Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism1234

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ABSTRACT

Background:

One-carbon metabolism involves both mitochondrial and cytosolic forms of folate-dependent enzymes in mammalian cells, but few in vivo data exist to characterize the biochemical processes involved.

Objective:

We conducted a stable-isotopic investigation to determine the fates of exogenous serine and serine-derived one-carbon units in homocysteine remethylation in hepatic and whole-body metabolism.

Design:

A healthy man aged 23 y was administered [2,3,3-2H3]serine and [5,5,5-2H3]leucine by intravenous primed, constant infusion. Serial plasma samples were analyzed to determine the isotopic enrichment of free glycine, serine, leucine, methionine, and cystathionine. VLDL apolipoprotein B-100 served as an index of liver free amino acid labeling.

Results:

[2H1]Methionine and [2H2]methionine were labeled through homocysteine remethylation. We propose that [2H2]methionine occurs by remethylation with [2H2]methyl groups (as 5-methyltetrahydrofolate) formed only from cytosolic processing of [2H3]serine, whereas [2H1]methionine is formed with labeled one-carbon units from mitochondrial oxidation of C-3 serine to [2H1]formate to yield cytosolic [2H1]methyl groups. The labeling pattern of cystathionine formed from homocysteine and labeled serine suggests that cystathionine is derived mainly from a serine pool different from that used in apolipoprotein B-100 synthesis.

Conclusions:

The appearance of both [2H1]- and [2H2]methionine forms indicates that both cytosolic and mitochondrial metabolism of exogenous serine generates carbon units in vivo for methyl group production and homocysteine remethylation. This study also showed the utility of serine infusion and indicated functional roles of cytosolic and mitochondrial compartments in one-carbon metabolism.

KEY WORDS

Serine hydroxymethyltransferase
apolipoprotein B-100
methionine
homocysteine
cystathionine
leucine
remethylation
transsulfuration

Cited by (0)

1

From the Department of Nutritional Sciences, University of California Berkeley; the Food Science and Human Nutrition Department, the Institute of Food and Agricultural Sciences, University of Florida, Gainesville; and the Division of Endocrinology and Metabolism, the College of Medicine, the Departments of Medicine and Biochemistry and Molecular Biology, University of Florida, Gainesville.

2

Florida Agricultural Experiment Station journal series no. R-07701.

3

Supported in part by USDA-NRICGP grant 96-35200-3210 and NIH General Clinical Research Center grant RR00082. GJC was supported in part by postdoctoral fellowship award 9840016FL from the American Heart Association, Florida affiliate.

4

Address reprint requests to JF Gregory III, Food Science and Human Nutrition Department, University of Florida, PO Box 110370, Gainesville, FL 32611-0370. E-mail: [email protected].