAGE of MtHIBADH show that the enzyme is a dimer. The enzyme preferentially uses NAD(+) as the cofactor and is specific to S-hydroxyisobutyric acid (HIBA). It can also use R-HIBA, L-serine and 3-hydroxypropanoic acid (3-HP) as substrates, but with much less efficiency. The pH optimum for activity is similar to 11. Structures of the native enzyme, the holoenzyme, binary complexes with NAD(+), S-HIBA, R-HIBA, L-serine and 3-HP and ternary complexes involving the substrates and NAD(+) have been determined. None of the already known structures of HIBADH contain a substrate molecule at the binding site. The structures reported here provide for the first time, among other things, a clear indication of the location and interactions of the substrates at the active site. They also define the entrance of the substrates to the active site region. The structures provide information on the role of specific residues at the active site and the entrance. The results obtained from crystal structures are consistent with solution studies including mutational analysis. They lead to the proposal of a plausible mechanism of the action of the enzyme.

Item Type: Journal Article
Additional Information: Copy right for this article belong to PORTLAND PRESS LTD, CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 24 Sep 2018 15:37
Last Modified: 24 Sep 2018 15:37
URI: http://eprints.iisc.ac.in/id/eprint/60703

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