The many flavors of hyperhomocyst(e)inemia: insights from transgenic and inhibitor-based mouse models of disrupted one-carbon metabolism.
Mouse models that perturb homocysteine metabolism, including genetic mouse models that result in deficiencies of methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine beta-synthase, and a pharmaceutically induced mouse model with a transient deficiency in betainehomocysteine methyl transferase, have now been characterized and can be compared. Although each of these enzyme deficiencies is associated with moderate to severe hyperhomocyst(e)inemia, the broader metabolic profiles are profoundly different. In particular, the various models differ in the degree to which tissue ratios of S-adenosylmethionine to S-adenosylhomocysteine are reduced in the face of elevated plasma homocyst(e)ine, and in the distribution of the tissue folate pools. These different metabolic profiles illustrate the potential complexities of hyperhomocyst(e)inemia in humans and suggest that comparison of the disease phenotypes of the various mouse models may be extremely useful in dissecting the underlying risk factors associated with human hyperhomocyst(e)inemia.
Elmore
C Lee
CL
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
Matthews
Rowena G
RG
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D003541:Cystathionine beta-Synthase / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D005287:Ferredoxin-NADP Reductase / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000378:metabolism*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D015394:Molecular Structure; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase
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