Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair

Ruetz, Markus; Campanello, Gregory C.; Purchal, Meredith; Shen, Haihong; McDevitt, Liam; Gouda, Harsha; Wakabayashi, Shoko; Zhu, Junhao; Rubín, Eric J.; Warncke, Kurt; Mootha, Vamsi K.; Koutmos, Markos; Banerjee, Ruma

doi:10.1126/science.aay0934

Cited by 90 publications

(131 citation statements)

References 57 publications

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“…Notably, our novel observation that DCA decreased levels of the recently discovered catabolic mediator itaconate without repressing expression of Irg1 mRNA or protein are compatible with the notion that post‐translational mechanisms may decrease this TCA cycle reprogramming intermediate. In support of this is a recent report that itaconate can be is metabolized to itaconyl CoA in prokaryotes and mammalian cells and alters level of vitamin B12 . That DCA reduces itaconate while concomitantly increasing TCA cycle intermediates provides a possible mechanistic explanation for our recent reported discovery that targeting PDC by DCA increases anabolic bioenergetics in isolated hepatocytes and splenocyte preparations while improving survival in septic mice .…”

Section: Discussionsupporting

confidence: 67%

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Zhu

Long

Zabalawi

et al. 2020

Journal of Leukocyte Biology

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The pyruvate dehydrogenase complex (PDC)/pyruvate dehydrogenase kinase (PDK) axis directs the universal survival principles of immune resistance and tolerance in monocytes by controlling anabolic and catabolic energetics. Immune resistance shifts to immune tolerance during inflammatory shock syndromes when inactivation of PDC by increased PDK activity disrupts the tricarboxylic acid (TCA) cycle support of anabolic pathways. The transition from immune resistance to tolerance also diverts the TCA cycle from citrate‐derived cis‐aconitate to itaconate, a recently discovered catabolic mediator that separates the TCA cycle at isocitrate and succinate dehydrogenase (SDH). Itaconate inhibits succinate dehydrogenase and its anabolic role in mitochondrial ATP generation. We previously reported that inhibiting PDK in septic mice with dichloroacetate (DCA) increased TCA cycle activity, reversed septic shock, restored innate and adaptive immune and organ function, and increased survival. Here, using unbiased metabolomics in a monocyte culture model of severe acute inflammation that simulates sepsis reprogramming, we show that DCA‐induced activation of PDC restored anabolic energetics in inflammatory monocytes while increasing TCA cycle intermediates, decreasing itaconate, and increasing amino acid anaplerotic catabolism of branched‐chain amino acids (BCAAs). Our study provides new mechanistic insight that the DCA‐stimulated PDC homeostat reconfigures the TCA cycle and promotes anabolic energetics in monocytes by reducing levels of the catabolic mediator itaconate. It further supports the theory that PDC is an energy sensing and signaling homeostat that restores metabolic and energy fitness during acute inflammation.

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Section: Discussionsupporting

confidence: 67%

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Zhu

Long

Zabalawi

et al. 2020

Journal of Leukocyte Biology

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“…Itaconyl-CoA, a derivative of a newly discovered mammalian metabolite, itaconate, inhibits B12dependent methylmalonyl-CoA mutase [14].…”

Section: Enzymementioning

confidence: 99%

“…The acyl groups formed during the metabolism of glucose, amino acids and fatty acids in human cells and those produced by gut microbiota are attached to CoA-SH to form its thioester derivatives, such as acetyl-CoA, succinyl-CoA, propionyl-CoA, isovaleryl-CoA, isobutyryl-CoA, αmethylbutyryl-CoA, and fatty acyl-CoA (commonly referred to as acyl-CoA), e.g., palmitoyl-, oleoyl-, and stearoyl-CoA ( Figure 1A). Itaconyl-CoA, a derivative of a newly discovered mammalian metabolite, itaconate, inhibits B12dependent methylmalonyl-CoA mutase [14].…”

Section: Enzymementioning

confidence: 99%

The Pathophysiological Role of CoA

Czumaj

Szrok-Jurga

Hebanowska

et al. 2020

IJMS

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The importance of coenzyme A (CoA) as a carrier of acyl residues in cell metabolism is well understood. Coenzyme A participates in more than 100 different catabolic and anabolic reactions, including those involved in the metabolism of lipids, carbohydrates, proteins, ethanol, bile acids, and xenobiotics. However, much less is known about the importance of the concentration of this cofactor in various cell compartments and the role of altered CoA concentration in various pathologies. Despite continuous research on these issues, the molecular mechanisms in the regulation of the intracellular level of CoA under pathological conditions are still not well understood. This review summarizes the current knowledge of (a) CoA subcellular concentrations; (b) the roles of CoA synthesis and degradation processes; and (c) protein modification by reversible CoA binding to proteins (CoAlation). Particular attention is paid to (a) the roles of changes in the level of CoA under pathological conditions, such as in neurodegenerative diseases, cancer, myopathies, and infectious diseases; and (b) the beneficial effect of CoA and pantethine (which like CoA is finally converted to Pan and cysteamine), used at pharmacological doses for the treatment of hyperlipidemia.

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“…Given that these four nutrients are not normally used as metabolites, it can be argued that these molecules may be inhibitors that slow down metabolism as either drug-like or signal molecules. Indeed, in case of itaconic acid, the ability of such chemical derivatives of metabolites to inhibit the bacterial growth through metabolic interference has been previously demonstrated [57]. The other explanation, which may be the reason for glyoxylic acid, is that these nutrients themselves tune down the metabolism through feedback.…”

Section: Discussionmentioning

confidence: 96%

Metabolic profiling reveals nutrient preferences during carbon utilization inBacillusspecies

Chang

Vaughan

Liu

et al. 2020

Preprint

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Pathogenic bacteria take host nutrients to support their growth, division, survival, and pathogenesis. The genus Bacillus includes species with diverse natural histories, including free-living nonpathogenic heterotrophs such as B. subtilis and host-dependent pathogens such as B. anthracis (the etiological agent of the disease anthrax) and B. cereus, a cause of food poisoning. Although highly similar genotypically, the ecological niches of these three species are mutually exclusive, which raises the untested hypothesis that their metabolism has speciated along a nutritional tract. Here, we employed a quantitative measurement of the number of reducing equivalents as a function of growth on hundreds of different sources of carbon to gauge the “culinary preferences” of three distinct Bacillus species, and related Staphylococcus aureus. We show that each species had widely varying metabolic ability to utilize diverse sources of carbon that correlated to their ecological niches. In addition, carbohydrates are shown to be the preferred sources of carbon when grown under ideal in vitro conditions. Rather unexpectedly, these metabolic utilizations did not correspond one-to-one with an increase in biomass, which brings to question what cellular activity should be considered productive when it comes to virulence. Finally, we applied this system to the growth and survival of B. anthracis in a blood-based environment and find that amino acids become the preferred source of energy while demonstrating the possibility of applying this approach to identifying xenobiotics or host compounds that can promote or interfere with bacterial metabolism during infection.Author summarySuccessful organisms must make nutritional adaptations to thrive in their environment. Bacterial pathogens are no exception, having evolved for survival inside their hosts. The host combats these pathogens by depriving them of potential biochemical resources, termed nutritional immunity. This places pathogens under pressure to utilize their resources efficiently and strategically, and their metabolism must in turn be tailored for this situation. In this study, we examined the carbon metabolism of three human pathogens of varying virulence (Bacillus anthracis, Bacillus cereus, and Staphylococcus aureus) and one nonpathogenic Bacillus (Bacillus subtilis) via a phenotype microarray that senses reducing equivalents produced during metabolism. Our analysis shows the existence of distinct preferences by these pathogens towards only a select few carbohydrates and implies reliance on specific metabolic pathways. These metabolic signatures obtained could be distinguished from one bacterial species to another, and we conclude that nutrient preferences offer a new perspective into investigating how pathogens can thrive during infection despite host-induced starvation.

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Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair

Cited by 90 publications

References 57 publications

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

The Pathophysiological Role of CoA

Metabolic profiling reveals nutrient preferences during carbon utilization inBacillusspecies

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