Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inborn errors of vitamin B12 (cobalamin, Cbl) metabolism are autosomal recessive disorders and have been classified into nine distinct complementation classes (cblA-cblH and mut). Disorders affecting methylcobalamin metabolism cause megaloblastic anemia, which may be accompanied by leukopenia and thrombocytopenia, and a variety of neurological problems. Disorders affecting adenosylcobalamin cause methylmalonic acidemia and metabolic acidosis. Previous studies have shown that cobalamin binds to two enzymes in humans: methylmalonyl-CoA mutase in mitochondria and methionine synthase in the cytosol. In this study, cobalamin binding patterns were analyzed in crude mitochondrial fractions obtained from both control and patient fibroblasts that had been incubated with [57Co]cyanocobalamin. Crude mitochondrial fractions from control fibroblasts confirmed that the majority of [57Co]Cbl eluted with methylmalonyl-CoA mutase. However, in six of the nine disorders, at least one previously unidentified mitochondrial cobalamin binding protein was observed to bind [57Co]Cbl. The proportion of [57Co]Cbl that binds, is increased compared to controls when a deficiency in either adenosylcobalamin synthesis or utilization prevents binding to methylmalonyl-CoA mutase. Furthermore, unique cobalamin binding profiles emerged demonstrating how known mutations in these patients affect cobalamin binding to as yet unidentified proteins.
Mol Genet Metab 2007 Feb
PMID:Mitochondrial vitamin B12-binding proteins in patients with inborn errors of cobalamin metabolism. 1701 Dec 24

Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut(0) and mut(-)) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut(-) defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut(0) defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut(-) defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype.
Mol Genet Metab 2007 Mar
PMID:Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations. 1711 6

A boy who was diagnosed with methylmalonic aciduria (MMA) at the age of 10 days developed persistent hepatomegaly and raised transaminases from the age of 4 years. He was subsequently diagnosed with Leigh syndrome and required a kidney transplantation for end-stage renal failure. A massive hepatoblastoma led to his death by the age of 11 years. Methylmalonyl-CoA mutase activity was undetectable on both cultured skin fibroblasts and kidney biopsy and multiple respiratory chain deficiency was demonstrated in the kidney. Mitochondrial dysfunction and/or post-transplant immunosuppressive therapy should be considered as a possible cause of liver cancer in this patient.
Mol Genet Metab
PMID:Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria. 1867 66

A stop codon defect in methylmalonyl-CoA mutase (resulting in a truncated unstable protein) accounts for up to 14% of mutations identified as causes of Methylmalonic aciduria. There are currently limited treatment regimes for patients with this inherited condition. We aimed to investigate the use of stop codon read-through drugs in a genomic reporter assay cell line with a defect in the mutase gene. A single C-T base change was introduced into exon 6 of the human MUT sequence in the BAC clone RP11-463L20 resulting in an arginine residue being replaced with a TGA stop codon. An enhanced green fluorescent protein reporter gene was introduced in-frame with exon 13 of the MUT gene. The construct was transfected into HeLa cells to produce the genomic reporter assay cell line. To test the suppression of nonsense mutations, cells were incubated in the presence of different compounds for a period of 72 h then analysed by flow cytometry. Treatment of the cells with gentamicin resulted in a 1.6-fold increase in reporter protein, whilst G418 treatment resulted in no change, however the two drugs together acted synergistically to increase the production of methylmalonyl-CoA mutase 2.0-fold (confirmed by mRNA, flow cytometry and enzyme activity). Zidovudine, adefovir and cisplatin were also found to have some activity in the stop codon read-through genomic reporter assay. These results encourage further testing of compounds as well as follow up animal studies. This is the first study to demonstrate the use of stop codon read-through drugs for the potential treatment of Methylmalonic aciduria.
Mol Genet Metab 2009 Aug
PMID:Stop codon read-through of a methylmalonic aciduria mutation. 1942 50

MMAB (methylmalonic aciduria type B) is a mitochondrial enzyme involved in the metabolism of vitamin B(12). It functions as the ATP:cob(I)alamin adenosyltransferase for the generation of adenosylcobalamin (AdoCbl), the cofactor of methylmalonyl-CoA mutase (MCM). Impaired MMAB activity leads to the inherited disorder methylmalonic aciduria and is responsible for the cblB complementation group. In this study, the effects on substrate binding of two catalytically inactive patient mutations, R190H and R186W, were investigated using intrinsic fluorescence quenching of MMAB as a measure of ligand-binding. We report the dissociation constant (K(d)) of wild-type MMAB for HOCbl is 51 microM and for ATP is 365 microM and show that cobalamin enhances the affinity of MMAB for ATP, while ATP does not show detectable effects on cobalamin binding. We confirm that residue Arg190 plays a role in the formation of the ATP-binding site as described previously [H.L. Schubert, C.P. Hill, Structure of ATP-bound human ATP:cobalamin adenosyltransferase, Biochemistry 45 (2006) 15188-15196]. Unexpectedly, mutation R186W does not disrupt the binding of HOCbl to MMAB as predicted; instead, both R190H and R186W significantly disrupt the affinity between MMAB and AdoCbl. We surmise that these two residues may be critical for the transfer of the 5'-deoxyadenosyl group from ATP to cob(I)alamin, possibly by contributing to the precise positioning of the two substrates to permit catalysis to occur. Characterization of ligand-binding by MMAB provides insight into the mechanism of cobalamin adenosylation and the effect of patient mutations in the inherited disorder.
Mol Genet Metab 2009 Nov
PMID:Ligand-binding by catalytically inactive mutants of the cblB complementation group defective in human ATP:cob(I)alamin adenosyltransferase. 1962 2

Methylmalonic acidemia (MMA) is an organic acidemia caused by deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). This disorder is associated with lethal metabolic instability and carries a poor prognosis for long-term survival. A murine model of MMA that replicates a severe clinical phenotype was used to examine the efficacy of recombinant adeno-associated virus (rAAV) serotype 8 gene therapy as a treatment for MMA. Lifespan extension, body weight, circulating metabolites, transgene expression, and whole animal propionate oxidation were examined as outcome parameters after gene therapy. One-hundred percent of the untreated Mut(-/-) mice (n = 58) died by day of life (DOL) 72, whereas >95% of the adeno-associated virus-treated Mut(-/-) mice (n = 27) have survived for > or = 1 year. Despite a gradual loss of transgene expression and elevated circulating metabolites in the treated Mut(-/-) mice, the animals are indistinguishable from unaffected control littermates in size and activity levels. These experiments provide the first definitive evidence that gene therapy will have clinical utility in the treatment of MMA and support the development of gene therapy for other organic acidemias.
Mol Ther 2010 Jan
PMID:Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy. 1986 51

The measurement of plasma or serum methylmalonic acid (MMA) is useful for monitoring therapy in patients with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency, defects of vitamin B12 metabolism, and also for the determination of functional vitamin B12 deficiency. This method utilizes a stable-isotope labeled internal standard (trideuterated MMA), which is added to the standards, controls, and patient samples prior to extraction. MMA is derivatized by butylation and the amount quantified against a seven-point standard curve using specific selected ions from both the labeled and unlabeled MMA.
Methods Mol Biol 2010
PMID:Quantitation of methylmalonic acid in serum or plasma using isotope dilution-selected ion gas chromatography-mass spectrometry. 2007 88

Desulfobacterium autotrophicum HRM2 is a metabolically versatile sulfate-reducing bacterium, capable of heterotrophic (e.g. with organic acids and alcohols) and chemolithoautotrophic growth (with H(2)/CO(2)). It employs the Wood-Ljungdahl pathway for complete oxidation of acetyl-CoA to CO(2) and for CO(2) fixation. Here, we investigated substrate-dependent regulation at different levels of anaerobic carbon catabolism in this bacterium. (a) Whole-cell adaptation studies indicated an inducibleutilization of short-chained alcohols, agreeing with a substrate-specific abundance increase (up to 40-fold) of alcohol dehydrogenase Adh4. Simultaneous utilization of lactate and 1-propanol was paralleled by adh4 expression and Adh4 formation, respectively. (b) Degradation of propionate generally involves methylmalonyl-CoA mutase (Sbm). Expression of sbm was upregulated during growth with 1-propanol, but not with a mixture of lactate and 1-propanol. Correspondingly, propionate was excreted during growth with this substrate mixture. (c) CO dehydrogenase, the key enzyme of the Wood-Ljungdahl pathway, is encoded by several genes (cdhC, cdh1 and cdh2) located at different genomic positions. Expression of all of these genes during heterotrophic and autotrophic growth points to a reversible operation of the Wood-Ljungdahl pathway. In summary, the different regulatory patterns displayed by Db. autotrophicum HRM2 at the tested metabolic levels point to a multi-layered regulatory network.
J Mol Microbiol Biotechnol 2010
PMID:Substrate-dependent regulation of carbon catabolism in marine sulfate-reducing Desulfobacterium autotrophicum HRM2. 2011 Jul 31

Vitamin B(12) (cobalamin) is essential in animals and humans for metabolism of methylmalonic acid, for the remethylation of homocysteine to methionine and, consequently, for all S-adenosylmethionine-dependent methylation reactions, including DNA synthesis. In man, cobalamin deficiency leads to anemia and neurologic and cognitive impairment. In the cblF inborn error of vitamin B(12) metabolism, free vitamin accumulates in lysosomes and cannot be converted to cofactors for mitochondrial methylmalonyl-CoA mutase and cytosolic methionine synthase. Recent work has shown that this defect is caused by mutations in the lysosomal membrane protein LMBD1, which shows significant homology to lipocalin membrane receptors, thereby indicating that LMBD1 is a lysosomal membrane exporter for cobalamin.
J Mol Med (Berl) 2010 May
PMID:Insights into lysosomal cobalamin trafficking: lessons learned from cblF disease. 2017 75

Cobalamin (Cbl, B(12)) is an essential micronutrient required to fulfill the enzymatic reactions of cytosolic methylcobalamin-dependent methionine synthase and mitochondrial adenosylcobalamin-dependent methylmalonyl-CoA mutase. Mutations in the MMACHC gene (cblC complementation group) disrupt processing of the upper-axial ligand of newly internalized cobalamins, leading to functional deficiency of the vitamin. Patients with cblC disease present with both hyperhomocysteinemia and methylmalonic acidemia, cognitive dysfunction, and megaloblastic anemia. In the present study we show that cultured skin fibroblasts from cblC patients export increased levels of both homocysteine and methylmalonic acid compared to control skin fibroblasts, and that they also have decreased levels of total intracellular folates. This is consistent with the clinical phenotype of functional cobalamin deficiency in vivo. The protein changes that accompany human functional Cbl deficiency are unknown. The proteome of control and cblC fibroblasts was quantitatively examined by two dimensional difference in-gel electrophoresis (2D-DIGE) and liquid chromatography-electrospray ionization-mass spectrometry (LC/ESI/MS). Major changes were observed in the expression levels of proteins involved in cytoskeleton organization and assembly, the neurological system and cell signaling. Pathway analysis of the differentially expressed proteins demonstrated strong associations with neurological disorders, muscular and skeletal disorders, and cardiovascular diseases in the cblC mutant cell lines. Supplementation of the cell cultures with hydroxocobalamin did not restore the cblC proteome to the patterns of expression observed in control cells. These results concur with the observed phenotype of patients with the cblC disorder and their sometimes poor response to treatment with hydroxocobalamin. Our findings could be valuable for designing alternative therapies to alleviate the clinical manifestation of the cblC disorder, as some of the protein changes detected in our study are common hallmarks of known pathologies such as Alzheimer's and Parkinson's diseases as well as muscular dystrophies.
Mol Genet Metab 2011 Jul
PMID:The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. 2149 20


<< Previous 1 2 3 4 5 6 Next >>