{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:38:04Z","timestamp":1792895884315,"version":"4.5.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007353","name":"Fondation J\u00e9r\u00f4me Lejeune","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007353","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004361","name":"Krebsliga Schweiz","doi-asserted-by":"publisher","award":["KLS-4504-08-2018"],"award-info":[{"award-number":["KLS-4504-08-2018"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005869","name":"University of Fribourg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005869","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell. Mol. Life Sci."],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cystathionine beta-synthase (CBS) is a pivotal enzyme of the transsulfuration pathway responsible for diverting homocysteine to the biosynthesis of cysteine and production of hydrogen sulfide (H<jats:sub>2<\/jats:sub>S). Aberrant upregulation of CBS and overproduction of H<jats:sub>2<\/jats:sub>S contribute to pathophysiology of several diseases including cancer and Down syndrome. Therefore, pharmacological CBS inhibition has emerged as a prospective therapeutic approach. Here, we characterized binding and inhibitory mechanism of aminooxyacetic acid (AOAA), the most commonly used CBS inhibitor. We found that AOAA binds CBS tighter than its respective substrates and forms a dead-end PLP-bound intermediate featuring an oxime bond. Surprisingly, serine, but not cysteine, replaced AOAA from CBS and formed an aminoacrylate reaction intermediate, which allowed for the continuation of the catalytic cycle. Indeed, serine rescued and essentially normalized the enzymatic activity of AOAA-inhibited CBS. Cellular studies confirmed that AOAA decreased H<jats:sub>2<\/jats:sub>S production and bioenergetics, while additional serine rescued CBS activity, H<jats:sub>2<\/jats:sub>S production and mitochondrial function. The crystal structure of AOAA-bound human CBS showed a lack of hydrogen bonding with residues G305 and Y308, found in the serine-bound model. Thus, AOAA-inhibited CBS could be reactivated by serine. This difference may be important in a cellular environment in multiple pathophysiological conditions and may modulate the CBS-inhibitory activity of AOAA. In addition, our results demonstrate additional complexities of using AOAA as a CBS-specific inhibitor of H<jats:sub>2<\/jats:sub>S biogenesis and point to the urgent need to develop a potent, selective and specific pharmacological CBS inhibitor.<\/jats:p>","DOI":"10.1007\/s00018-022-04479-9","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T22:02:23Z","timestamp":1658440943000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine"],"prefix":"10.1007","volume":"79","author":[{"given":"Maria","family":"Petrosino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Zuhra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jola","family":"Kopec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Hutchin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba","family":"Szabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2751-2124","authenticated-orcid":false,"given":"Tomas","family":"Majtan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"4479_CR1","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/0955-2863(90)90070-2","volume":"1","author":"JD Finkelstein","year":"1990","unstructured":"Finkelstein JD (1990) Methionine metabolism in mammals. J Nutr Biochem 1:228\u2013237","journal-title":"J Nutr Biochem"},{"issue":"5","key":"4479_CR2","doi-asserted-by":"publisher","first-page":"697","DOI":"10.3390\/biom10050697","volume":"10","author":"K Zuhra","year":"2020","unstructured":"Zuhra K et al (2020) Cystathionine-beta-synthase: molecular regulation and pharmacological inhibition. Biomolecules 10(5):697","journal-title":"Biomolecules"},{"issue":"17","key":"4479_CR3","doi-asserted-by":"publisher","first-page":"11601","DOI":"10.1074\/jbc.M808026200","volume":"284","author":"T Chiku","year":"2009","unstructured":"Chiku T et al (2009) H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem 284(17):11601\u201311612","journal-title":"J Biol Chem"},{"issue":"33","key":"4479_CR4","doi-asserted-by":"publisher","first-page":"22457","DOI":"10.1074\/jbc.M109.010868","volume":"284","author":"S Singh","year":"2009","unstructured":"Singh S et al (2009) Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. J Biol Chem 284(33):22457\u201322466","journal-title":"J Biol Chem"},{"issue":"4","key":"4479_CR5","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1089\/ars.2017.7009","volume":"28","author":"T Majtan","year":"2018","unstructured":"Majtan T et al (2018) Biogenesis of hydrogen sulfide and thioethers by cystathionine beta-synthase. Antioxid Redox Signal 28(4):311\u2013323","journal-title":"Antioxid Redox Signal"},{"key":"4479_CR6","first-page":"1","volume":"37","author":"SH Mudd","year":"1985","unstructured":"Mudd SH et al (1985) The natural history of homocystinuria due to cystathionine b-synthase deficiency. Am J Hum Genet 37:1\u201331","journal-title":"Am J Hum Genet"},{"key":"4479_CR7","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1007\/s00439-021-02386-w","volume":"141","author":"WD Kruger","year":"2021","unstructured":"Kruger WD (2021) How to fix a broken protein: restoring function to mutant human cystathionine beta-synthase. Hum Genet 141:1299\u20131308","journal-title":"Hum Genet"},{"issue":"13","key":"4479_CR8","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.2174\/1389450117666160302094910","volume":"17","author":"T Majtan","year":"2016","unstructured":"Majtan T et al (2016) Targeting cystathionine beta-synthase misfolding in homocystinuria by small ligands: state of the art and future directions. Curr Drug Targets 17(13):1455\u20131470","journal-title":"Curr Drug Targets"},{"issue":"30","key":"4479_CR9","doi-asserted-by":"publisher","first-page":"12474","DOI":"10.1073\/pnas.1306241110","volume":"110","author":"C Szabo","year":"2013","unstructured":"Szabo C et al (2013) Tumor-derived hydrogen sulfide, produced by cystathionine-beta-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci USA 110(30):12474\u201312479","journal-title":"Proc Natl Acad Sci USA"},{"issue":"11","key":"4479_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079167","volume":"8","author":"S Bhattacharyya","year":"2013","unstructured":"Bhattacharyya S et al (2013) Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance. PLoS\u00a0One 8(11):e79167","journal-title":"PLoS\u00a0One"},{"key":"4479_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102331","volume":"53","author":"K Ascencao","year":"2022","unstructured":"Ascencao K, Szabo C (2022) Emerging roles of cystathionine beta-synthase in various forms of cancer. Redox Biol 53:102331","journal-title":"Redox Biol"},{"issue":"38","key":"4479_CR12","doi-asserted-by":"publisher","first-page":"18769","DOI":"10.1073\/pnas.1911895116","volume":"116","author":"T Panagaki","year":"2019","unstructured":"Panagaki T et al (2019) Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome. Proc Natl Acad Sci USA 116(38):18769\u201318771","journal-title":"Proc Natl Acad Sci USA"},{"issue":"5","key":"4479_CR13","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1089\/adt.2009.0200","volume":"7","author":"TG Holt","year":"2009","unstructured":"Holt TG et al (2009) Label-free high-throughput screening via mass spectrometry: a single cystathionine quantitative method for multiple applications. Assay Drug Dev Technol 7(5):495\u2013506","journal-title":"Assay Drug Dev Technol"},{"issue":"17","key":"4479_CR14","doi-asserted-by":"publisher","first-page":"4641","DOI":"10.1002\/anie.201300841","volume":"52","author":"MK Thorson","year":"2013","unstructured":"Thorson MK et al (2013) Identification of cystathionine beta-synthase inhibitors using a hydrogen sulfide selective probe. Angew Chem Int Ed Engl 52(17):4641\u20134644","journal-title":"Angew Chem Int Ed Engl"},{"issue":"Pt A","key":"4479_CR15","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.phrs.2016.08.016","volume":"113","author":"N Druzhyna","year":"2016","unstructured":"Druzhyna N et al (2016) Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine beta-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer. Pharmacol Res 113(Pt A):18\u201337","journal-title":"Pharmacol Res"},{"issue":"17","key":"4479_CR16","doi-asserted-by":"publisher","first-page":"5267","DOI":"10.1016\/S0021-9258(17)33156-3","volume":"251","author":"T Beeler","year":"1976","unstructured":"Beeler T, Churchich JE (1976) Reactivity of the phosphopyridoxal groups of cystathionase. J Biol Chem 251(17):5267\u20135271","journal-title":"J Biol Chem"},{"issue":"4","key":"4479_CR17","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1002\/pro.3119","volume":"26","author":"NA Nadvi","year":"2017","unstructured":"Nadvi NA et al (2017) High resolution crystal structures of human kynurenine aminotransferase-I bound to PLP cofactor, and in complex with aminooxyacetate. Protein Sci 26(4):727\u2013736","journal-title":"Protein Sci"},{"issue":"22","key":"4479_CR18","doi-asserted-by":"publisher","first-page":"3134","DOI":"10.1021\/acs.biochem.8b00092","volume":"57","author":"YP Tu","year":"2018","unstructured":"Tu YP et al (2018) Crystal structures of cystathionine beta-synthase from saccharomyces cerevisiae: one enzymatic step at a time. Biochemistry 57(22):3134\u20133145","journal-title":"Biochemistry"},{"issue":"4","key":"4479_CR19","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1124\/pr.117.014050","volume":"69","author":"C Szabo","year":"2017","unstructured":"Szabo C, Papapetropoulos A (2017) International union of basic and clinical pharmacology. CII: pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. Pharmacol Rev 69(4):497\u2013564","journal-title":"Pharmacol Rev"},{"issue":"8","key":"4479_CR20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105290","volume":"9","author":"T Majtan","year":"2014","unstructured":"Majtan T et al (2014) Domain organization, catalysis and regulation of eukaryotic cystathionine beta-synthases. PLoS\u00a0One 9(8):e105290","journal-title":"PLoS\u00a0One"},{"issue":"40","key":"4479_CR21","doi-asserted-by":"publisher","first-page":"E3790","DOI":"10.1073\/pnas.1313683110","volume":"110","author":"J Ereno-Orbea","year":"2013","unstructured":"Ereno-Orbea J et al (2013) Structural basis of regulation and oligomerization of human cystathionine beta-synthase, the central enzyme of transsulfuration. Proc Natl Acad Sci USA 110(40):E3790\u2013E3799","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"4479_CR22","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1021\/bi026681n","volume":"42","author":"SM Aitken","year":"2003","unstructured":"Aitken SM, Kirsch JF (2003) Kinetics of the yeast cystathionine beta-synthase forward and reverse reactions: continuous assays and the equilibrium constant for the reaction. Biochemistry 42(2):571\u2013578","journal-title":"Biochemistry"},{"key":"4479_CR23","doi-asserted-by":"publisher","first-page":"3542","DOI":"10.1016\/j.csbj.2021.05.052","volume":"19","author":"C Fernandez-Rodriguez","year":"2021","unstructured":"Fernandez-Rodriguez C et al (2021) Structural insight into the unique conformation of cystathionine beta-synthase from Toxoplasma gondii. Comput Struct Biotechnol J 19:3542\u20133555","journal-title":"Comput Struct Biotechnol J"},{"key":"4479_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114267","volume":"182","author":"K Zuhra","year":"2020","unstructured":"Zuhra K et al (2020) Mechanism of cystathionine-\u03b2-synthase inhibition by disulfiram: the role of bis(N, N-diethyldithiocarbamate)-copper(II). Biochem Pharmacol 182:","journal-title":"Biochem Pharmacol"},{"issue":"Pt 4","key":"4479_CR25","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1107\/S0907444911007773","volume":"67","author":"C Vonrhein","year":"2011","unstructured":"Vonrhein C et al (2011) Data processing and analysis with the autoPROC toolbox. Acta Crystallogr D Biol Crystallogr 67(Pt 4):293\u2013302","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"4479_CR26","unstructured":"Tickle, I.J.F., C.; Keller, P.; Paciorek, W.; Sharff, A.; Vonrhein, C.; Bricogne, G., STARANISO (http:\/\/staraniso.globalphasing.org\/cgi-bin\/staraniso.cgi). 2018, Global Phasing Ltd.: Cambridge, UK."},{"issue":"Pt 4","key":"4479_CR27","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","volume":"40","author":"AJ McCoy","year":"2007","unstructured":"McCoy AJ et al (2007) Phaser crystallographic software. J Appl Crystallogr 40(Pt 4):658\u2013674","journal-title":"J Appl Crystallogr"},{"issue":"52","key":"4479_CR28","doi-asserted-by":"publisher","first-page":"36018","DOI":"10.1074\/jbc.M114.610782","volume":"289","author":"TJ McCorvie","year":"2014","unstructured":"McCorvie TJ et al (2014) Inter-domain communication of human cystathionine beta-synthase: structural basis of S-adenosyl-L-methionine activation. J Biol Chem 289(52):36018\u201336030","journal-title":"J Biol Chem"},{"issue":"Pt 12 Pt 1","key":"4479_CR29","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1107\/S0907444904019158","volume":"60","author":"P Emsley","year":"2004","unstructured":"Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60(Pt 12 Pt 1):2126\u20132132","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"4479_CR30","volume-title":"BUSTER","author":"GBE Bricogne","year":"2017","unstructured":"Bricogne GBE, Brandl M, Flensburg C, Keller P, Paciorek W, Roversi P, Sharff A, Smart OS, Vonrhein C, Womack TO (2017) BUSTER. Global Phasing Ltd., Cambridge"},{"issue":"Pt 1","key":"4479_CR31","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","volume":"66","author":"VB Chen","year":"2010","unstructured":"Chen VB et al (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 66(Pt 1):12\u201321","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"issue":"49","key":"4479_CR32","doi-asserted-by":"publisher","first-page":"20958","DOI":"10.1073\/pnas.1011448107","volume":"107","author":"M Koutmos","year":"2010","unstructured":"Koutmos M et al (2010) Structural basis for substrate activation and regulation by cystathionine beta-synthase (CBS) domains in cystathionine {beta}-synthase. Proc Natl Acad Sci USA 107(49):20958\u201320963","journal-title":"Proc Natl Acad Sci USA"},{"issue":"13","key":"4479_CR33","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen EF et al (2004) UCSF Chimera\u2013a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605\u20131612","journal-title":"J Comput Chem"},{"issue":"6","key":"4479_CR34","doi-asserted-by":"publisher","first-page":"4360","DOI":"10.1074\/jbc.M111.288423","volume":"287","author":"T Wang","year":"2012","unstructured":"Wang T, Leyh TS (2012) Three-stage assembly of the cysteine synthase complex from Escherichia coli. J Biol Chem 287(6):4360\u20134367","journal-title":"J Biol Chem"},{"issue":"11","key":"4479_CR35","doi-asserted-by":"publisher","first-page":"4513","DOI":"10.1073\/pnas.0807974105","volume":"106","author":"RDD Bianca","year":"2009","unstructured":"Bianca RDD et al (2009) Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci USA 106(11):4513\u20134518","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"4479_CR36","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/ajh.2011.149","volume":"25","author":"A Roy","year":"2012","unstructured":"Roy A et al (2012) Interdependency of cystathione gamma-lyase and cystathione beta-synthase in hydrogen sulfide-induced blood pressure regulation in rats. Am J Hypertens 25(1):74\u201381","journal-title":"Am J Hypertens"},{"issue":"2","key":"4479_CR37","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1152\/physrev.00017.2011","volume":"92","author":"R Wang","year":"2012","unstructured":"Wang R (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92(2):791\u2013896","journal-title":"Physiol Rev"},{"issue":"4","key":"4479_CR38","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1111\/bph.12171","volume":"169","author":"A Asimakopoulou","year":"2013","unstructured":"Asimakopoulou A et al (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE). Br J Pharmacol 169(4):922\u2013932","journal-title":"Br J Pharmacol"},{"issue":"3","key":"4479_CR39","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1042\/bj1710771","volume":"171","author":"RA John","year":"1978","unstructured":"John RA, Charteris A (1978) The reaction of amino-oxyacetate with pyridoxal phosphate-dependent enzymes. Biochem J 171(3):771\u2013779","journal-title":"Biochem J"},{"issue":"11","key":"4479_CR40","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1038\/nsb1101-963","volume":"8","author":"P Burkhard","year":"2001","unstructured":"Burkhard P et al (2001) Structural insight into Parkinson\u2019s disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol 8(11):963\u2013967","journal-title":"Nat Struct Biol"},{"key":"4479_CR41","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.abb.2013.10.002","volume":"544","author":"MD Toney","year":"2014","unstructured":"Toney MD (2014) Aspartate aminotransferase: an old dog teaches new tricks. Arch Biochem Biophys 544:119\u2013127","journal-title":"Arch Biochem Biophys"},{"issue":"3","key":"4479_CR42","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.jmb.2003.09.059","volume":"334","author":"N Choy","year":"2003","unstructured":"Choy N, Raussens V, Narayanaswami V (2003) Inter-molecular coiled-coil formation in human apolipoprotein E C-terminal domain. J Mol Biol 334(3):527\u2013539","journal-title":"J Mol Biol"},{"issue":"15","key":"4479_CR43","doi-asserted-by":"publisher","first-page":"3910","DOI":"10.1093\/emboj\/20.15.3910","volume":"20","author":"M Meier","year":"2001","unstructured":"Meier M et al (2001) Structure of human cystathionine beta-synthase: a unique pyridoxal 5\u2019-phosphate-dependent heme protein. Embo J 20(15):3910\u20133916","journal-title":"Embo J"},{"issue":"37","key":"4479_CR44","doi-asserted-by":"publisher","first-page":"E3845","DOI":"10.1073\/pnas.1414545111","volume":"111","author":"J Ereno-Orbea","year":"2014","unstructured":"Ereno-Orbea J et al (2014) Structural insight into the molecular mechanism of allosteric activation of human cystathionine beta-synthase by S-adenosylmethionine. Proc Natl Acad Sci USA 111(37):E3845\u2013E3852","journal-title":"Proc Natl Acad Sci USA"},{"key":"4479_CR45","doi-asserted-by":"publisher","first-page":"361","DOI":"10.2119\/molmed.2016.00102","volume":"22","author":"C Chao","year":"2016","unstructured":"Chao C et al (2016) Cystathionine-beta-synthase inhibition for colon cancer: enhancement of the efficacy of aminooxyacetic acid via the prodrug approach. Mol Med 22:361\u2013379","journal-title":"Mol Med"},{"issue":"4","key":"4479_CR46","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1016\/j.celrep.2014.04.045","volume":"7","author":"CF Labuschagne","year":"2014","unstructured":"Labuschagne CF et al (2014) Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 7(4):1248\u20131258","journal-title":"Cell Rep"},{"issue":"7424","key":"4479_CR47","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/nature11540","volume":"491","author":"B Chaneton","year":"2012","unstructured":"Chaneton B et al (2012) Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491(7424):458\u2013462","journal-title":"Nature"},{"issue":"11","key":"4479_CR48","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1016\/S0929-693X(97)88974-9","volume":"4","author":"C Mircher","year":"1997","unstructured":"Mircher C et al (1997) Variation of amino acids in relation to age in Down syndrome subjects. Arch Pediatr 4(11):1093\u20131099","journal-title":"Arch Pediatr"},{"issue":"1","key":"4479_CR49","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s10020-020-00225-8","volume":"26","author":"L Pecze","year":"2020","unstructured":"Pecze L, Randi EB, Szabo C (2020) Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome. Mol Med 26(1):102","journal-title":"Mol Med"},{"key":"4479_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104352","volume":"149","author":"JD Zeng","year":"2019","unstructured":"Zeng JD et al (2019) Serine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer. Pharmacol Res 149:104352","journal-title":"Pharmacol Res"},{"issue":"8","key":"4479_CR51","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/nrc3557","volume":"13","author":"JW Locasale","year":"2013","unstructured":"Locasale JW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13(8):572\u2013583","journal-title":"Nat Rev Cancer"},{"key":"4479_CR52","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10575","volume":"5","author":"XR Bao","year":"2016","unstructured":"Bao XR et al (2016) Mitochondrial dysfunction remodels one-carbon metabolism in human cells. Elife 5:e10575","journal-title":"Elife"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-022-04479-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-022-04479-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-022-04479-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T07:06:26Z","timestamp":1666508786000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-022-04479-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,21]]},"references-count":52,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["4479"],"URL":"https:\/\/doi.org\/10.1007\/s00018-022-04479-9","relation":{},"ISSN":["1420-682X","1420-9071"],"issn-type":[{"value":"1420-682X","type":"print"},{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,21]]},"assertion":[{"value":"2 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 June 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 July 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"438"}}