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 CO2, NH3, and a 1-carbon unit. CO2 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 CO2 generation in healthy volunteers (3 male, 3 female, aged 21–26 y), primed, constant infusions were conducted using 9.26 μmol·h−1·kg−1 of [1,2-13C]glycine and 1.87 μmol·h−1·kg−1 of [5,5,5-2H3]leucine, followed by an infusion protocol using [1-13C]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 [1,2-13C]glycine and [5,5,5-2H3]leucine and with [1-13C]glycine and [5,5,5-2H3]leucine tracers, which showed high reproducibility between the tracer protocols. Using the [1-13C]glycine tracer, breath CO2 data showed a total rate of glycine decarboxylation of 96 ± 8 μmol·h−1·kg−1, which was 22 ± 3% of whole-body glycine flux. In contrast, infusion of [1,2-13C]glycine yielded a glycine-to-CO2 flux of 146 ± 37 μmol·h−1·kg−1 (P = 0.026). By difference, this implies a rate of CO2 formation from the glycine 2-carbon of 51 ± 40 μmol·h−1·kg−1, which accounts for ∼35% of the total CO2 generated in glycine catabolism. These findings also indicate that ∼65% of the CO2 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 (∼96 μmol·h−1·kg−1), which is ∼20 times the demand for methyl groups for homocysteine remethylation.