Deciphering functional redundancy and energetics of malate oxidation in mycobacteria.

Autor:	Harold LK; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. Electronic address: liamharold@gmail.com., Jinich A; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Hards K; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand., Cordeiro A; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Keighley LM; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., Cross A; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., McNeil MB; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand., Rhee K; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Cook GM; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. Electronic address: greg.cook@otago.ac.nz.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 May; Vol. 298 (5), pp. 101859. Date of Electronic Publication: 2022 Mar 23.
DOI:	10.1016/j.jbc.2022.101859
Abstrakt:	Oxidation of malate to oxaloacetate, catalyzed by either malate dehydrogenase (Mdh) or malate quinone oxidoreductase (Mqo), is a critical step of the tricarboxylic acid cycle. Both Mqo and Mdh are found in most bacterial genomes, but the level of functional redundancy between these enzymes remains unclear. A bioinformatic survey revealed that Mqo was not as widespread as Mdh in bacteria but that it was highly conserved in mycobacteria. We therefore used mycobacteria as a model genera to study the functional role(s) of Mqo and its redundancy with Mdh. We deleted mqo from the environmental saprophyte Mycobacterium smegmatis, which lacks Mdh, and found that Mqo was essential for growth on nonfermentable carbon sources. On fermentable carbon sources, the Δmqo mutant exhibited delayed growth and lowered oxygen consumption and secreted malate and fumarate as terminal end products. Furthermore, heterologous expression of Mdh from the pathogenic species Mycobacterium tuberculosis shortened the delayed growth on fermentable carbon sources and restored growth on nonfermentable carbon sources at a reduced growth rate. In M. tuberculosis, CRISPR interference of either mdh or mqo expression resulted in a slower growth rate compared to controls, which was further inhibited when both genes were knocked down simultaneously. These data reveal that exergonic Mqo activity powers mycobacterial growth under nonenergy limiting conditions and that endergonic Mdh activity complements Mqo activity, but at an energetic cost for mycobacterial growth. We propose Mdh is maintained in slow-growing mycobacterial pathogens for use under conditions such as hypoxia that require reductive tricarboxylic acid cycle activity. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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