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, 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.

中文翻译：

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甘氨酸稳态需要反向 SHMT 通量

叶酸依赖性酶丝氨酸羟甲基转移酶 (SHMT) 可逆地将丝氨酸转化为甘氨酸和四氢叶酸结合的一碳单位。这种一碳单位的产生在发育、免疫系统和癌症中发挥着至关重要的作用。使用啮齿动物模型，我们表明全身 SHMT 通量起到净消耗而不是产生甘氨酸的作用。全身 SHMT1/2 的药理学抑制和肝脏 SHMT2 的基因敲除使循环甘氨酸水平升高达八倍。稳定同位素示踪显示，肝脏将甘氨酸转化为丝氨酸，然后丝氨酸脱水酶将丝氨酸转化为丙酮酸并在三羧酸循环中燃烧。针对缺乏丝氨酸和甘氨酸的饮食，生物合成通量没有改变，但 SHMT2 和丝氨酸脱水酶介导的分解代谢通量较低。因此，葡萄糖衍生的丝氨酸合成在很大程度上对全身需求不敏感。相反，循环丝氨酸和甘氨酸稳态是通过可变消耗来维持的，肝脏 SHMT2 是主要的甘氨酸消耗酶。