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Glycine homeostasis requires reverse SHMT flux.
McBride, Matthew J; Hunter, Craig J; Zhang, Zhaoyue; TeSlaa, Tara; Xu, Xincheng; Ducker, Gregory S; Rabinowitz, Joshua D.
Afiliación
  • McBride MJ; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
  • Hunter CJ; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
  • Zhang Z; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • TeSlaa T; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Xu X; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Ducker GS; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Rabinowitz JD; Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA. Electronic address: joshr@princeton.edu.
Cell Metab ; 36(1): 103-115.e4, 2024 01 02.
Article en En | MEDLINE | ID: mdl-38171330
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicina Hidroximetiltransferasa / Glicina Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicina Hidroximetiltransferasa / Glicina Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos