Formaldehyde regulates <i>S</i> -adenosylmethionine biosynthesis and one-carbon metabolism
Vanha N. Pham, Kevin J. Bruemmer, Joel D. W. Toh, Eva J. Ge, Logan Tenney, Carl C. Ward, Felix A. Dingler, Christopher L. Millington, Carlos A. García‐Prieto, Mia C. Pulos-Holmes, Nicholas T. Ingolia, Lucas B. Pontel, Manel Esteller, Ketan J. Patel, Daniel K. Nomura, Christopher J. Chang
Abstract
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.