NDLI: Role of Serine140 in the mode of action of Mycobacterium tuberculosis β-ketoacyl-ACP Reductase (MabA)

Content Provider	Springer Nature : BioMed Central
Author	Rosado, Leonardo A Caceres, Rafael Andrade de Azevedo, Walter Filgueira Basso, Luiz A Santos, Diógenes S
Abstract	Background Tuberculosis (TB) still remains one of the most deadly infectious diseases in the world. Mycobacterium tuberculosis β-ketoacyl-ACP Reductase (MabA) is a member of the fatty acid elongation system type II, providing precursors of mycolic acids that are essential to the bacterial cell growth and survival. MabA has been shown to be essential for M. tuberculosis survival and to play a role in intracellular signal transduction of bacilli. Findings Here we describe site-directed mutagenesis, recombinant protein expression and purification, steady-state kinetics, fluorescence spectroscopy, and molecular modeling for S140T and S140A mutant MabA enzymes. No enzyme activity could be detected for S140T and S140A. Although the S140T protein showed impaired NADPH binding, the S140A mutant could bind to NADPH. Computational predictions for NADPH binding affinity to WT, S140T and S140A MabA proteins were consistent with fluorescence spectroscopy data. Conclusions The results suggest that the main role of the S140 side chain of MabA is in catalysis. The S140 side chain appears to also play an indirect role in NADPH binding. Interestingly, NADPH titrations curves shifted from sigmoidal for WT to hyperbolic for S140A, suggesting that the S140 residue may play a role in displacing the pre-existing equilibrium between two forms of MabA in solution. The results here reported provide a better understanding of the mode of action of MabA that should be useful to guide the rational (function-based) design of inhibitors of MabA enzyme activity which, hopefully, could be used as lead compounds with anti-TB action.
Related Links	https://bmcresnotes.biomedcentral.com/counter/pdf/10.1186/1756-0500-5-526.pdf
Ending Page	10
Page Count	10
Starting Page	1
File Format	HTM / HTML
ISSN	17560500
DOI	10.1186/1756-0500-5-526
Journal	BMC Research Notes
Issue Number	1
Volume Number	5
Language	English
Publisher	BioMed Central
Publisher Date	2012-09-25
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health Life Sciences Mycobacterium tuberculosis β-Ketoacyl-ACP Reductase MabA Site-directed mutagenesis Enzyme activity Fluorescence spectroscopy Molecular modeling Medicine/Public Health
Content Type	Text
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	1.6/2023

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