Glycine homeostasis requires reverse SHMT flux.

The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbon unit production plays a critical role in development, the immune system, and cancer. Using rodent models, here we show that the whole-body SHMT flux acts to net consume rather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 and genetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold. Stable-isotope tracing revealed that the liver converts glycine to serine, which is then converted by serine dehydratase into pyruvate and burned in the tricarboxylic acid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered, but SHMT2- and serine-dehydratase-mediated catabolic flux was lower. Thus, glucose-derived serine synthesis is largely insensitive to systemic demand. Instead, circulating serine and glycine homeostasis is maintained through variable consumption, with liver SHMT2 a major glycine-consuming enzyme.

Glycine homeostasis requires reverse SHMT flux.

The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbon unit production plays a critical role in development, the immune system, and cancer. Here we show that the whole-body SHMT flux acts to net consume rather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 and genetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold. Stable isotope tracing revealed that the liver converts glycine to serine, which is then converted by serine dehydratase into pyruvate and burned in the tricarboxylic acid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered but SHMT2- and serine dehydratase-mediated catabolic flux was lower. Thus, glucose-derived serine synthesis does not respond to systemic demand. Instead, circulating serine and glycine homeostasis is maintained through variable consumption, with liver SHMT2 as a major glycine-consuming enzyme.

Initial signaling response to acute exercise bout is similar in hearts of rats bred for divergent exercise capacities.

Rats artificially selected as low capacity runners (LCR) exhibit features of the metabolic syndrome, and blunted exercise training-induced cardiac hypertrophy compared with high capacity runners (HCR). We tested the hypothesis that the divergent cardiac phenotypes may be due to diminished activation of signaling proteins in LCR vs HCR rats. LCR (n=18) and HCR (n=18) rats were randomly assigned to acute exercise or control groups. Ten minutes after a 10-min bout of high intensity treadmill exercise, rats were euthanized, and left ventricles (LV) were harvested. LV homogenates were immunoblotted for phosphorylated and total levels of extracellular regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, Akt, S6, and the ribosomal S6 protein kinases S6K and p90RSK. Alterations in protein ubiquitination were examined as an index of protein turnover. In LCR and HCR rats, S6 was activated to a similar extent after exercise (5-fold vs control), as were JNK1/2, p38, and ERK1/2 (each 1.5-fold). Exercise significantly reduced ubiquitination of some proteins, suggesting diminished post-exercise protein degradation. That no significant LCR/HCR differences were observed 10-min post-exercise in the signaling pathways studied herein suggests that the source of the differing cardiac phenotypes in LCR/HCR rats may involve differing activation times and/or other signaling pathways.