Human ATP:Cob(I)alamin Adenosyltransferase and Its Interaction with Methionine Synthase Reductase

Leal, Nicole A.; Olteanu, Horatiu; Banerjee, Ruma; Bobik, Thomas A.

doi:10.1074/jbc.m405449200

Cited by 61 publications

(65 citation statements)

References 38 publications

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“…Associated SNPs include a non-synonymous SNP in MMAB, rs9593. Although both alleles of rs9593, encoding lysine and methionine, are predicted to have normal physiological activity (20), we cannot exclude that this variant may also affect HDL-C level.…”

Section: Discussionmentioning

confidence: 97%

“…MMAB is a mitochondrial enzyme that catalyzes conversion of vitamin B12 into its active form, adenosylcobalamin (4). MMAB is an essential participant in the catabolism of certain amino acids, short chain fatty acids and the side chain of cholesterol to the citric acid cycle intermediate succinyl-CoA (20). An increase in expression of MMAB might therefore be expected to lower levels of total cholesterol, including levels of HDL-C.…”

Section: Discussionmentioning

confidence: 99%

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Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK

Fogarty

Xiao

Prokunina‐Olsson

et al. 2010

Human Molecular Genetics

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Genome-wide association studies (GWAS) have identified numerous loci associated with various complex traits for which the underlying susceptibility gene(s) remain unknown. In a GWAS for high-density lipoprotein-cholesterol (HDL-C) level, one strongly associated locus contains at least two biologically compelling candidates, methylmalonic aciduria cblB type (MMAB) and mevalonate kinase (MVK). To detect evidence of cis-acting regulation at this locus, we measured relative allelic expression of transcribed SNPs in five genes using human hepatocyte samples heterozygous for the transcribed SNP. If an HDL-C-associated SNP allele differentially regulates mRNA level in cis, samples heterozygous both for a transcribed SNP and an HDL-C-associated SNP should display allelic expression imbalance (AEI) of the transcribed SNP. We designed statistical tests to detect AEI in a comprehensive set of linkage disequilibrium (LD) scenarios between the transcribed SNP and an HDL-C-associated SNP (rs7298565) in phase unknown samples. We observed significant AEI of 22% in MMAB (P 5 1.4 3 10 213 , transcribed SNP rs11067231), and the allele associated with lower HDL-C level was associated with greater MMAB transcript level. The same rs7298565 allele was also associated with higher MMAB mRNA level (P 5 0.0081) and higher MMAB protein level (P 5 0.0020). In contrast, MVK, UBE3B, KCTD10 and ACACB did not show significant AEI (P ! 0.05). These data suggest MMAB is the most likely gene influencing HDL-C levels at this locus and demonstrate that measuring AEI at loci containing more than one candidate gene can prioritize genes for functional studies.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK

Fogarty

Xiao

Prokunina‐Olsson

et al. 2010

Human Molecular Genetics

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“…It is not known if a dedicated reductase couples to the ATR. In vitro studies have demonstrated that flavoprotein oxidoreductases such methionine synthase reductase, ferredoxin, and flavodoxin can couple to ATRs (64,65).…”

Section: Tailoring Of Adocbl In the Mitochondrionmentioning

confidence: 99%

Navigating the B12 Road: Assimilation, Delivery, and Disorders of Cobalamin

Gherasim

Lofgren

Banerjee

2013

Journal of Biological Chemistry

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168

123

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The reactivity of the cobalt-carbon bond in cobalamins is the key to their chemical versatility, supporting both methyl transfer and isomerization reactions. During evolution of higher eukaryotes that utilize vitamin B 12 , the high reactivity of the cofactor coupled with its low abundance pressured development of an efficient system for uptake, assimilation, and delivery of the cofactor to client B 12 -dependent enzymes. Although most proteins suspected to be involved in B 12 trafficking were discovered by 2009, the recent identification of a new protein reveals that the quest for elucidating the intracellular B 12 highway is still far from complete. Herein, we review the biochemistry of cobalamin trafficking.Cofactors are variously deployed in nature to stabilize macromolecular structures, expand catalytic functionality, transport gases, transduce signals, and function as sensors. Due to their relative rarity and/or reactivity, cells have evolved strategies for sequestering and regulating the movement of cofactors from their point of entry into the cell to their point of docking in target proteins (1). A subset of cofactors, i.e. the vitamins, is obtained in a precursor form from the diet. Reactions catalyzing the assimilation of inactive cofactors into their active forms are integral to their trafficking pathways. Similarly, elaboration of metals into clusters often occurs on chaperones that subsequently transfer the cofactor to target proteins. The interprotein transfer of metals can occur via ligand exchange reactions that are driven by differences in metal coordination geometry and affinity between the donor and acceptor proteins (2, 3). Seclusion of cofactors in chaperones during assembly/processing into their active forms minimizes unwanted side reactions, whereas guided delivery averts dilution and promotes specificity of cofactor docking.In contrast to our understanding of cellular strategies used for trafficking metals (4 -6) and metal clusters (7), significantly less is known about strategies for shepherding organic and organometallic cofactors to target proteins. This picture has been changing, however, with the convergence of clinical genetics and biochemical approaches that are beginning to illuminate an elaborate pathway for assimilation and delivery of dietary vitamin B 12 or cobalt-containing cobalamin, a complex organometallic cofactor (8 -10). Much less is known about how the tetrapyrrolic cousins of B 12 , e.g. iron protoporphyrin (heme), nickel corphin (F430), and magnesium chlorin (chlorophyll), are guided to specific destinations.In this minireview, we describe a model for mammalian cobalamin trafficking, which includes strategies for conversion of inactive precursors to the active cofactor forms methylcobalamin (MeCbl) 3 and 5Ј-deoxyadenosylcobalamin (AdoCbl; coenzyme B 12 ) and discuss the human diseases that result from impairments along the trafficking highway. We posit that the navigation strategy for B 12 , in which a rare, reactive, and high value cofactor is sequestered and targ...

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“…Leal et al performed direct complementation of a bacterial pduO mutant with a bovine cDNA expression library, isolated the bovine homologue and then the human gene homologue which they called ATP: cob(I)alamin adenosyltransferase (ATR) [23]. Recently, methionine synthase reductase (MSR), an enzyme thought to have a primary role in the reductive reactivation of methionine synthase, has been demonstrated to localize to the mitochondria and associate with the MMAB gene product in vitro [25]. A model for MSR involvement in the ATP:cob(I)alamin adenosyltransferase reaction has been proposed.…”

Section: Mmabmentioning

confidence: 99%

“…The position of the MMAA gene product reflects the probable role that this protein has in the protection of MCM [22]. A mitochondrial isoform of the methionine synthase reductase gene may protect or interact with the product of the MMAB gene [25] and is shown with a dashed line.…”

Section: Other Eukaryotic Model Systemsmentioning

confidence: 99%

Genetic and genomic systems to study methylmalonic acidemia

Chandler

Venditti

2005

Molecular Genetics and Metabolism

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Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinylCoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia.

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Human ATP:Cob(I)alamin Adenosyltransferase and Its Interaction with Methionine Synthase Reductase

Cited by 61 publications

References 38 publications

Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK

Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK

Navigating the B12 Road: Assimilation, Delivery, and Disorders of Cobalamin

Genetic and genomic systems to study methylmalonic acidemia

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