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1 Food Science & Human Nutrition Department, Institute of Food Agricultural Sciences, University of Florida, Gainesville, FL, USA
2 Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, FL, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA
3 Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, FL, USA
4 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA
* To whom correspondence should be addressed. E-mail: jfgy{at}mail.ifas.ufl.edu.
Hyperhomocysteinemia in humans is associated with genetic variants of several enzymes of folate and one-carbon metabolism, and deficiencies of folate and vitamins B12 and B6. In each case hyperhomocysteinemia might be caused by diminished folate-dependent homocysteine remethylation, but this has not been confirmed in vivo. Since published stable isotopic tracer approaches cannot distinguish folate-dependent from folate-independent remethylation, we developed a dual tracer procedure in which a [U-13C5]methionine tracer is used in conjunction with a [3-13C]serine tracer to simultaneously measure rates of total and folate-dependent homocysteine remethylation. In young female subjects plasma [U-13C4]homocysteine enrichment, a surrogate measure of intracellular [U-13C5]methionine enrichment, reached ~90% of the plasma [U-13C5]methionine enrichment. Methionine-methyl and carboxyl group fluxes were in the range of previous reports (~25 and ~17 µmole kg-1 h-1, respectively). However, the rate of overall homocysteine remethylation (~8 µmole kg-1 h-1) was twice that of previous reports, which suggests a larger role for homocysteine remethylation in methionine metabolism than previously thought. Using estimates of intracellular [3-13C]serine enrichment based on a conservative correction of plasma [3-13C]serine enrichment, serine was calculated to contribute approximately 100% of the methyl groups used for total body homocysteine remethylation under the conditions of this protocol. This contribution represented only a small fraction (~2.8%) of total serine flux. Our dual tracer procedure is well suited to measure the effects of nutrient deficiencies, genetic polymorphisms, and other metabolic perturbations on homocysteine synthesis and total and folate-dependent homocysteine remethylation.
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