Drugs Against Mycobacterium Tuberculosis 3-Isopropylmalate Dehydrogenase Can be Developed using Homologous Enzymes as Surrogate Targets

ISSN: 1875-5305 (Online)
ISSN: 0929-8665 (Print)


Volume 21, 12 Issues, 2014


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Protein & Peptide Letters

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Drugs Against Mycobacterium Tuberculosis 3-Isopropylmalate Dehydrogenase Can be Developed using Homologous Enzymes as Surrogate Targets

Author(s): Éva Gráczer, András Bacsó, Dénes Kónya, Adrián Kazi, Tibor Soós, Laura Molnár, Tamás Szimler, László Beinrohr, András Szilágyi, Péter Závodszky and Mária Vas

Affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences H-1117 Budapest, Magyar tudósok körútja 2

Abstract

3-Isopropylmalate dehydrogenase (IPMDH) from Mycobacterium tuberculosis (Mtb) may be a target for specific drugs against this pathogenic bacterium. We have expressed and purified Mtb IPMDH and determined its physical-chemical and enzymological properties. Size-exclusion chromatography and dynamic light scattering measurements (DLS) suggest a tetrameric structure for Mtb IPMDH, in contrast to the dimeric structure of most IPMDHs. The kinetic properties (kcat and Km values) of Mtb IPMDH and the pH-dependence of kcat are very similar to both Escherichia coli (Ec) and Thermus thermophilus (Tt) IPMDHs. The stability of Mtb IPMDH in 8 M urea is close to that of the mesophilic counterpart, Ec IPMDH, both of them being much less stable than the thermophilic (Tt) enzyme. Two known IPMDH inhibitors, O-methyl oxalohydroxamate and 3-methylmercaptomalate, have been synthesised. Their inhibitory effects were found to be independent of the origin of IPMDHs. Thus, experiments with either Ec or Tt IPMDH would be equally relevant for designing specific inhibitory drugs against Mtb IPMDH


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Article Details

Volume: 21
First Page: 1
Last Page: 1
Page Count: 1
DOI: 10.2174/0929866521666140606111019
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