Formaldehyde regulates S-adenosylmethionine biosynthesis and one-carbon metabolism

• 成果类型: Article
• 署名作者: Pham, Vanha N.; Bruemmer, Kevin J.; Toh, Joel D. W.; Ge, Eva J.; Tenney, Logan; Ward, Carl C.; Dingler, Felix A.; Millington, Christopher L.; Garcia-Prieto, Carlos A.; Pulos-Holmes, Mia C.; Ingolia, Nicholas T.; Pontel, Lucas B.; Esteller, Manel; Patel, Ketan J.; Nomura, Daniel K.; Chang, Christopher J.
• 署名单位: University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of Oxford; Institut de Recerca Contra la Leucemia Josep Carreras (IJC); Universitat Politecnica de Catalunya; Barcelona Supercomputer Center (BSC-CNS); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Max Planck Society; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; ICREA; University of Barcelona; University of North Carolina; University of North Carolina Charlotte
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10823
• DOI: 10.1126/science.abp9201
• 发表日期: 2023-11-03
• 关键词: methionine adenosyltransferase; occupational-exposure; liver-disease; rat-liver; histone; cancer; serine; quantification; identification; transcription

摘要

One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. In this work, we show how formaldehyde (FA), a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. FA reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). FA exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic FA overload showed a decrease n SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle between FA and SAM one-carbon units.