Production of 1-Carbon Units from Glycine Is Extensive in Healthy Men and Women

Abstract

Glycine undergoes decarboxylation in the glycine cleavage system (GCS) to yield CO(2), NH(3), and a 1-carbon unit. CO(2) also can be generated from the 2-carbon of glycine by 10-formyltetrahydrofolate-dehydrogenase and, after glycine-to-serine conversion by serine hydroxymethyltransferase, from the tricarboxylic acid cycle. To evaluate the relative fates of glycine carbons in CO(2) generation in healthy volunteers (3 male, 3 female, aged 21-26 y), primed, constant infusions were conducted using 9.26 micromol x h(-1) x kg(-1) of [1,2-(13)C]glycine and 1.87 micromol x h(-1) x kg(-1) of [5,5,5-(2)H(3)]leucine, followed by an infusion protocol using [1-(13)C]glycine as the glycine tracer. The time period between the infusion protocols was >6 mo. In vivo rates of whole-body glycine and leucine flux were nearly identical in protocols with [1,2-(13)C]glycine and [5,5,5-(2)H(3)]leucine and with [1-(13)C]glycine and [5,5,5-(2)H(3)]leucine tracers, which showed high reproducibility between the tracer protocols. Using the [1-(13)C]glycine tracer, breath CO(2) data showed a total rate of glycine decarboxylation of 96 +/- 8 micromol x h(-1) x kg(-1), which was 22 +/- 3% of whole-body glycine flux. In contrast, infusion of [1,2-(13)C]glycine yielded a glycine-to-CO(2) flux of 146 +/- 37 micromol x h(-1) x kg(-1) (P = 0.026). By difference, this implies a rate of CO(2) formation from the glycine 2-carbon of 51 +/- 40 micromol x h(-1) x kg(-1), which accounts for approximately 35% of the total CO(2) generated in glycine catabolism. These findings also indicate that approximately 65% of the CO(2) generation from glycine occurs by decarboxylation, primarily from the GCS. Further, these results suggest that the GCS is responsible for the entry of 5,10-methylenetetrahydrofolate into 1-carbon metabolism at a very high rate ( approximately 96 micromol x h(-1) x kg(-1)), which is approximately 20 times the demand for methyl groups for homocysteine remethylation.

2061 Metabolism of Primed, Constant Infusions of [1,2-13c2] Glycine and [1-13c1] Phenylalanine to Urinary Oxalate

“…We did not detect the enrichment of either glycolate or oxalate with a single labeled carbon, indicating that the metabolism did not involve the splitting of the carbon-carbon bond. Whole body flux values were calculated for each of the glycine infusion levels (Table 2) and were similar to those previously reported [23][24][25][26][27]. Our results suggest that glycine metabolism increased at the higher infusion rate when plasma glycine levels were increased, as the flux was 72% higher (P = 0.02).…”

Structure of the Homodimeric Glycine Decarboxylase P-protein from Synechocystis sp. PCC 6803 Suggests a Mechanism for Redox Regulation

“…see Refs. [1][2][3][4][5][6]. Because the GCS-catalyzed reactions are reversible (7,8), they can also perform de novo synthesis of glycine from one-carbon units, CO 2 , and NH 3 (9,10).…”

Mammalian Mitochondrial and Cytosolic Folylpolyglutamate Synthetase Maintain the Subcellular Compartmentalization of Folates

“…However, a recent metabolomics study indicates that cytosolic purine synthesis incorporate carbon 13-labeled glycine only by direct incorporation by the glycinamide ribonucleotide synthetase reaction and not by 1-carbon transfers of C2 and C8 of the purine ring, and that the majority of C5-methyl groups of thymidylate come from serine and not mitochondrial glycine (37). Studies in intact mouse embryos and whole body studies in humans suggest that the majority of the methyl groups donated to S-adenosylhomocysteine are derived from mitochondrial folate metabolism and that the mitochondrial GCS generates as much as 20 times more 1-carbon units than needed for all methylation reactions (38,39). Recent studies have broadened our perspectives on mitochondrial 1-carbon metabolism with the observation that the large percentage of mitochondrial glycine-derived 1-carbon units in mammalian-transformed cells are oxidized completely, generating a major proportion of cellular NADPH (37).…”