Drugs against Mycobacterium tuberculosis 3-isopropylmalate dehydrogenase can be developed using homologous enzymes as surrogate targets.

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 physicalchemical 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.

journal_name

Protein Pept Lett

authors

Graczer E,Bacso A,Konya D,Kazi A,Soos T,Molnar L,Szimler T,Beinrohr L,Szilagyi A,Zavodszky P,Vas M

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

1295-307

issue

12

eissn

0929-8665

issn

1875-5305

pii

PPL-EPUB-60859

journal_volume

21

pub_type

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