Structural basis for the broad substrate specificity of two acyl-CoA dehydrogenases FadE5 from mycobacteria

Chen, Xiaobo; Chen, Jiayue; Yan, Bing; Zhang, Wei; Guddat, L.W.; Liu, Xiang; Rao, Zihe

doi:10.1073/pnas.2002835117

Cited by 8 publications

(10 citation statements)

References 53 publications

(48 reference statements)

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“…Recently, Chen et al (2020) reported that FadE5 from Mtb and Msm contributed to drug resistance. 64 Our lipidomics data set showed a significantly lowered production of mycolic acids (Figure 5D and Table 2). This is consistent with our prior observation (Figure 1) that a treatment with either DA-CB or ETH was associated with similar global metabolomics changes, which, in turn, suggests a shared general MoA that includes disrupting mycolic acid biosynthesis.…”

Section: Integration Of Lipidomics and Proteomics Data Demonstrates D...mentioning

confidence: 83%

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Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

et al. 2022

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The mechanism of action (MoA) of a clickable fatty acid analogue 8-(2-cyclobuten-1-yl)octanoic acid (DA-CB) has been investigated for the first time. Proteomics, metabolomics, and lipidomics were combined with a network analysis to investigate the MoA of DA-CB against Mycobacterium smegmatis (Msm). The metabolomics results showed that DA-CB has a general MoA related to that of ethionamide (ETH), a mycolic acid inhibitor that targets enoyl-ACP reductase (InhA), but DA-CB likely inhibits a step downstream from InhA. Our combined multi-omics approach showed that DA-CB appears to disrupt the pathway leading to the biosynthesis of mycolic acids, an essential mycobacterial fatty acid for both Msm and Mycobacterium tuberculosis (Mtb). DA-CB decreased keto-meromycolic acid biosynthesis. This intermediate is essential in the formation of mature mycolic acid, which is a key component of the mycobacterial cell wall in a process that is catalyzed by the essential polyketide synthase Pks13 and the associated ligase FadD32. The multi-omics analysis revealed further collateral alterations in bacterial metabolism, including the overproduction of shorter carbon chain hydroxy fatty acids and branched chain fatty acids, alterations in pyrimidine metabolism, and a predominate downregulation of proteins involved in fatty acid biosynthesis. Overall, the results with DA-CB suggest the exploration of this and related compounds as a new class of tuberculosis (TB) therapeutics. Furthermore, the clickable nature of DA-CB may be leveraged to trace the cellular fate of the modified fatty acid or any derived metabolite or biosynthetic intermediate.

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Section: Integration Of Lipidomics and Proteomics Data Demonstrates D...mentioning

confidence: 83%

“…Acyl-CoA dehydrogenases introduce unsaturation into the carbon chains during lipid metabolism, which correlates with the observed accumulation of unsaturated fatty acids in cells treated with DA-CB. Recently, Chen et al (2020) reported that FadE5 from Mtb and Msm contributed to drug resistance …”

Section: Resultsmentioning

confidence: 99%

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

et al. 2022

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“…The fixA-fixB gene products probably participate in FAO-related electron transport (39). The fadE5 is likely involved in β-oxidation of the acyl side chain of cholesterol (40), and a recent study showed broad specificity of FadE5 for acyl-CoAs (41). The icl encodes multifunctional isocitrate lyase/methylisocitrate lyase required for both the glyoxylate shunt and the methylcitrate cycle (15,42).…”

Section: Resultsmentioning

confidence: 99%

Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence

Dong

Nie

Zhu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. The mutant showed defective growth but high substrate consumption on fatty acids. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)–responsive repressor of genes involved in fatty acid degradation and modification. We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from β-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. This study thus presents FdmR as a potentially attractive target for chemotherapy.

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“…Most importantly, in this study, fadE5 gene demonstrated consistent down-regulation of RNA transcript and protein level in both stress and exponential growth conditions of the hypervirulent M. tuberculosis H112. The fadE5 of M. tuberculosis plays a role in the catabolism of fatty acids, particularly in the long-chain carbon substrates used for lipogenesis in pathogenic mycobacteria [ 30 ]. The regulation of abundance and chain length of the virulence-related lipids is vital for the impermeability of the mycobacterial cell envelope because overactive fatty acids catabolism is detrimental to the pathogenicity and growth of the mycobacteria [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

A multi-omics investigation into the mechanisms of hyper-virulence in Mycobacterium tuberculosis

et al. 2022

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Clinical manifestations of tuberculosis range from asymptomatic infection to a life-threatening disease such as tuberculous meningitis (TBM). Recent studies showed that the spectrum of disease severity could be related to genetic diversity among clinical strains of Mycobacterium tuberculosis (Mtb). Certain strains are reported to preferentially invade the central nervous system, thus earning the label “hypervirulent strains”.However, specific genetic mutations that accounted for enhanced mycobacterial virulence are still unknown. We previously identified a set of 17 mutations in a hypervirulent Mtb strain that was from TBM patient and exhibited significantly better intracellular survivability. These mutations were also commonly shared by a cluster of globally circulating hyper-virulent strains. Here, we aimed to validate the impact of these hypervirulent-specific mutations on the dysregulation of gene networks associated with virulence in Mtb via multi-omic analysis. We surveyed transcriptomic and proteomic differences between the hyper-virulent and low-virulent strains using RNA-sequencing and label-free quantitative LC-MS/MS approach, respectively. We identified 25 genes consistently differentially expressed between the strains at both transcript and protein level, regardless the strains were growing in a nutrient-rich or a physiologically relevant multi-stress condition (acidic pH, limited nutrients, nitrosative stress, and hypoxia). Based on integrated genomic-transcriptomic and proteomic comparisons, the hypervirulent-specific mutations in FadE5 (g. 295,746 C >T), Rv0178 (p. asp150glu), higB (p. asp30glu), and pip (IS 6110 -insertion) were linked to deregulated expression of the respective genes and their functionally downstream regulons. The result validated the connections between mutations, gene expression, and mycobacterial pathogenicity, and identified new possible virulence-associated pathways in Mtb .

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Structural basis for the broad substrate specificity of two acyl-CoA dehydrogenases FadE5 from mycobacteria

Cited by 8 publications

References 53 publications

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence

A multi-omics investigation into the mechanisms of hyper-virulence in Mycobacterium tuberculosis

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