Effects of the disruption of transmethylation in the central nervous system: an animal model.
BACKGROUND
Central nervous system (CNS) methyltransferases methylate a wide range of substrates including proteins, lipids, nucleic acids and hormones. In every instance the methyl donor is S-adenosylmethionine (SAMe) and the demethylated product is S-adenosylhomocysteine (SAH). Methylation can be disrupted when there is an inadequate supply of methionine synthase (following vitamin B12 deficiency or folate deficiency), SAMe synthetase (due to ethanol), or SAH hydrolase (for unknown reasons).


METHODS
5-week-old pigs were maintained in an environment of either air or nitrous oxide, which inhibits methionine synthase, and were fed either a methionine-unsupplemented or methionine-enriched diet. After 3 to 10 weeks, pigs were killed by pentobarbitone injection and the levels of methionine and SAMe in the pigs' brain, spinal cord, plasma, liver, and kidney assessed.


RESULTS
Pigs maintained in nitrous oxide displayed a dramatic fall in methionine levels in plasma and brain tissues but maintained relatively normal SAMe levels in these tissues. Brain and spinal cord cystathionine levels were markedly elevated, especially in those animals receiving oral methionine, as in the absence of methionine synthase homocysteine can be metabolized only through the catabolic pathway to cystathionine and cysteine.


CONCLUSIONS
Disorders such as vitamin B12 deficiency or folate deficiency inhibit methylation by limiting the availability of SAMe or by elevating levels of the inhibitor SAH. In either case, the disruption of a wide range of methylation reactions can cause clinical sequelae ranging from structural abnormalities such as myelopathy to functional abnormalities such as depression.
Scott
J M
JM
Department of Biochemistry, Trinity College, Dublin, Ireland.
Molloy
A M
AM
Kennedy
D G
DG
Kennedy
S
S
Weir
D G
DG
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D003540:Cystathionine / Q000096:biosynthesis; D003866:Depressive Disorder / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000493:pharmacokinetics*; D013116:Spinal Cord / Q000378:metabolism*; D013552:Swine; D014804:Vitamin B Deficiency / Q000378:metabolism
D003540:Cystathionine; D012436:S-Adenosylmethionine; D008780:Methyltransferases; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase