Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B12 metabolism

Plesa, Maria; Kim, Jaeseung; Paquette, Stéphane G.; Gagnon, Hubert; Ng-Thow-Hing, Christopher; Gibbs, Bernard F.; Hancock, Mark A.; Rosenblatt, David S.; Coulton, James W.

doi:10.1016/j.ymgme.2010.10.011

Cited by 39 publications

(42 citation statements)

References 43 publications

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“…In a recent study, Mmachc mRNA was present and highly expressed in the bulbus cordis and endocardial cushion at E11 in mice (Pupavac et al 2011). The role of MMACHC in development is unknown but given that MMADHC, a related enzyme in the pathway and a MMACHC binding partner (Plesa et al 2011), was not expressed in the same temporal/spatial pattern may indicate a unique role for MMACHC in cardiac physiology and/or development (Pupavac et al 2011). Other factors related to the biology of MMACHC may be contributory: MMACHC can localize to mitochondria (Pagliarini et al 2008) and cblC patients and their fibroblasts have increased markers of oxidative stress suggesting underlying mitochondrial dysfunction (Richard et al 2009;Mc Guire et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

Tanpaiboon

Sloan

Callahan³

et al. 2012

JIMD Reports

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Cobalamin C disease (cblC), a form of combined methylmalonic acidemia and hyperhomocysteinemia caused by mutations in the MMACHC gene, may be the most common inborn error of intracellular cobalamin metabolism. The clinical manifestations of cblC disease are diverse and range from intrauterine growth retardation to adult onset neurological disease. The occurrence of structural heart defects appears to be increased in cblC patients and may be related to the function of the MMACHC enzyme during cardiac embryogenesis, a concept supported by the observation that Mmachc is expressed in the bulbis cordis of the developing mouse heart. Here we report an infant who presented with hydrops fetalis, ventricular dysfunction, and echocardiographic evidence of LVNC, a rare congenital cardiomyopathy. Metabolic evaluations, complementation studies, and mutation analysis confirmed the diagnosis of cblC disease. These findings highlight an intrauterine cardiac phenotype that can be displayed in cblC disease in association with nonimmune hydrops.

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Section: Discussionmentioning

confidence: 99%

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

Tanpaiboon

Sloan

Callahan³

et al. 2012

JIMD Reports

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“…Work by Stucki et al indicated that MMADHC is a single protein with two different domains that interact with either cytosolic or mitochondrial targets [ 48 ]. Plesa et al were the first to demonstrate that MMACHC and MMADHC interact [ 49 ]. Surface plasmon resonance studies showed that the two proteins interact at a 1:1 stoichiometry with an affinity in the midnanomolar range [ 49 ].…”

Section: Biophysical and Structural Characterization Of The B 12 -Promentioning

confidence: 99%

“…Plesa et al were the first to demonstrate that MMACHC and MMADHC interact [ 49 ]. Surface plasmon resonance studies showed that the two proteins interact at a 1:1 stoichiometry with an affinity in the midnanomolar range [ 49 ]. Phage display assays identified five putative MMACHC-binding sites.…”

Section: Biophysical and Structural Characterization Of The B 12 -Promentioning

confidence: 99%

“…Phage display assays identified five putative MMACHC-binding sites. Two of these belong within the ABC-transporter homology domain, and the other three potential binding sites comprise residues in the C-terminal portion of MMADHC [ 49 ]. Further, phage display studies performed by Deme et al identified several putative MMACHC binding sites in MMADHC, as well as self-binding regions in MMACHC [ 50 ].…”

Section: Biophysical and Structural Characterization Of The B 12 -Promentioning

confidence: 99%

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Proteomics of vitamin B12 processing

Hannibal

DiBello

Jacobsen³

2013

Clinical Chemistry and Laboratory Medicine

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The causes of cobalamin (B 12 , Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B 12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B 12 deficiency in a cblC -disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.

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“…For instance, it has been shown that MMACHC can catalyze a reductive decyanation reaction of cyanocobalamin (CNCbl) to yield cob(II)alamin (Kim et al 2008) and a dealkylation reaction of AdoCbl or MeCbl using glutathione as an electron donor Kim et al 2009). Furthermore, MMACHC has been proposed to interact with combined methylmalonic aciduria and homocystinuria cblD type (MMADHC), the downstream protein in the cobalamin pathway (Deme et al 2012;Plesa et al 2011). Recently the three-dimensional structure of human MMACHC was determined (Froese et al 2012;Koutmos et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type

et al. 2013

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Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B 12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.

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Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B12 metabolism

Cited by 39 publications

References 43 publications

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

Proteomics of vitamin B12 processing

Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type

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