Deciphering functional redundancy and energetics of malate oxidation in mycobacteria

Abstract

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. 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. Bacteria frequently encode multiple enzymes for the same metabolic reactions, but it is not understood whether such enzymes are functionally redundant or possess differential roles. A critical step in central metabolism is the oxidation of malate, which can be performed by either malate dehydrogenase (Mdh) or malate quinone oxidoreductase (Mqo). Bacteria can encode varying combinations of these enzymes, but the physiological consequences behind each permutation are not well understood. In this communication, we compared the role of malate oxidation in the fast-growing soil actinomycete Mycobacterium smegmatis, which encodes only Mqo, and the closely related slow-growing human pathogen Mycobacterium tuberculosis, which encodes both Mqo and Mdh. We show that energization of the electron transport chain by exergonic Mqo is critical for powering aerobic mycobacterial growth and that there is an energetic cost to using endergonic Mdh under these conditions. Mdh has been conserved by mycobacterial species that require growth and survival under diverse physiological states. The tricarboxylic acid (TCA) cycle, which links energy generation to carbon flux, is central to the carbon metabolism of many organisms in the communities responsible for essential life processes. In aerobic organisms, the TCA cycle is used to release stored chemical energy from acetyl-CoA (1Mailloux R.J. Beriault R. Lemire J. Singh R. Chenier D.R. Hamel R.D. Appanna V.D. The tricarboxylic acid cycle, an ancient metabolic network with a novel twist.PLoS One. 2007; 2e690Crossref PubMed Scopus (240) Google Scholar). Malate oxidation is a critical step for the completion of the TCA cycle and the regeneration of oxaloacetate. Two predominant enzymes have evolved that are capable of malate oxidation to oxaloacetate, malate dehydrogenase (Mdh) and malate quinone oxidoreductase (Mqo). Studies on malate oxidation have primarily focused on Mdh, while Mqo investigation has been limited. There is an alternative path for malate oxidation out of the TCA cycle using malic enzyme (Mez), a member of the anaphoretic node. Mez performs the oxidative decarboxylation of malate to pyruvate producing NAD(P)H from NADP (2Gourdon P. Baucher M.F. Lindley N.D. Guyonvarch A. Cloning of the malic enzyme gene from Corynebacterium glutamicum and role of the enzyme in lactate metabolism.Appl. Environ. Microbiol. 2000; 66: 2981-2987Crossref PubMed Scopus (80) Google Scholar). Mqo is a monotopic membrane protein that utilizes a FAD cofactor to couple malate oxidation to quinone reduction, thereby providing a link between central carbon metabolism and the electron transport chain (3Mogi T. Murase Y. Mori M. Shiomi K. Omura S. Paranagama M.P. Kita K. Polymyxin B identified as an inhibitor of alternative NADH dehydrogenase and malate: Quinone oxidoreductase from the Gram-positive bacterium Mycobacterium smegmatis.J. Biochem. 2009; 146: 491-499Crossref PubMed Scopus (48) Google Scholar, 4van der Rest M.E. Frank C. Molenaar D. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Escherichia coli.J. Bacteriol. 2000; 182: 6892-6899Crossref PubMed Scopus (84) Google Scholar, 5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar, 6Molenaar D. van der Rest M.E. Drysch A. Yucel R. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Corynebacterium glutamicum.J. Bacteriol. 2000; 182: 6884-6891Crossref PubMed Scopus (106) Google Scholar). Coupling malate oxidation to quinone reduction is exergonic (thermodynamically favorable) giving Mqo an energetic advantage over Mdh. Malate oxidation using Mdh is highly endergonic (unfavorable) when coupled to the reduction of NAD+ with an apparent standard Gibbs reaction energy of +30 kJ/mol at pH = 7 (5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar, 6Molenaar D. van der Rest M.E. Drysch A. Yucel R. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Corynebacterium glutamicum.J. Bacteriol. 2000; 182: 6884-6891Crossref PubMed Scopus (106) Google Scholar, 7Thauer R.K. Jungermann K. Decker K. Energy conservation in chemotrophic anaerobic bacteria.Bacteriol. Rev. 1977; 41: 100-180Crossref PubMed Google Scholar). Due to this thermodynamic unfavorability, Mdh has evolved mechanisms, in combination with other energetically favorable enzymes, such as crosstalk and substrate channeling to enable malate oxidation (8Wu F. Minteer S. Krebs cycle metabolon: Structural evidence of substrate channeling revealed by cross-linking and mass spectrometry.Angew. Chem. Int. Ed. Engl. 2015; 54: 1851-1854Crossref PubMed Scopus (96) Google Scholar, 9Wang Q. Yu L. Yu C.A. Cross-talk between mitochondrial malate dehydrogenase and the cytochrome bc1 complex.J. Biol. Chem. 2010; 285: 10408-10414Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Mqo and Mdh commonly co-occur within a single bacterium, with one enzyme being primarily responsible for malate oxidation (4van der Rest M.E. Frank C. Molenaar D. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Escherichia coli.J. Bacteriol. 2000; 182: 6892-6899Crossref PubMed Scopus (84) Google Scholar, 5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar). In Escherichia coli, Mdh is responsible for malate oxidation under aerobic conditions with Mqo having no prescribed role (4van der Rest M.E. Frank C. Molenaar D. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Escherichia coli.J. Bacteriol. 2000; 182: 6892-6899Crossref PubMed Scopus (84) Google Scholar). Conversely, in Corynebacterium glutamicum, Mqo is the primary driver of malate oxidation with Mdh proposed to operate in the reductive direction (5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar). Mez is also present in E. coli and does not take over the role of Mqo during growth (4van der Rest M.E. Frank C. Molenaar D. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Escherichia coli.J. Bacteriol. 2000; 182: 6892-6899Crossref PubMed Scopus (84) Google Scholar). Some bacteria such as Mycobacterium smegmatis, an environmental saprophyte, have lost the Mdh enzyme from their genome altogether, and no Mdh activity is detected in this bacterium (10Hards K. Adolph C. Harold L.K. McNeil M.B. Cheung C.Y. Jinich A. Rhee K.Y. Cook G.M. Two for the price of one: Attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents.Prog. Biophys. Mol. Biol. 2020; 152: 35-44Crossref PubMed Scopus (9) Google Scholar, 11Tian J. Bryk R. Itoh M. Suematsu M. Nathan C. Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: Identification of -ketoglutarate decarboxylase.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10670-10675Crossref PubMed Scopus (156) Google Scholar). Human pathogens from the same genus have lost Mqo (e.g., Mycobacterium leprae) or maintained both enzymes (e.g., Mycobacterium tuberculosis) (10Hards K. Adolph C. Harold L.K. McNeil M.B. Cheung C.Y. Jinich A. Rhee K.Y. Cook G.M. Two for the price of one: Attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents.Prog. Biophys. Mol. Biol. 2020; 152: 35-44Crossref PubMed Scopus (9) Google Scholar, 11Tian J. Bryk R. Itoh M. Suematsu M. Nathan C. Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: Identification of -ketoglutarate decarboxylase.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10670-10675Crossref PubMed Scopus (156) Google Scholar). is not understood of either enzyme or conservation of both enzymes for malate oxidation in mycobacterial In species such as M. tuberculosis Mdh to a reductive TCA cycle to produce fumarate for use as a terminal electron S. M. M.B. U. activity an membrane in anaerobic Mycobacterium Scopus Google Scholar). an alternative electron for M. tuberculosis in conditions of hypoxia thereby providing a to the membrane and In M. does not have the to either of these but has evolved alternative to such as M. C. R. Cook G.M. aerobic soil bacterium to reductive during Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M. Cook G.M. in energy metabolism mycobacteria to and One. 2010; Scopus Google Scholar, C. M. K. Cook G.M. R. A soil using Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In C. glutamicum, a of both functionally Mqo and Mdh enzymes are present and of malate and (5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar). Mqo is the most enzyme in C. glutamicum for malate and Mdh a role in reduction (5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar). The reaction of Mqo and Mdh is to oxidoreductase and a role as an or be in the of malate or (5Molenaar D. van der Rest M.E. Petrovic S. Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum.Eur. J. Biochem. 1998; 254: 395-403Crossref PubMed Scopus (86) Google Scholar). M. tuberculosis can also use Mqo and Mdh in combination to a cycle to a enzyme C. L. F. D. to and in 2005; PubMed Scopus Google Scholar). there is a between the energetic of Mqo and is in with use of the Mdh enzyme for malate we a study to the role of Mqo and Mdh in mycobacterial We performed a and energetic of the from M. and M. tuberculosis and Mdh to functional redundancy and the physiological role of Mqo and Mdh. a the and redundancy of Mqo and Mdh in we performed an of bacterial to the and of the enzymes revealed that Mdh is the for malate to being found in of bacterial species compared to of species of bacterial species possess both enzymes, and of species possess enzyme of species an Mqo with the in the and and Mqo was for in the with of species in of a mqo mycobacterial species out of M. and the Mycobacterium only Mqo of the species with a single Mqo are mycobacteria. In pathogenic mycobacteria both Mqo and Mdh enzymes with the of M. with a single Mdh, a bacterium that has reductive and be in The that both Mqo and Mdh use a reductive TCA cycle in conditions thereby conservation of these enzymes for both growth during energy and survival and during hypoxia The conservation of Mqo at the of Mdh in the that Mqo a critical role in carbon and energy metabolism for these the role of Mqo in mycobacterial we a gene of mqo in M. and of mqo and mdh in M. The M. Δmqo mutant was using a and using genome and to Mqo enzyme activity The chain activity of Mqo in M. was using membrane were with malate as the electron = of was that Mqo was and of the electron transport chain in M. A is by the chain at using but the level of activity was the endergonic of this reaction = in mycobacteria K. M. T. 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Mqo was a protein that malate coupled to the reduction of in the electron transport study oxygen consumption in and to the of Mqo on we both and oxygen consumption in the and Δmqo mutant of oxygen consumption were detected in the with both electron oxygen consumption was in the Δmqo mutant compared to the and oxygen consumption was the of the of mqo in the mutant We the Δmqo mutant further by the enzyme activity of Mqo by malate oxidation in coupled to The rate of malate oxidation in the was malate and this was reduced to malate protein in the Δmqo mutant These there was no of malate oxidation in the electron transport chain of M. and Mqo a on the other chain a physiological the Δmqo mutant growth compared to the on fermentable carbon sources, and no growth was on nonfermentable carbon sources of the Δmqo mutant on either or as the carbon and energy was delayed with a to the the growth of the Δmqo mutant the was the of a on these carbon sources, we the on and the on the fermentable carbon We the growth of these and found that the maintained the growth in the Δmqo mutant were not and that growth of the Δmqo mutant was a physiological for M. to malate in the TCA cycle in the of Mqo is to use Mez to the decarboxylation of malate to pyruvate with reduction of In M. tuberculosis, Mez is not for growth on or and the role proposed for this enzyme in M. tuberculosis is as a to produce NAD(P)H for P. A. Singh A. R. L. J. The is essential for the survival of Mycobacterium Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that Mez activity was not responsible for the growth of the M. Δmqo we the activity of Mez in the of the Δmqo mutant during the of and compared it to the We found that the Δmqo mutant activity of Mez to the it was not for the of Mqo with nonfermentable carbon sources malate, or the Δmqo mutant was to of the essential for a functional Mqo enzyme under these conditions this of growth on nonfermentable carbon sources was to the of to these carbon sources, were on and their with electron either or was used as an electron for the at a rate of protein and In the of the Δmqo mutant was protein and protein on and We from these that the Δmqo mutant reduced to nonfermentable carbon sources to growth. further these in we the of the by using the to the electron transport chain to of the the of Mycobacterium tuberculosis PubMed Scopus Google Scholar, K. M. L. 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We the of the as the between the and the either or as the electron the of by The Δmqo mutant as by the of of these data show that the Δmqo mutant a with electron that the electron transport growth on we that the Δmqo mutant the growth to a pH of in to pH for the that the Δmqo mutant was an end the growth We that the Δmqo mutant one or acid of the TCA cycle as the end the pH of the this we performed of and secreted for the Δmqo mutant and the malate was in the we detected of secreted malate in the growth of the Δmqo mutant the level of malate secreted we used a and found an of for the Δmqo compared to no for this malate of the carbon in the growth Furthermore, for both fumarate and the of malate in the TCA cycle, an of and in the Δmqo mutant to was the of these we the of TCA We found the TCA cycle were with of malate, and having an to of and the of to by an of and the of was mqo in of TCA cycle of the malate oxidation with of malate, and The of that a of carbon from to malate and the dehydrogenase and in the of malate S. C. J. D. Rhee K.Y. S. is an essential of malate for carbon in Mycobacterium Natl. Acad. Sci. U. S. A. PubMed Scopus Google the of the one of the and therefore it is to use as a for in metabolic the of is an to the of the functional of S. C. J. D. Rhee K.Y. S. is an essential of malate for carbon in Mycobacterium Natl. Acad. Sci. U. S. A. PubMed Scopus Google and is to the of malate in to These data that of mqo in M. a in the TCA cycle the to acid of the TCA cycle to growth on fermentable carbon sources. the of TCA does not a to growth on nonfermentable carbon sources. The in the pH of the growth to the of these a to down of of the electron transport chain as lowered oxygen consumption this be by the producing of to protein F. A. The of a mycobacterial 2005; PubMed Scopus Google a of the mycobacterial chain L. C. T. R. J. J. A member of the protein of in Mycobacterium tuberculosis is for in and of the gene for a Microbiol. 2005; PubMed Scopus Google Scholar, M. 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Full Text Full Text PDF PubMed Scopus Google Scholar). be with the growth on aerobic and the reduced in the M. Δmqo the to which Mqo and Mdh are functionally redundant in mycobacteria and use of the that M. only we whether the Δmqo mutant be with a of mdh from M. we genetic one to M. mqo and the other to M. tuberculosis mdh We found that both and resulted in of the Δmqo mutant to growth on the fermentable carbon sources and compared to the growth with the A and and were used for on the nonfermentable carbon sources malate and restored growth to on both carbon sources. was delayed with but at growth the and growth was in the Δmqo mutant and has no on growth of the and that the of the the growth of a C. glutamicum mqo but not in a mutant both Mqo and Mdh, Mdh can for Mqo when is in the growth D. van der Rest M.E. Drysch A. Yucel R. Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Corynebacterium glutamicum.J. Bacteriol. 2000; 182: 6884-6891Crossref PubMed Scopus (106) Google Scholar). was in growth we no on the growth of either the or the Δmqo mutant on either malate or and no of with Mdh in the Δmqo was that was in M. and the role of Mqo and Mdh in M. tuberculosis, we used CRISPR interference to the expression of either mqo mdh under growth conditions M.B. Cook G.M. of CRISPR interference to as a in Mycobacterium Scopus Google Scholar, A. M. G.M. D. in mycobacteria using an CRISPR interference Microbiol. PubMed Scopus Google Scholar). We single and of mqo and mdh in M. tuberculosis, with a essential gene and an We that the single were of their and from in A and we found that to the the mqo single resulted in an of while the mdh single an of A and The of both mqo and mdh resulted in an of mqo and of mdh A and of the mqo or mdh single evidence of to for the of the alternative gene A and these data that we were to the expression of either or both in combination in M. the of the single and of either mqo mdh on M. tuberculosis we with each of the on with either or as the primary carbon fermentable and nonfermentable and of the essential gene no growth under the conditions used as and M.B. Cook G.M. of CRISPR interference to as a in Mycobacterium Scopus Google Scholar). We found that on both carbon sources, of either mqo or mdh resulted in delayed and slower growth compared to the and of both mqo and mdh in combination on either carbon resulted in a growth compared to the and the gene mqo and mdh and we the growth rate of M. tuberculosis between and we found that of either mqo or mdh slower growth compared to the and the of both an in a slower growth rate the single and These data show that either Mqo or Mdh can be used to oxidation of malate in M. tuberculosis, but the growth rate is reduced compared to both enzymes there is functional of mqo and mdh on fermentable carbon sources that both enzymes are for growth of M. S. A to the metabolic to hypoxia in Mycobacterium Chem. Biol. Full Text Full Text PDF PubMed Scopus Google that Mdh is for the metabolism and survival of M. tuberculosis in and in chemical of M. tuberculosis Mdh the to growth and in and during of the S. A to the metabolic to hypoxia in Mycobacterium Chem. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). on we propose that the of an inhibitor of Mqo, in combination with Mdh the growth of M. tuberculosis further while activity In this Mqo is not found in and have been that the mitochondrial oxidoreductase of the K. Y. R.J. M. D. M. E. Y. A. of membrane mitochondrial a Biophys. PubMed Scopus Google Scholar). The between the human and mycobacterial Mdh enzymes S. A to the metabolic to hypoxia in Mycobacterium Chem. Biol. Full Text Full Text PDF PubMed Scopus Google a combination of Mqo and Mdh be for tuberculosis carbon metabolism is as a in mycobacterial metabolism with being identified as (10Hards K. Adolph C. Harold L.K. McNeil M.B. Cheung C.Y. Jinich A. Rhee K.Y. Cook G.M. Two for the price of one: Attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents.Prog. Biophys. Mol. Biol. 2020; 152: 35-44Crossref PubMed Scopus (9) Google Scholar, K. M. T. Cook G.M. of dehydrogenase in Mycobacterium and its role in the generation of the membrane under PubMed Scopus (48) Google Scholar, S. C. J. D. Rhee K.Y. S. is an essential of malate for carbon in Mycobacterium Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, R. C. S. P. Rhee K.Y. S. protein and and Mycobacterium Chem. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Rhee K.Y. of metabolism in to hypoxia in Mycobacterium Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). We that Mqo is in and in Mqo is over Mdh. the mqo gene of M. was it growth of and an of and M. tuberculosis mdh was to functionally mqo in M. on nonfermentable carbon sources. In M. tuberculosis when either mqo or mdh was there was a slower growth rate compared to the which was lowered further when both enzymes were in these data that Mqo is critical for growth and carbon metabolism in and of malate oxidation to central carbon In M. tuberculosis, it has been that Mdh is critical to its survival during of hypoxia to the reductive TCA cycle activity S. A to the metabolic to hypoxia in Mycobacterium Chem. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). data that in to using Mdh for reductive TCA under M. tuberculosis can use Mdh for oxidation of malate during aerobic growth Mqo is

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