Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats.

Stabler, Sally P.; Brass, Eric P.; Marcell, Paul D.; Allen, Robert H.

doi:10.1172/jci115148

Cited by 69 publications

(56 citation statements)

References 34 publications

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“…Thus, at the highest concentration of cobinamide tested, the cobinamide concentration was 400 times that of the deoxyadenosylcobalamin concentration. The lack of inhibition of either enzyme by cobinamide is consistent with studies reported by others on various cobalamin analogs including cobinamide (47,48).…”

Section: Efficacy Of Cobinamide As a No Scavenger In A Drosophilasupporting

confidence: 91%

“…Previous studies have found little or no toxicity of cobinamide to mammalian cells, but these studies were done at low micromolar or submicromolar concentrations of the drug (48,72,73). We similarly found no toxicity of cobinamide to mammalian cells at low micromolar concentrations but began to observe toxicity at a concentration of about 50 M. Because each cobinamide molecule can potentially neutralize two NO molecules (22), cobinamide may be able to neutralize NO concentrations up to 100 M before exhibiting significant toxicity.…”

Section: Discussionsupporting

confidence: 64%

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Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Broderick¹,

Veena²,

Zhuang

et al. 2005

Journal of Biological Chemistry

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Nitric oxide (NO) is an important signaling molecule, and a number of NO synthesis inhibitors and scavengers have been developed to allow study of NO functions and to reduce excess NO levels in disease states. We showed previously that cobinamide, a cobalamin (vitamin B 12 ) precursor, binds NO with high affinity, and we now evaluated the potential of cobinamide as a NO scavenger in biologic systems. We found that cobinamide reversed NO-stimulated fluid secretion in Drosophila Malpighian tubules, both when applied in the form of a NO donor and when produced intracellularly by nitricoxide synthase. Moreover, feeding flies cobinamide markedly attenuated subsequent NO-induced increases in tubular fluid secretion. Cobinamide was taken up efficiently by cultured rodent cells and prevented NOinduced phosphorylation of the vasodilator-stimulated phosphoprotein VASP both when NO was provided to the cells and when NO was generated intracellularly. Cobinamide appeared to act via scavenging NO because it reduced nitrite and nitrate concentrations in both the fly and mammalian cell systems, and it did not interfere with cGMP-induced phosphorylation of VASP. In rodent and human cells, cobinamide exhibited toxicity at concentrations >50 M with toxicity completely prevented by providing equimolar amounts of cobalamin. Combining cobalamin with cobinamide had no effect on the ability of cobinamide to scavenge NO. Cobinamide did not inhibit the in vitro activity of either of the two mammalian cobalamin-dependent enzymes, methionine synthase or methylmalonyl-coenzyme A mutase; however, it did inhibit the in vivo activities of the enzymes in the absence, but not presence, of cobalamin, suggesting that cobinamide toxicity was secondary to interference with cobalamin metabolism. As part of these studies, we developed a facile method for producing and purifying cobinamide. We conclude that cobinamide is an effective intra-and extracellular NO scavenger whose modest toxicity can be eliminated by cobalamin.

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Section: Efficacy Of Cobinamide As a No Scavenger In A Drosophilasupporting

confidence: 91%

Section: Discussionsupporting

confidence: 64%

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Broderick¹,

Veena²,

Zhuang

et al. 2005

Journal of Biological Chemistry

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“…Earlier efforts have used nutritional [16] and cobalamin-analog treatments [17] to induce methylmalonic aciduria in rats. Both of these treatments are artificial and produce an incomplete block, especially in the case of nutritional deficiency, causing combined methionine synthase and methylmalonylCoA mutase functional impairment.…”

Section: Introductionmentioning

confidence: 99%

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Chandler¹,

Aswani²,

Tsai³

et al. 2006

Molecular Genetics and Metabolism

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We have utilized Caenorhabditis elegans to study human methylmalonic acidemia. Using bioinformatics, a full complement of mammalian homologues for the conversion of propionyl-CoA to succinyl-CoA in the genome of C. elegans, including propionyl-CoA carboxylase subunits A and B (pcca-1, pccb-1), methylmalonic acidemia cobalamin A complementation group (mmaa-1), co(I) balamin adenosyltransferase (mmab-1), MMACHC (cblc-1), methylmalonyl-CoA epimerase (mce-1) and methylmalonyl-CoA mutase (mmcm-1) were identified. To verify predictions that the entire intracellular adenosylcobalamin metabolic pathway existed and was functional, the kinetic properties of the C. elegans mmcm-1 were examined. RNA interference against mmcm-1, mmab-1, mmaa-1 in the presence of propionic acid revealed a chemical phenotype of increased methylmalonic acid; deletion mutants of mmcm-1, mmab-1 and mce-1 displayed reduced 1-[ 14 C]-propionate incorporation into macromolecules. The mutants produced increased amounts of methylmalonic acid in the culture medium, proving that a functional block in the pathway caused metabolite accumulation. Lentiviral delivery of the C. elegans mmcm-1 into fibroblasts derived from a patient with mut o class methylmalonic acidemia could partially restore propionate flux. The C. elegans mce-1 deletion mutant demonstrates for the first time that a lesion at the racemase step of methylmalonyl-CoA metabolism can functionally impair flux through the methylmalonyl-CoA mutase pathway and suggests that malfunction of MCEE may cause methylmalonic acidemia in humans. The C. elegans system we describe represents the first lower metazoan model organism of mammalian propionate spectrum disorders and demonstrates that mass spectrometry can be employed to study a small molecule chemical phenotype in C. elegans RNAi and deletion mutants.

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“…We evaluated effects of the dodecylamine derivative of OH-Cbl (1.0 μmol/L) on total and holo-MCM activities of the cells grown in OH-Cbl (at 0, 0.1, and 1.0 μmol/L)-supplemented medium, compared with the OH-Cbl [c-lactam] that is known as the Cbl-dependent enzyme inhibitor [8] [9]. When total MCM activity was significantly decreased with increase in concentration of the added OH-Cbl, 1.0 μmol/L dodecylamine and c-lactam derivatives did not affect the total enzyme activity at each concentration of authentic OH-Cbl (Figure 4).…”

Section: Effect Of the Oh-cbl Dodecylamine Derivative And Oh-cbl [C-lmentioning

confidence: 99%

“…The Cbl analogue with a modification of the side chain of C-ring, Cbl [c-lactam], has been reported to antagonize Cbl in the cultured HL 60 cells [8]. Subcutaneous administration of hydroxocobalamin (OH-Cbl) [c-lactam] to rats has indicated that the analogue has the ability to act as a potent inhibitor of the mammalian Cbl-dependent enzymes to make the rats Cbl-deficient [9]. However, considerably high concentration of OH-Cbl [c-lactam] must be administrated for several weeks with osmotic mini pumps in order to prepare Cbl-deficient rats because IF hardly binds OH-Cbl [c-lactam] [9].…”

Section: Introductionmentioning

confidence: 99%

Dodecylamine Derivative of Hydroxocobalamin Acts as a Potent Inhibitor of Cobalamin-Dependent Methionine Synthase in Mammalian Cultured COS-7 Cells

Bito¹,

Yasui²,

Iwaki³

et al. 2014

FNS

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We evaluated whether the dodecylamine derivative of hydroxocobalamin acts as a potent inhibitor of cobalamin-dependent enzymes in an African green monkey kidney cell, COS-7. When the dodecylamine derivative (1.0 μmol/L) did not show any cytotoxicity in the cultured cells, the derivative could not affect methylmalonyl-CoA mutase (holo-enzyme) activity, but significantly inhibit methionine synthase (holo-enzyme) activity in the cell homogenates of COS-7 grown in 1.0 μmol/L hydroxocobalamin-supplemented medium. An immunoblot analysis indicated that the dodecylamine derivative could not decrease the protein level of methionine synthase, but significantly inhibit the enzyme activity.

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Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats.

Abstract: To determine which parts of the cobalamin (cbl)

Cited by 69 publications

References 34 publications

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Dodecylamine Derivative of Hydroxocobalamin Acts as a Potent Inhibitor of Cobalamin-Dependent Methionine Synthase in Mammalian Cultured COS-7 Cells

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