title: Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase.
abstract: 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 hyperhomocyst(e)inemia may be useful in understanding biological effects of elevated homocyst(e)ine.
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors: C Lee
authors: CL
authors: Elmore
authors: Xuchu
authors: X
authors: Wu
authors: Daniel
authors: D
authors: Leclerc
authors: Erica D
authors: ED
authors: Watson
authors: Teodoro
authors: T
authors: Bottiglieri
authors: Natalia I
authors: NI
authors: Krupenko
authors: Sergey A
authors: SA
authors: Krupenko
authors: James C
authors: JC
authors: Cross
authors: Rima
authors: R
authors: Rozen
authors: Roy A
authors: RA
authors: Gravel
authors: Rowena G
authors: RG
authors: Matthews
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics* / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism*; D006321:Heart / Q000196:embryology; D006710:Homocysteine / Q000097:blood / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000378:metabolism; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D006710:Homocysteine; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine; D008715:Methionine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase