Disease relevance of D-methylmalonyl-CoA

• A derivative of BAP1 was engineered that harbors the AHBA biosynthetic operon, the bicistronic RifA construct and the pccB and accA1 genes from Streptomyces coelicolor, which enable methylmalonyl-CoA biosynthesis [1].
• The alignments allow the mutations of human methylmalonyl-CoA mutase to be mapped onto the structure of the cobalamin-binding fragment of methionine synthase from Escherichia coli (EC 2.1.1.13), which has recently been determined by x-ray crystallography [2].
• Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid [3].
• Sequence of the sodium ion pump methylmalonyl-CoA decarboxylase from Veillonella parvula [4].
• A soluble enzyme preparation from M. tuberculosis var. bovis BCG incorporated methylmalonyl-CoA into mycocerosic acids [5].

High impact information on D-methylmalonyl-CoA

• These children have no evidence of a deficiency of vitamin B12, which acts as a cofactor with methylmalonyl-CoA mutase, and they did not respond to the administration of vitamin B12 [6].
• Conversion of the chemical energy of methylmalonyl-CoA decarboxylation into a Na+ gradient [7].
• Gene transfer of a functional methylmalonyl CoA mutase cDNA clone into mut fibroblasts reconstitutes holoenzyme activity measured by metabolism of [14C]-propionate in culture [8].
• Exposure of rats to nitrous oxide rapidly inactivated the cytosol enzyme, methionine synthetase, but the mitochondrial enzyme, methylmalonyl CoA mutase, seemed to be unaffected, although both enzymes require vitamin B12 [9].
• In the active site, the labile carboxylate group of methylmalonyl-CoA is stabilized by interaction with the N-termini of two alpha-helices [10].

Chemical compound and disease context of D-methylmalonyl-CoA

• Fatty acid biosynthesis in Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin. Purification and characterization of a novel fatty acid synthase, mycocerosic acid synthase, which elongates n-fatty acyl-CoA with methylmalonyl-CoA [11].
• The recently solved X-ray crystal structure of methylmalonyl-CoA mutase from Propionibacterium shermanii has shown that tyrosine 89 is an active-site residue involved in substrate binding [12].
• The reaction catalysed by methylmalonyl-CoA epimerase from Propionibacterium shermanii was studied in tritiated water, in the direction with (2R)-methylmalonyl-CoA as substrate, under 'irreversible' conditions [13].
• Adenosylcobalamin-dependent methylmalonyl-CoA mutase from Propionibacterium shermanii contains no intramolecular disulphide bridges, but two of the six thiol groups in the heterodimer are only revealed after reduction of the denatured enzyme with dithiothreitol [14].
• Propionyl-CoA carboxylase and combined methylmalonyl-CoA (MMA-CoA) racemase and -mutase activities were studied in liver and fibroblasts of two patients with the acute neonatal form of nonketotic hyperglycemia [15].

Biological context of D-methylmalonyl-CoA

• Mapping of human methylmalonyl CoA mutase (MUT) locus on chromosome 6 [16].
• The recent cloning and sequencing of a cDNA for human methylmalonyl CoA mutase enables molecular characterization of mutations underlying mut phenotypes [17].
• Examination of bacterial operons containing genes in close proximity to the gene for methylmalonyl-CoA mutase and searching for orthologous sequences in the human genome yielded potential candidates [18].
• We identified compound heterozygous mutations in a mut0 fibroblast cell (MAS) line by cloning the methylmalonyl CoA mutase cDNA by using the polymerase chain reaction (PCR), sequencing with internal primers, and confirming the pathogenicity of observed mutations by DNA-mediated gene transfer [17].
• This was accomplished by searching bacterial genomes for genes in close proximity to the methylmalonyl-CoA mutase gene that might encode a protein with the properties of an adenosyltransferase [19].

Anatomical context of D-methylmalonyl-CoA

• Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines [20].
• Methylmalonyl-CoA mutase (EC 5.4.99.2; mutase), a cytoplasmically synthesized mitochondrial matrix enzyme, is translated in a cell-free system programmed with rat liver RNA as a larger precursor polypeptide, designated pre-mutase, which appears to be 3-4 kDa larger than the subunit of purified mutase (77.5 kDa) [21].
• The purified enzymes from both subcellular fractions exhibit similar physical and catalytic properties and are distinctly different from rat liver methylmalonyl-CoA epimerase [22].
• Biogenesis of the mitochondrial enzyme methylmalonyl-CoA mutase. Synthesis and processing of a precursor in a cell-free system and in cultured cells [21].
• Following degradation of the TCII, Cbl is subsequently found in either the cytoplasm bound to methionine synthase or in the mitochondria bound to methylmalonyl CoA mutase [23].

Associations of D-methylmalonyl-CoA with other chemical compounds

• L-Methylmalonyl-CoA mutase (MCM, EC 5.4.99.2) is a mitochondrial adenosylcobalamin-requiring enzyme that catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA [20].
• Cyanocobalamin [c-lactam] reversibly impaired the incorporation of 5-[14CH3]-tetrahydrofolate and [1-(14)C] propionic acid by intact cells, consistent with inhibition of methionine synthase and methylmalonyl-CoA mutase [24].
• Certain amino acids and other compounds are metabolized via: Propionyl-CoA carboxylase in equilibrium D-methylmalonyl-CoA racemase in equilibrium L-methylmalonyl-CoA (adenosylcobalamin) mutase in equilibrium succinyl-CoA in equilibrium tricarboxylic acid cycle [25].
• This fatty acid synthase elongated long-chain fatty acyl-CoA primers using methylmalonyl-CoA and NADPH to produce multimethyl-branched mycocerosic acids [11].
• The delta-subunit of methylmalonyl-CoA decarboxylase and the gamma-subunit of oxaloacetate decarboxylase did not show significant sequence homology [4].

Gene context of D-methylmalonyl-CoA

• The second encodes a chimera composed of the mitochondrial leader sequence of human methylmalonyl CoA mutase and the mature PCCA protein [26].
• We have determined that YgfG is methylmalonyl CoA decarboxylase, YgfH is propionyl CoA:succinate CoA transferase, and Sbm is methylmalonyl CoA mutase [27].
• ATP:cob(I)alamin adenosyltransferase (MMAB protein; methylmalonic aciduria type B) is an enzyme of vitamin B(12) metabolism that converts reduced cob(I)alamin to the adenosylcobalamin co-factor required for the functional activity of methylmalonyl-CoA mutase [28].
• Localization of the murine methylmalonyl CoA mutase (Mut) locus on chromosome 17 by in situ hybridization [29].
• Surprisingly, the methylmalonyl-CoA generated from the matB pathway was not converted into 6dEB [30].

Analytical, diagnostic and therapeutic context of D-methylmalonyl-CoA

• We describe a novel method for differential diagnosis of mut and cbl methylmalonic aciduria using DNA-mediated gene transfer of a methylmalonyl CoA mutase cDNA clone [8].
• We developed a radioimmunoassay to quantitate material crossreacting immunochemically with human methylmalonyl-CoA mutase (methylmalonyl-CoA CoA-carbonylmutase, EC 5.4.99.2), and have applied this assay to extracts of fibroblasts from controls and from 32 patients with methylmalonic acidemia due to inherited deficiencies in mutase activity [31].
• In this study, we have used site-directed mutagenesis to create the H610A and H610N variants of methylmalonyl-CoA mutase and report that both mutations exhibit both diminished activity (5,000- and 40,000-fold, respectively) and profoundly weakened affinity for the native cofactor, AdoCbl [32].
• Methylmalonyl-CoA mutase, one of two known cobalamin-dependent enzymes present in mammalian tissues, has been isolated from 2.5 kg of human placenta utilizing affinity chromatography on 5'-deoxyadenosylcobalamin-Sepharose as the major purification step [33].
• 2. Under these conditions, methylmalonyl-CoA was incorporated into very long acids which were identified as mycocerosic acids by radio gas-liquid chromatography [5].

References