scholarly journals Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tiago Beites ◽  
Robert S. Jansen ◽  
Ruojun Wang ◽  
Adrian Jinich ◽  
Kyu Y. Rhee ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Deletion Mutant ◽  
Dehydrogenase Deficiency ◽  
Long Chain Fatty Acids ◽  
Human Pathogen ◽  
Antitubercular Drugs ◽  
Acyl Coa Dehydrogenases ◽  
Long Chain

AbstractThe human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant’s metabolome reveals a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit β and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.

scholarly journals Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

2021 ◽  
Author(s):  
Tiago Beites ◽  
Robert S Jansen ◽  
Ruojun Wang ◽  
Adrian Jinich ◽  
Kyu Y Rhee ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Acid Metabolism ◽  
Dehydrogenase Deficiency ◽  
Long Chain Fatty Acids ◽  
Human Pathogen ◽  
Antitubercular Drugs ◽  
Acyl Coa Dehydrogenases

The human pathogen Mycobacterium tuberculosis (Mtb) devotes a significant fraction of its genome to fatty acid metabolism. Although Mtb depends on host fatty acids as a carbon source, fatty acid β-oxidation is mediated by genetically redundant enzymes, which has hampered the development of antitubercular drugs targeting this metabolic pathway. Here, we identify rv0338c, referred to as etfDMtb, to encode a membrane dehydrogenase essential for fatty acid β-oxidation in Mtb. An etfD deletion mutant (ΔetfD) was incapable of growing on fatty acids in vitro, with long-chain fatty acids being bactericidal, and failed to grow and survive in mice. The ΔetfD metabolome revealed a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs). In many organisms, including humans, ACADs are functionally dependent on an electron transfer flavoprotein (ETF) and cognate dehydrogenase. Immunoprecipitation identified EtfD in complex with FixA (EtfBMtb). FixA (EtfBMtb) and FixB (EtfAMtb) are homologous to the human ETF subunits. Our results demonstrate that EtfBAMtb constitutes Mtb's ETF, while EtfDMtb, although not homologous to human EtfD, functions as the dehydrogenase. These findings identify Mtb's fatty acid β-oxidation as a novel potential target for TB drug development.

scholarly journals Rumen Fermentation In Vitro as Influenced by Long Chain Fatty Acids

1984 ◽  
Vol 67 (7) ◽  
pp. 1439-1444 ◽  
Author(s):  
William Chalupa ◽  
Bonnie Rickabaugh ◽  
D. Kronfeld ◽  
S. David Sklan
Keyword(s):  
Fatty Acids ◽  
Rumen Fermentation ◽  
Long Chain Fatty Acids ◽  
Long Chain ◽  
Chain Fatty Acids

scholarly journals The Multifunctional β-Oxidation Enzyme Is Required for Full Symptom Development by the Biotrophic Maize Pathogen Ustilago maydis

2006 ◽  
Vol 5 (12) ◽  
pp. 2047-2061 ◽  
Author(s):  
Jana Klose ◽  
James W. Kronstad
Keyword(s):  
Fatty Acids ◽  
Ustilago Maydis ◽  
Long Chain Fatty Acids ◽  
In Planta ◽  
Gene Encoding ◽  
Metabolic Role ◽  
Fungal Phytopathogen ◽  
Long Chain ◽  
Chain Fatty Acids

ABSTRACT The transition from yeast-like to filamentous growth in the biotrophic fungal phytopathogen Ustilago maydis is a crucial event for pathogenesis. Previously, we showed that fatty acids induce filamentation in U. maydis and that the resulting hyphal cells resemble the infectious filaments observed in planta. To explore the potential metabolic role of lipids in the morphological transition and in pathogenic development in host tissue, we deleted the mfe2 gene encoding the multifunctional enzyme that catalyzes the second and third reactions in β-oxidation of fatty acids in peroxisomes. The growth of the strains defective in mfe2 was attenuated on long-chain fatty acids and abolished on very-long-chain fatty acids. The mfe2 gene was not generally required for the production of filaments during mating in vitro, but loss of the gene blocked extensive proliferation of fungal filaments in planta. Consistent with this observation, mfe2 mutants exhibited significantly reduced virulence in that only 27% of infected seedlings produced tumors compared to 88% tumor production upon infection by wild-type strains. Similarly, a defect in virulence was observed in developing ears upon infection of mature maize plants. Specifically, the absence of the mfe2 gene delayed the development of teliospores within mature tumor tissue. Overall, these results indicate that the ability to utilize host lipids contributes to the pathogenic development of U. maydis.

Synthesis in vitro of very long chain fatty acids in Vibrio sp. strain ABE-1

1992 ◽  
Vol 157 (3) ◽  
pp. 223-228 ◽  
Author(s):  
Naoki Morita ◽  
Nobuhiro Okajima ◽  
Masaru Gotoh ◽  
Hideyuki Hayashi ◽  
Hidetoshi Okuyama ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Long Chain Fatty Acids ◽  
Long Chain ◽  
Chain Fatty Acids

scholarly journals Fatty acids synthesis in rat adipose tissue. Tracer concentration effects in vitro

1968 ◽  
Vol 106 (1) ◽  
pp. 179-183 ◽  
Author(s):  
W. G. Duncombe
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Acid Synthesis ◽  
Long Chain Fatty Acids ◽  
Concentration Effects ◽  
Tracer Concentration ◽  
Adipose Tissue In Vitro ◽  
Rat Adipose Tissue ◽  
Long Chain

1. The use of labelled acetate for studying the synthesis of long-chain fatty acids in rat adipose tissue in vitro has been examined, with special reference to the effect of acetate concentration. 2. The incorporation of acetate into fatty acids is proportional to the concentration of acetate in the medium when the latter does not exceed about 10μm. Above this concentration, the relative incorporation becomes progressively less, and reasons for this are discussed. 3. In particular it is shown that this is not necessarily due to disturbance of the endogenous rate of fatty acid synthesis by a relatively large amount of acetyl-CoA derived from added acetate. 4. However, to ensure that the added acetate does not cause such a disturbance its concentration must be kept sufficiently low. For labelled acetate used under present conditions, this concentration should not be more than about 10μm.

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