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Project Detail

Reversed Methyl Folate Trap In Zinc Deficiency

Project Number: 5R01DK033703-02 Source: National Institutes of Health
Principal Investigator: Tsunenobu Tamura Organization: University Of Alabama At Birmingham
Project Duration: 12/01/1984 - 11/30/1987 Fiscal Year: 1986
Recovery Act: No   No Award: no data

Application Type: Non-competing Continuation
Funding Institution: National Institute of Diabetes and Digestive and Kidney Diseases
Activity: Research Project
Year of Support: 2

In preliminary studies we have observed that the activity of methionine
synthetase as significantly increased in zinc-deficient rats (ZD) compared
to restricted-fed (RF) or ad-libitum-fed controls. Concomitantly, there
was: 1) a decreased proportion of methyltetrahydrofolate (methylTHF) in the
liver; 2) a reduction in plasma folate levels, and 3) an increased rate of
in vivo histidine oxidation. These phenomena represent a complete reversal
of what is observed in vitamin B12 deficiency and is currently known as the
"methyl trap" theory. In this condition, methionine synthetase activity is
inhibited and, as a result, there is increased methyl THF, elevated plasma
folate levels, and impaired histidine oxidation. We are calling the
altered folate metabolism due to zinc deficiency a "reverse methyl trap"
and hypothesize that the activity of methionine synthetase is, as in the
"classical "methyl trap", the factor primarily responsible for establishing
the steady-state distribution of the various folate coenzymes and for
increasing the rate of methyltetrahydrofolate turnover in tissues. We
postulate, furthermore, that the increased methionine synthetase activity
in zinc deficiency is due either to decreased levels of methionine (or
S-adenosylmethionine), or to changes in endocrine function secondary to
zinc deficiency.

To test the hypothesis, we propose the following specific aims: 1) To
determine the rate of methyltetrahydrofolate turnover and the relative
distribution and poly-Gamma-glytamyl chain length of various
one-carbonsubstituted folates in the liver of zinc-deficient rats; 2) To
study the effects of: a) methionine supplementation, b) testosterone
injections and c) thyroxine administration on the activities of methionine
synthetase, methylenetetrahydrofolate reductase, serine hydroxymethylase,
and formiminotransferase in ZD and RF rats. In these same animals we
propose to determine also the turnover of methyltetrahydrofolate, the
patterns of hepatic folate coenzymes and the rate of histidine oxidation.
In addition, to provide identical food intake to both ZD and control
groups, we will feed the liquid diets to rats using a gastric tube. This
experiment will be carried out particularly in evaluating the effects of
testosterone or thyroxine administration on the activities methionine
synthetase, and methylenetetrahydrofolate reductase in tube-fed ZD and
control rats.