Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: The 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. The pathogen Mycobacterium tuberculosis depends on host fatty acids and cholesterol as carbon sources. Here, Beites et al. identify a protein complex that is essential for fatty acid and cholesterol utilization and thus for survival of M. tuberculosis during infection, supporting this pathway as a potential target for tuberculosis drug development.

SUBMITTER: Beites T

PROVIDER: S-EPMC8593149 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Multiple acyl-coA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

Project description: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 b-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 b-oxidation in Mtb. An etfD deletion mutant (DetfD) 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 DetfD metabolome revealed a block in b-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 b-oxidation as a novel potential target for TB drug development.

2021-09-29 | MTBLS2374 | MetaboLights

Pancreatitis in multiple acyl CoA dehydrogenase deficiency: An underdiagnosed complication.

Project description:BackgroundMultiple acyl-CoA dehydrogenase (MADD) deficiency represents a rare fatty acid oxidation disorder where sporadic reports of pancreatitis already exist. Here, we report three cases of MADD with pancreatic involvement raising questions whether this represents an incidental finding or it is related to the pathophysiology of MADD.MethodsWe have retrospectively studied the clinical, biochemical and radiologic data of patients with MADD diagnosed in our department over the last 20 years to identify patients with pancreatic involvement.ResultsThree out of 17 patients had pancreatic involvement. All three patients were diagnosed with MADD in the neonatal period (two-third symptomatic-riboflavin nonresponsive, one-third asymptomatic via newborn screening-riboflavin responsive). Age at presentation of pancreatitis ranged from 20 months to 11 years. Presentations included a single episode of acute pancreatitis in the first patient, chronic necrotizing pancreatitis in the second patient, while the third patient was diagnosed with chronic pancreatitis (CP) incidentally through ultrasonography. All patients had inflammation features on either abdominal computed tomography or ultrasound. Pancreatic enzymes were elevated in two patients. Management of pancreatitis was done conservatively while the patient with necrotic CP required subtotal pancreatectomy.DiscussionOur data suggest that pancreatitis might be more common in patients with MADD than previously reported, requiring a high index of suspicion in patients with acute metabolic decompensation or nonspecific abdominal symptoms. We hypothesize that the underlying mechanism of pancreatitis in MADD is similar to that in mitochondrial disorders, both resulting from disordered energy metabolism and oxidative phosphorylation.

| S-EPMC7802625 | biostudies-literature

Impaired fat oxidation during exercise in multiple acyl-CoA dehydrogenase deficiency.

Project description:We investigated the in vivo skeletal muscle metabolism in patients with multiple acyl-CoA dehydrogenase deficiency (MADD) during exercise, and the effect of a glucose infusion. Two adults with MADD on riboflavin and l-carnitine treatment and 10 healthy controls performed an incremental exercise test measuring maximal oxidative capacity (VO2max) and a submaximal exercise test (?1 hour) on a cycle ergometer. During submaximal exercise, we studied fat and carbohydrate oxidation, using stable isotope tracer methodology and indirect calorimetry. On another day, the patients repeated the submaximal exercise receiving a 10% glucose infusion. The patients had a lower VO2max than controls and stopped the submaximal exercise test at 51 and 58?minutes due to muscle pain and exhaustion. The exercise-induced increase in total fatty acid oxidation was blunted in the patients (7.1 and 1.1 vs 12?±?4 ?mol × kg-1 ×?min-1 in the healthy controls), but total carbohydrate oxidation was higher (67 and 63 vs 25?±?11??mol?×?kg-1 ×?min-1 in controls). With glucose infusion, muscle pain decreased and average heart rate during exercise dropped in both patients from 124 to 119?bpm and 138 to 119?bpm. We demonstrate that exercise intolerance in MADD-patients relates to an inability to increase fat oxidation appropriately during exercise, which is compensated partially by an increase in carbohydrate metabolism.

| S-EPMC6498824 | biostudies-literature

FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening.

Project description:BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by variants in ETFA, ETFB, and ETFDH. Recently, riboflavin transporter genes and the mitochondrial FAD transporter gene have also been associated with MADD-like phenotype.MethodsWe present a case of MADD identified by newborn biochemical screening in a full-term infant suggestive of both medium-chain acyl-CoA dehydrogenase deficiency and MADD. Urine organic acid GC/MS analysis was also concerning for both disorders. However, panel sequencing of ETFA, ETFB, ETFDH, and ACADM was unrevealing. Ultimately, a variant in the FAD synthase gene, FLAD1 was found explaining the clinical presentation.ResultsExome sequencing identified compound heterozygous variants in FLAD1: NM_025207.4: c.[442C>T];[1588C>T], p.[Arg148*];[Arg530Cys]. The protein damaging effects were confirmed by Western blot. The patient remained asymptomatic and there was no clinical decompensation during the first year of life. Plasma acylcarnitine and urinary organic acid analyses normalized without any treatment. Riboflavin supplementation was started at 15 months.ConclusionNewborn screening, designed to screen for specific treatable congenital metabolic diseases, may also lead to the diagnosis of additional, very rare metabolic disorders such as FLAD1 deficiency. The case further illustrates that even milder forms of FLAD1 deficiency are detectable in the asymptomatic state by newborn screening.

| S-EPMC6732309 | biostudies-literature

Combined isobutyryl‐CoA and multiple acyl‐CoA dehydrogenase deficiency in a boy with altered riboflavin homeostasis

Project description:Abstract In this report, we describe the case of an 11‐year‐old boy, who came to our attention for myalgia and muscle weakness, associated with inappetence and vomiting. Hypertransaminasemia was also noted, with ultrasound evidence of hepatomegaly. Biochemical investigations revealed acylcarnitine and organic acid profiles resembling those seen in MADD, that is, multiple acyl‐CoA dehydrogenase deficiencies (OMIM #231680) a rare inherited disorder of fatty acids, amino acids, and choline metabolism. The patient carried a single pathogenetic variant in the ETFDH gene (c.524G>A, p.Arg175His) and no pathogenetic variant in the riboflavin (Rf) homeostasis related genes (SLC52A1, SLC52A2, SLC52A3, SLC25A32, FLAD1). Instead, compound heterozygosity was found in the ACAD8 gene (c.512C>G, p.Ser171Cys; c.822C>A, p.Asn274Lys), coding for isobutyryl‐CoA dehydrogenase (IBD), whose pathogenic variants are associated to IBD deficiency (OMIM #611283), a rare autosomal recessive disorder of valine catabolism. The c.822C>A was never previously described in a patient. Subsequent further analyses of Rf homeostasis showed reduced levels of flavins in plasma and altered FAD‐dependent enzymatic activities in erythrocytes, as well as a significant reduction in the level of the plasma membrane Rf transporter 2 in erythrocytes. The observed Rf/flavin scarcity in this patient, possibly associated with a decreased ETF:QO efficiency might be responsible for the observed MADD‐like phenotype. The patient's clinical picture improved after supplementation of Rf, l‐carnitine, Coenzyme Q10, and also 3OH‐butyrate. This report demonstrates that, even in the absence of genetic defects in genes involved in Rf homeostasis, further targeted molecular analysis may reveal secondary and possibly treatable biochemical alterations in this pattern.

| S-EPMC9259400 | biostudies-literature

Novel ETFDH mutations in four cases of riboflavin responsive multiple acyl-CoA dehydrogenase deficiency.

Project description:Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships.

| S-EPMC6031868 | biostudies-literature

Acute-onset multiple acyl-CoA dehydrogenase deficiency mimicking Guillain-Barre syndrome: two cases report.

Project description:BACKGROUND:Multiple acyl-CoA dehydrogenase deficiency (MADD) showed great clinical heterogeneity and poses a challenge to diagnosis. Guillain-Barré syndrome (GBS) is an acute-onset autoimmune-mediated peripheral neuropathy. However, no patients of acute-onset MADD mimicking the GBS phenotype are reported previously. CASE PRESENTATION:Two patients displayed acute-onset limb weakness, areflexia, and length-dependent sensory disturbances, which clinically indicate the diagnosis of GBS, but electrophysiological and cerebrospinal fluid results threw doubtful points to the initial diagnosis. The muscle biopsy showed lipid storage disorder; and compound heterozygous mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene were found in the two patients through targeted next generation sequencing, which provided the definite diagnostic evidences of late-onset MADD. Muscle weakness was quickly improved by riboflavin supplementation, but sensory disturbances required a long-term treatment. DISCUSSION:The present two cases have demonstrated that MADD can mimic GBS. Taking into consideration the significant differences of therapeutic regimen and prognosis, MADD should be included in the differential diagnosis of GBS.

| S-EPMC6306005 | biostudies-literature

Prolonged exercise testing in two children with a mild Multiple Acyl-CoA-Dehydrogenase deficiency.

Project description:BACKGROUND: Multiple Acyl-CoA-Dehydrogenase deficiency (MADD) is an inherited metabolic disorder characterized by impaired oxidation of fatty acids and some amino acids. METHODS: We were interested whether children with MADD could tolerate a prolonged low-intensity exercise test and if this test could have any additional diagnostic value. Therefore, we performed a maximal exercise test and a low-intensity prolonged exercise test in 2 patients with MADD and in 5 control subjects. During a prolonged exercise test the subjects exercised on a cycle ergometer at a constant workload of 30% of their maximum for 90 minutes and heart rate, oxygen uptake, fuel utilization and changes in relevant blood and urinary parameters were monitored. RESULTS: The tests were tolerated well. During the prolonged exercise test the fatty acid oxidation (FAO) was quite low compared to 5 control subjects, while characteristic metabolites of MADD appeared in plasma and urine. CONCLUSION: We suggest that the prolonged exercise test could be of diagnostic importance and might replace the fasting test as a diagnostic procedure in some cases, particularly in patients with anamnestic signs of intolerance for prolonged exercise.

| S-EPMC1159171 | biostudies-literature

Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency.

Project description:Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing SCAD gene mutations and/or variants. SCAD gene variants are present in homozygous form in approximately 6% of the general population and considered to confer susceptibility to development of clinical disease. Clinically, SCADD generally appears to present early in life and to be most frequently associated with developmental delay, hypotonia, epilepsy, behavioral disorders, and hypoglycemia. However, these symptoms often ameliorate and even disappear spontaneously during follow-up and were found to be unrelated to the SCAD genotype. In addition, in some cases, symptoms initially attributed to SCADD could later be explained by other causes. Finally, SCADD relatives of SCADD patients as well as almost all SCADD individuals diagnosed by neonatal screening remained asymptomatic during follow-up. This potential lack of clinical consequences of SCADD has several implications. First, the diagnosis of SCADD should never preclude extension of the diagnostic workup for other potential causes of the observed symptoms. Second, patients and parents should be clearly informed about the potential lack of relevance of the disorder to avoid unfounded anxiety. Furthermore, to date, SCADD is not an optimal candidate for inclusion in newborn screening programs. More studies are needed to fully establish the relevance of SCADD and solve the question as to whether SCADD is involved in a multifactorial disease or represents a nondisease.

| S-EPMC2946545 | biostudies-literature

Carboxyltransferase Subunit of the Acyl-CoA Carboxylase in Mycobacterium tuberculosis.

Project description:The Mycobacterium tuberculosis acyl-CoA carboxylases provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase (FAS) I and for the elongation of FAS I end-products by the FAS II complex to produce meromycolic acids. M. tuberculosis genome contains three biotin carboxylase subunits (AccA1-3) and 6 carboxyltransferase subunits (AccD1-6) of which AccD6 is located in a genetic locus that contains members of the FAS II complex. We found by microarray and quantitative real-time RT-PCR analysis that the transcripts of AccA3, AccD4, AccD5 and AccD6 are expressed at high levels during exponential growth phases of M. tuberculosis in vitro. Keywords: Time course, developmental stages

2006-10-07 | GSE5977 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data