Formate induces a metabolic switch in nucleotide and energy metabolism

Abstract

<jats:p>Formate is a precursor for the <jats:italic>de novo</jats:italic> synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. <jats:italic>In vivo</jats:italic> data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the <jats:italic>in vitro</jats:italic> observations are recapitulated in mice following intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.</jats:p>

A Transfer Hydrogenation Approach to Activity-Based Sensing of Formate in Living Cells

“…1−5 In mammals, formate concentrations normally reside in range of 10−100 μM in blood 1 and can rise to above 1 mM within cells; 6 moreover, its levels can fluctuate greatly between healthy and diseased states. 4,5 Indeed, increased formate overflow is a potential biomarker for neurodegenerative Alzheimer's disease 7 and a hallmark of oxidative stress in cancer. 8 In one striking clinical study, formate was posited as a potential biomarker for esophageal cancer progression, with the observation that formate levels progressively increased in esophageal tumors relative to normal mucosae from Stage I (8.45×) to Stage II (13.51×) to Stage III (14.84×) to Stage IV (21.48×).…”

“…9 Despite its significant contributions to the fundamental chemistry of the cell and potential translational applications to medicine, methods for monitoring formate within intact living biological specimens remain underdeveloped. Along these lines, current methods for formate analysis in biological samples include its derivatization through amide bond formation to formyl-2-nitrophenyl-hydrazide for detection by LC-MS, 10,11 enzyme-mediated colorimetric detection in postlysis specimens, 5,12 and NMR analysis, 9 all of which enable formate quantification but only in simple biochemical mixtures and/or with extensive sample processing/destruction. We envisioned that activity-based sensing (ABS), which leverages the intrinsic chemical reactivity of an analyte for its selective and sensitive detection, 13,14 could present a complementary strategy for formate analysis that is compatible with live cells and can provide spatiotemporal information regarding one-carbon metabolic flux.…”