Biochemical characterization of human 3‐methylglutaconyl‐CoA hydratase and its role in leucine metabolism

  title={Biochemical characterization of human 3‐methylglutaconyl‐CoA hydratase and its role in leucine metabolism},
  author={Matthias Mack and Ute Schniegler-Mattox and Verena Peters and Georg F. Hoffmann and Michael Liesert and Wolfgang Buckel and Johannes Zschocke},
  journal={The FEBS Journal},
The metabolic disease 3‐methylglutaconic aciduria type I (MGA1) is characterized by an abnormal organic acid profile in which there is excessive urinary excretion of 3‐methylglutaconic acid, 3‐methylglutaric acid and 3‐hydroxyisovaleric acid. Affected individuals display variable clinical manifestations ranging from mildly delayed speech development to severe psychomotor retardation with neurological handicap. MGA1 is caused by reduced or absent 3‐methylglutaconyl‐coenzyme A (3‐MG‐CoA… 

Role of non‐enzymatic chemical reactions in 3‐methylglutaconic aciduria

Non‐enzymatic isomerisation of trans‐3MGC CoA drives AUH‐dependent HMG CoA dehydration and explains the occurrence of cis‐3mGC acid in urine of subjects with 3MGC aciduria.

Formation of 3‐hydroxyglutaric acid in glutaric aciduria type I: in vitro participation of medium chain acyl‐CoA dehydrogenase

Despite high Km (above 600 μM) and low turnover rate, the oxidation of glutaryl‐CoA by MCAD in combination with 3‐MGH could explain the urinary concentration of 3‐OH‐GA in GA I patients.

The Structure of LiuC, a 3‐Hydroxy‐3‐Methylglutaconyl CoA Dehydratase Involved in Isovaleryl‐CoA Biosynthesis in Myxococcus xanthus, Reveals Insights into Specificity and Catalysis

Surprisingly, LiuC shows higher sequence and structural similarity to human MGCH than to bacterial forms, although they convert the same substrate, and might open a path for biofuel research, as isovaleryl‐CoA is a source for isobutene, a precursor for renewable fuels and chemicals.

Deletion of 2‐aminoadipic semialdehyde synthase limits metabolite accumulation in cell and mouse models for glutaric aciduria type 1

In vivo data demonstrate that the saccharopine pathway is the main source of glutaric acid production in the brain and periphery of a mouse model for GA1, and support the notion that pharmacological inhibition of AASS may represent an attractive strategy to treat GA1.

On the origin of 3-methylglutaconic acid in disorders of mitochondrial energy metabolism

The existence of this biosynthetic machinery in these organisms supports a model wherein, under conditions of mitochondrial dysfunction, accumulation of acetyl CoA in the inner mitochondrial space as a result of inefficient fuel utilization drives de novo synthesis of 3MG CoA.

Valproic acid utilizes the isoleucine breakdown pathway for its complete β-oxidation.

3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature

The case of a 31-month-old female child referred to the authors' center after the detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening and the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis of MGCA1, exemplifies the importance of the biochemical phenotype in the differential diagnosis of metabolic diseases.

Metabolic reconstructions identify plant 3‐methylglutaconyl‐CoA hydratase that is crucial for branched‐chain amino acid catabolism in mitochondria

Gene network modeling in Arabidopsis and rice, and plant-prokaryote comparative genomics detected candidates for 3-methylglutaconyl-CoA hydratase, one of the missing plant enzymes of leucine catabolism, and evidence is shown that unlike the situation observed in Trypanosomatidae, leucinescatabolism does not contribute to the formation of the terpenoid precursor mevalonate.

Substrate specificity of 2-hydroxyglutaryl-CoA dehydratase from Clostridium symbiosum: toward a bio-based production of adipic acid.

The now possible conversion of (R)-2-hydroxyadipoyl-CoA and 2-hexenedioyl -CoA to 2- Hexanedioic acid paves the road for a bio-based production of adipic acid.



Mutations in the AUH gene cause 3‐methylglutaconic aciduria type I

It is reported that human 3‐methylglutaconyl‐ CoA hydratase is identical with a previously described RNA‐binding protein (designated AUH) possessing enoyl‐CoA hyDRatase activity, which appears to be compatible with normal development in some cases.

Fungal Metabolic Model for Type I 3-Methylglutaconic Aciduria*

Using the fungal type I 3- methylglutaconic aciduria model, it is shown that metabolites accumulating in the deficient strain are toxic, although less so than those accumulating in a ΔmccB strain deficient for the upstream enzyme 3-methylcrotonyl-CoA carboxylase.

Direct nonisotopic assay of 3-methylglutaconyl-CoA hydratase in cultured human skin fibroblasts to specifically identify patients with 3-methylglutaconic aciduria type I.

3-Methylglutaconic aciduria (3MGA) type I (McKusick 250950) is biochemically characterized by increased excretion of 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid in

Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria.

A new assay for 3- methylglutaconyl-coenzyme A (CoA) hydratase has been developed in which the substrate was synthesized using 3-methylcrotonyl-CoA carboxylase purified from bovine kidney and the rates of conversion from substrate are measured.

3-Methylglutaconic aciduria type I is caused by mutations in AUH.

Mutation analysis of AUH in two patients revealed a nonsense mutation (R197X) and a splice-site mutation (IVS8-1G-->A), demonstrating that mutations in AUH cause 3-methylglutaconic aciduria type I.

3-Methylglutaconic Acidemia in Smith-Lemli-Opitz Syndrome

Plasma levels of 3-methylglutaconic acid are measured in patients with a known defect of sterol biosynthesis, Smith-Lemli-Opitz syndrome, and it is found that the patients with the lowest cholesterol levels had abnormally increased plasma levels of the branched-chain organic acid.

Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation.

Crystal structure of 4-hydroxybutyryl-CoA dehydratase: radical catalysis involving a [4Fe-4S] cluster and flavin.

The structure provides insight into the function of these ubiquitous prosthetic groups in the chemically nonfacile, radical-mediated dehydration of 4-hydroxybutyryl-CoA and addresses the divergent evolution of the ancestral common gene.