Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase.

Drennan, Catherine L.; Matthews, Rowena G.; Rosenblatt, David S.; Ledley, Fred D.; Fenton, Wayne A.; Ludwig, Martha

doi:10.1073/pnas.93.11.5550

Cited by 18 publications

(10 citation statements)

References 42 publications

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“…The loop between IIβ1 and IIα1 contains His 627, which provides the ligand to cobalt in the enzyme. His627, Asp625, and Lys621 form part of a hydrogen bonded triad of residues that is proposed to modulate the reactivity at cobalt either by acting as a proton relay [7] or by positioning the histidine ligand at an unusually long distances from the cobalt atom [19]. p.P615T and p.P615L mutations likely have an important effect on the function of this critical domain, since the proline is critical for protein folding.…”

Section: Discussionmentioning

confidence: 98%

“…MethylmalonylCoA is subsequently hydrolyzed to CoA and methylmalonic acid [1,6], resulting in elevated blood and urine levels of methylmalonic acid. Affected individuals typically present in the first weeks or months of life with ketoacidosis, lethargy, vomiting and failure to thrive, hypotonia which may lead to early death if not treated [1,7]. Despite dietary treatment, affected patients remain vulnerable to life threatening metabolic crises and most patients have problems with growth and motor skills.…”

Section: Introductionmentioning

confidence: 99%

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Microarray based mutational analysis of patients with methylmalonic acidemia: Identification of 10 novel mutations

Dündar

Özgül

Güzel-Ozantürk

et al. 2012

Molecular Genetics and Metabolism

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Microarray based mutational analysis of patients with methylmalonic acidemia: Identification of 10 novel mutations

Dündar

Özgül

Güzel-Ozantürk

et al. 2012

Molecular Genetics and Metabolism

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“…All residues altered by mutations in this region affect residues that are common to human and mouse MCM and also to one subunit (MUTB) of the homologous MCM from Propionibacterium shermanii (Leadlay and Ledley, 1990). It is of particular interest that these mutations occur within a sequence motif common to several cobalamin-binding enzymes, including methionine synthase, methylmalonyl CoA mutase, and glutamine mutase (Marsh et al, 1989;Marsh and Holloway, 1992;Holloway et al, 1994;Drennan et al , 1994Drennan et al , , 1996. The two mutations in this region that produce a mut° phenotype affect amino acids within this conserved motif, while the mutations that produce a mutphenotype affect other residues within this region (Drennan et al, 1996).…”

Section: Enzyme Structure and Functionmentioning

confidence: 99%

“…It is of particular interest that these mutations occur within a sequence motif common to several cobalamin-binding enzymes, including methionine synthase, methylmalonyl CoA mutase, and glutamine mutase (Marsh et al, 1989;Marsh and Holloway, 1992;Holloway et al, 1994;Drennan et al , 1994Drennan et al , , 1996. The two mutations in this region that produce a mut° phenotype affect amino acids within this conserved motif, while the mutations that produce a mutphenotype affect other residues within this region (Drennan et al, 1996). This tends to confirm the suggestion of Marsh and Holloway (1992) that these residues are important for cobalamin binding.…”

Section: Enzyme Structure and Functionmentioning

confidence: 99%

Mutations in mut methylmalonic acidemia: Clinical and enzymatic correlations

Ledley

Rosenblatt

1997

Hum. Mutat.

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Mut methylmalonic acidemia is caused by mutations in the MUT locus encoding the enzyme methylmalonyl CoA mutase. Genotypic and phenotypic variability in this disease has been studied extensively by biochemical and somatic cell genetic techniques, by molecular cloning, and by gene transfer. Mutations have been identified that cause classic mut(o) phenotypes in which there is no detectable enzymatic activity, mut- phenotypes in which there is residual cobalamin-dependent activity, as well as a subset within both mut(o) and mut- phenotypes that exhibit interallelic complementation. These mutations illustrate the position, structure, and function of critical domains within this cobalamin-binding enzyme and provide new insights into the biochemical and clinical consequences of enzyme deficiency.

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“…The second enzyme, methylmalonyl-CoA mutase, uses AdoCbl as a coenzyme to convert methylmalonyl-CoA to succinyl-CoA, which can then enter the trichloroacetic acid cycle (6,7). This AdoCbl-dependent reaction is important in the catabolism of methionine, valine, threonine, isoleucine, odd chain fatty acids, and cholesterol (8,9).…”

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confidence: 99%

The Structural Basis for Methylmalonic Aciduria

Saridakis

Yakunin

et al. 2004

Journal of Biological Chemistry

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ATP:cobalamin adenosyltransferase MMAB was recently identified as the gene responsible for a disorder of cobalamin metabolism in humans (cblB complementation group). The crystal structure of the MMAB sequence homologue from Thermoplasma acidophilum (TA1434; GenBank TM identification number giͦ16082403) was determined to a resolution of 1.5 Å. TA1434 was confirmed to be an ATP:cobalamin adenosyltransferase, which depended absolutely on divalent metal ions (Mg 2؉ > Mn 2؉ > Co 2؉ ) and only used ATP or dATP as adenosyl donors. The apparent K m of TA1434 was 110 M (k cat ‫؍‬ 0.23 s ؊1 ) for ATP, 140 M (k cat ‫؍‬ 0.11 s ؊1 ) for dATP, and 3 M (k cat ‫؍‬ 0.18 s ؊1 ) for cobalamin. TA1434 is a trimer in solution and in the crystal structure, with each subunit composed of a five-helix bundle. The location of diseaserelated point mutations and other residues conserved among the homologues of TA1434 suggest that the active site lies at the junctions between the subunits. Mutations in TA1434 that correspond to the disease-related mutations resulted in proteins that were inactive for ATP:cobalamin adenosyltransferase activity in vitro, confirming that these mutations define the molecular basis of the human disease. Cobalamin (vitamin B 12 ) is an important cofactor in both prokaryotes and eukaryotes. A wide variety of cobalamin-dependent metabolic reactions are known, including acetyl-CoA synthesis, generation of deoxyribonucleotides for DNA synthesis, methane production in methanogenic archaea, and fermentation of small molecules (1). The metabolic requirement for cobalamin varies among different organisms. Some bacteria, such as Escherichia coli, use the vitamin but do not synthesize it (2), whereas other bacteria have no need for it (1). Animals require cobalamin but must rely on dietary sources, and it is believed that plants and fungi neither synthesize nor use cobalamin (1, 3). A characteristic that distinguishes cobalamin from all other vitamins is that only certain bacteria and archaea possess the ability for its de novo synthesis (3, 4).Prior to its use in the cell, cobalamin must be metabolized into one of two biologically active forms, adenosylcobalamin (AdoCbl) 1 and methylcobalamin (MeCbl). In humans, these cofactors are known to be used in two enzyme systems. The first enzyme, methionine synthase, uses MeCbl to produce methionine from homocysteine (2, 5). The second enzyme, methylmalonyl-CoA mutase, uses AdoCbl as a coenzyme to convert methylmalonyl-CoA to succinyl-CoA, which can then enter the trichloroacetic acid cycle (6, 7). This AdoCbl-dependent reaction is important in the catabolism of methionine, valine, threonine, isoleucine, odd chain fatty acids, and cholesterol (8, 9).Cobalamin itself comprises a central corrin ring that provides four ligands for a hexacoordinated cobalt ion (3, 4). The conversion of cobalamin to AdoCbl and MeCbl involves the reduction of the cobalt ion from a Co(III) oxidation state to Co(I) and then the addition of the functional ligand (2, 10). In the formation of AdoCbl, the 5...

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Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase.

Cited by 18 publications

References 42 publications

Microarray based mutational analysis of patients with methylmalonic acidemia: Identification of 10 novel mutations

Microarray based mutational analysis of patients with methylmalonic acidemia: Identification of 10 novel mutations

Mutations in mut methylmalonic acidemia: Clinical and enzymatic correlations

The Structural Basis for Methylmalonic Aciduria

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