美国普林斯顿大学Joshua D. Rabinowitz团队近期取得重要工作进展，他们研究提出，丝氨酸羟甲基转移酶（SHMT）能维持甘氨酸的稳态。相关研究成果2024年1月2日在线发表于《细胞—代谢》杂志上。

据介绍，叶酸依赖性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个碳单元。这种单碳单位的生产在发育、免疫系统和癌症中起着关键作用。

使用啮齿动物模型，研究人员发现全身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了8倍。稳定同位素追踪显示，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。在对缺乏丝氨酸和甘氨酸饮食的反应中，从头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系统需求不敏感。相反，循环丝氨酸和甘氨酸的稳态是通过可变的消耗来维持的，肝脏SHMT2是主要的甘氨酸消耗酶。

附：英文原文

Title: Glycine homeostasis requires reverse SHMT flux

Author: Matthew J. McBride, Craig J. Hunter, Zhaoyue Zhang, Tara TeSlaa, Xincheng Xu, Gregory S. Ducker, Joshua D. Rabinowitz

Issue&Volume: 2024/01/02

Abstract: The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly convertsserine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbonunit 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 consumerather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 andgenetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold.Stable-isotope tracing revealed that the liver converts glycine to serine, which isthen converted by serine dehydratase into pyruvate and burned in the tricarboxylicacid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered, but SHMT2- and serine-dehydratase-mediated catabolicflux was lower. Thus, glucose-derived serine synthesis is largely insensitive to systemicdemand. Instead, circulating serine and glycine homeostasis is maintained throughvariable consumption, with liver SHMT2 a major glycine-consuming enzyme.

DOI: 10.1016/j.cmet.2023.12.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00452-7