Loving the poison: the methylcitrate cycle and bacterial pathogenesis

Dolan, Stephen K.; Wijaya, Andre; Geddis, Stephen M.; Spring, David R.; Silva‐Rocha, Rafael; Welch, Martin

doi:10.1099/mic.0.000604

Cited by 45 publications

(44 citation statements)

References 67 publications

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“…Propionyl-CoA is a substrate for odd-chain fatty acid biosynthesis (Dolan et al, 2018) and this fate is consistent with a differential expression of several genes encoding enzymes involved in lipid metabolism ( Figs 4A and S2A, B). Surprisingly, among those, the only genes that have been functionally characterised are the ones involved in lipid biosynthesis (Supplementary file 5).…”

Section: Discussionsupporting

confidence: 76%

“…The induction of methylcitrate cycle enzymes and transcriptional activator was unexpected. In bacteria, the methylcitrate cycle is considered a detoxification pathway responsible for the degradation of propionate, which is generated during catabolism of certain lipids (Dolan et al , ). In Mtb, propionyl‐CoA is thought to be derived from β‐oxidation of odd‐chain fatty acids, degradation of host cholesterol and catabolism of branched amino acids.…”

Section: Resultsmentioning

confidence: 99%

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Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism

Serafini

Tan²,

Horswell

et al. 2019

Molecular Microbiology

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SummaryBacterial nutrition is an essential aspect of host–pathogen interaction. For the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans, fatty acids derived from lipid droplets are considered the major carbon source. However, many other soluble nutrients are available inside host cells and may be used as alternative carbon sources. Lactate and pyruvate are abundant in human cells and fluids, particularly during inflammation. In this work, we study Mtb metabolism of lactate and pyruvate combining classic microbial physiology with a ‘multi‐omics’ approach consisting of transposon‐directed insertion site sequencing (TraDIS), RNA‐seq transcriptomics, proteomics and stable isotopic labelling coupled with mass spectrometry‐based metabolomics. We discovered that Mtb is well adapted to use both lactate and pyruvate and that their metabolism requires gluconeogenesis, valine metabolism, the Krebs cycle, the GABA shunt, the glyoxylate shunt and the methylcitrate cycle. The last two pathways are traditionally associated with fatty acid metabolism and, unexpectedly, we found that in Mtb the methylcitrate cycle operates in reverse, to allow optimal metabolism of lactate and pyruvate. Our findings reveal a novel function for the methylcitrate cycle as a direct route for the biosynthesis of propionyl‐CoA, the essential precursor for the biosynthesis of the odd‐chain fatty acids.

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism

Serafini

Tan²,

Horswell

et al. 2019

Molecular Microbiology

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“…From our data, we conclude that methylmalonyl-CoA is formed from succinyl-CoA by methylmalonyl-CoA mutase, eventually as response to TCA cycle activity. Propionyl-CoA, the potentially alternative source for methylmalonyl-CoA via propionyl-CoA carboxylase was proven absent so that this route can be excluded, matching with the fact that propionyl-CoA typically occurs as catabolic intermediate during the degradation of odd-chain fatty acids [38,39] and branched-chain amino acids [40], not present here.…”

Section: The High Abundance Of Methylmalonyl-coa In C Glutamicum Is mentioning

confidence: 66%

A common approach for absolute quantification of short chain CoA thioesters in prokaryotic and eukaryotic microbes

et al. 2020

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Background: Thioesters of coenzyme A participate in 5% of all enzymatic reactions. In microbial cell factories, they function as building blocks for products of recognized commercial value, including natural products such as polyketides, polyunsaturated fatty acids, biofuels, and biopolymers. A core spectrum of approximately 5-10 short chain thioesters is present in many microbes, as inferred from their genomic repertoire. The relevance of these metabolites explains the high interest to trace and quantify them in microbial cells. Results: Here, we describe a common workflow for extraction and absolute quantification of short chain CoA thioesters in different gram-positive and gram-negative bacteria and eukaryotic yeast, i.e. Corynebacterium glutamicum, Streptomyces albus, Pseudomonas putida, and Yarrowia lipolytica. The approach assessed intracellular CoA thioesters down to the picomolar level and exhibited high precision and reproducibility for all microbes, as shown by principal component analysis. Furthermore, it provided interesting insights into microbial CoA metabolism. A succinyl-CoA synthase defective mutant of C. glutamicum exhibited an unaffected level of succinyl-CoA that indicated a complete compensation by the l-lysine pathway to bypass the disrupted TCA cycle. Methylmalonyl-CoA, an important building block of high-value polyketides, was identified as dominant CoA thioester in the actinomycete S. albus. The microbe revealed a more than 10,000-fold difference in the abundance of intracellular CoA thioesters. A recombinant strain of S. albus, which produced different derivatives of the antituberculosis polyketide pamamycin, revealed a significant depletion of CoA thioesters of the ethylmalonyl CoA pathway, influencing product level and spectrum. Conclusions: The high relevance of short chain CoA thioesters to synthetize industrial products and the interesting insights gained from the examples shown in this work, suggest analyzing these metabolites in microbial cell factories more routinely than done so far. Due to its broad application range, the developed approach appears useful to be applied this purpose. Hereby, the possibility to use one single protocol promises to facilitate automatized efforts, which rely on standardized workflows.

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“…Among these are three clustered genes encoding enzymes PrpC and PrpD and regulator PrpR, which are components of the methylcitrate cycle (MCC) that eliminates the toxic propionyl-CoA produced during in vivo catabolism of cholesterol and fatty acids ( Fig. 4A) 33,34 . The MCC genes are located in a highly variable genomic region, and these three, along with a few flanking genes, are completely or partially deleted in the other subspecies.…”

Section: Potential Gene Contents Contributing To the Success Of M Kamentioning

confidence: 99%

“…I strains, and perhaps contribute to their success in colonizing and causing disease in humans. When mycobacteria infect humans, they use host cholesterol and fatty acids as carbon sources, but the beta-oxidation of cholesterol and odd-chain fatty acids generate propionyl-CoA that is toxic to the bacilli 33,34,46,47 . Pathogenic mycobacteria alleviate the toxicity by consuming propionyl-CoA through the MCC cycle, which is important for the growth of mycobacteria within macrophages 34,47 .…”

Section: Genes Under Positive Selection In the M Kansasii Main Complexmentioning

confidence: 99%

Population genomics provides insights in diversity, epidemiology, evolution and pathogenicity of the waterborne pathogen Mycobacterium kansasii

Luo

Zhang

et al. 2020

Preprint

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Mycobacterium kansasii is a nontuberculous mycobacterium that can cause serious pulmonary disease. Genotyping suggested that the species is composed of at least six subtypes that vary in clinical significance, with subtype I being clinically dominant but less commonly isolated from environmental sources. Here we report a population genomics study of 358 M. kansasii isolates obtained from global water and clinical sources. Phylogenomic analyses revealed that the six subtypes are more accurately designated as closely related subspecies. These subspecies show ample evidence of recombination mediated by distributive conjugative transfer that has contributed to subspeciation and on-going diversification. Water was confirmed as a source of clinical infections by showing that genomes of clinical strains from an Australian outbreak were almost indistinguishable from strains contaminating the drinking water supply. Most clinical infections (nearly 80%) were due to a recently emerged group of strains designated the M. kansasii main complex (MKMC), which appears to have originated in Europe in 1900s and expanded globally over the past century. Comparative genomic analyses revealed that the MKMC has maintained the methylcitrate cycle and expanded ESX-I secretion-associated proteins, perhaps facilitating metabolic adaptation and pathogenicity for human hosts. Evidence of on-going positive selection in isolates of the MKMC was found in genes involved in carbon and secondary metabolism, metal ion homeostasis and cell surface remodeling that could represent adaptation to human hosts. These results further our understanding of the epidemiology and pathogenicity of M. kansasii and emphasize the importance of monitoring its potential transition to a more human-adapted pathogen.

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Loving the poison: the methylcitrate cycle and bacterial pathogenesis

Cited by 45 publications

References 67 publications

Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism

Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism

A common approach for absolute quantification of short chain CoA thioesters in prokaryotic and eukaryotic microbes

Population genomics provides insights in diversity, epidemiology, evolution and pathogenicity of the waterborne pathogen Mycobacterium kansasii

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