Activation of methionine synthase: Further characterization of the flavoprotein system

Fujii, Katsuhiko; Galivan, John; Huennekens, F.M.

doi:10.1016/0003-9861(77)90238-7

Cited by 92 publications

(82 citation statements)

References 28 publications

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“…1B). Every thousand or so turnovers, the active cob(I)alamin cofactor of methionine synthase becomes oxidized by molecular oxygen producing cob(II)alamin [9,10]. Cob(II)alamin is incapable of accepting a methyl group from methyltetrahydrofolate and must be reactivated by reductive methylation; the one-electron reduction is catalyzed by MTRR [1] and transfer of a methyl group from AdoMet [11] then regenerates the active methylcobalamin form of the enzyme (Fig.…”

Section: Introductionmentioning

confidence: 99%

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

122

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Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of methionine synthase activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase. This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity. Mtrr gt/gt mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate. Unexpectedly, Mtrr gt/gt mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocysteinemia may be useful in understanding biological effects of elevated homocyst(e)ine.

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Section: Introductionmentioning

confidence: 99%

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

122

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“…1) (8 -13). For the synthesis of CH 3 Cbl, cob(II)alamin associated with MS is reductively methylated to form CH 3 Cbl (6,14,15). For this reaction (which is also used for the reductive activation of MS following adventitious oxidation of the cobalamin cofactor), S-adenosylmethionine is the methyl-group donor and methionine synthase reductase (MSR) reduces cob(II)alamin to cob(I)alamin (16,17).…”

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confidence: 99%

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

Leal

Olteanu

Banerjee

et al. 2004

Journal of Biological Chemistry

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“…Cobalamin reductases have been studied previously in S. enterica, Clostridium tetanomorphum, Propionibacterium shermanii, Euglena gracilis, rat, rabbit and human (Brady & Barker, 1961;Brady et al, 1962;Fonseca & EscalanteSemerena, 2000, 2001Fujii & Huennekens, 1974;Fujii et al, 1977;Pezacka, 1993;Walker et al, 1969;Watanabe et al, 1987Watanabe et al, , 1993Watanabe et al, , 1996Weissbach et al, 1961;Wilson et al, 1999). Of the enzymes that have been investigated, the corresponding gene is known in five cases.…”

Section: Discussionmentioning

confidence: 99%

“…In S. enterica, the Fre protein was reported to catalyse the production of reduced flavin nucleotides which, in turn, reduce cob(III)alamin chemically to cob(II)alamin (Fonseca & Escalante-Semerena, 2000). The E. coli FldA protein, the human methionine synthase reductase (MSR) and the human novel reductase 1 (NR1) were shown to reduce cob(II)alamin to cob(I)alamin for the reductive activation of methionine synthase (Fujii et al, 1977;Olteanu & Banerjee, 2003;Paine et al, 2000;Wilson et al, 1999). In addition, the FldA protein in combination with the Fpr protein was reported to reduce cob(III)alamin to cob(I)alamin for AdoCbl production by the CobA adenosyltransferase (Fonseca & EscalanteSemerena, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…First, CNCbl is converted to HOCbl by cobalamin b-ligand transferase (Brady & Barker, 1961;Pezacka et al, 1990;Pezacka, 1993;Watanabe et al, 1987;Weissbach et al, 1962). Next, two successive one-electron reductions of the central cobalt atom of HOCbl lead to the formation of cob(II)alamin and cob(I)alamin (Brady & Barker, 1961;Brady et al, 1962;Fonseca & Escalante-Semerena, 2000, 2001Fujii & Huennekens, 1974;Fujii et al, 1977;Pezacka, 1993;Walker et al, 1969;Watanabe et al, 1987Watanabe et al, , 1993Watanabe et al, , 1996Weissbach et al, 1961). These reactions are catalysed by cob(III)alamin reductase and cob(II)alamin reductase, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical evidence that the pduS gene encodes a bifunctional cobalamin reductase

2005

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Salmonella enterica degrades 1,2-propanediol (1,2-PD) by a pathway that requires coenzyme B 12 (adenosylcobalamin; AdoCbl). The genes specifically involved in 1,2-PD utilization ( pdu) are found in a large contiguous cluster, the pdu locus. Earlier studies have indicated that this locus includes genes for the conversion of vitamin B 12 (cyanocobalamin; CNCbl) to AdoCbl and that the pduO gene encodes an ATP : cob(I)alamin adenosyltransferase which catalyses the terminal step of this process. Here, in vitro evidence is presented that the pduS gene encodes a bifunctional cobalamin reductase that catalyses two reductive steps needed for the conversion of CNCbl into AdoCbl. The PduS enzyme was produced in high levels in Escherichia coli. Enzyme assays showed that cell extracts from the PduS expression strain reduced cob(III)alamin (hydroxycobalamin) to cob(II)alamin at a rate of 91 nmol min "1 mg "1 and cob(II)alamin to cob(I)alamin at a rate of 7?8 nmol min "1 mg "1 . In contrast, control extracts had only 9?9 nmol min "1 mg "1 cob(III)alamin reductase activity and no detectable cob(II)alamin reductase activity. Thus, these results indicated that the PduS enzyme is a bifunctional cobalamin reductase. Enzyme assays also showed that the PduS enzyme reduced cob(II)alamin to cob(I)alamin for conversion into AdoCbl by purified PduO adenosyltransferase. Moreover, studies in which iodoacetate was used as a chemical trap for cob(I)alamin indicated that the PduS and PduO enzymes physically interact and that cob(I)alamin is sequestered during the conversion of cob(II)alamin to AdoCbl by these two enzymes. This is likely to be important physiologically, since cob(I)alamin is extremely reactive and would need to be protected from unproductive by-reactions. Lastly, bioinformatic analyses showed that the PduS enzyme is unrelated in amino acid sequence to enzymes of known function currently present in GenBank. Hence, results indicate that the PduS enzyme represents a new class of cobalamin reductase. INTRODUCTIONSalmonella enterica degrades 1,2-propanediol (1,2-PD) in a coenzyme B 12 (adenosylcobalamin; AdoCbl)-dependent fashion (Jeter, 1990). 1,2-PD is a major product of the fermentation of the common plant sugars rhamnose and fucose and is thought to be an important carbon source in anaerobic environments such as the large intestines of higher animals (Obradors et al., 1988;Toraya et al., 1980). Virtually all natural isolates of Salmonella degrade 1,2-PD and in vivo studies with mice have suggested that the degradation of this small molecule may be important for the interaction of S. enterica with its host organisms (Conner et al., 1998;Heithoff et al., 1999).The pathway of 1,2-PD degradation begins with the conversion of 1,2-PD to propionaldehyde by AdoCbldependent diol dehydratase (Bobik et al., 1997;Obradors et al., 1988;Toraya et al., 1979). Subsequently, propionaldehyde is converted to propanol and propionate by alcohol dehydrogenase, CoA-dependent propionaldehyde dehydrogenase, phosphotransacylase and propionate kinase (O...

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Activation of methionine synthase: Further characterization of the flavoprotein system

Cited by 92 publications

References 28 publications

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

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

Biochemical evidence that the pduS gene encodes a bifunctional cobalamin reductase

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