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dc.contributor.authorChen, Fangyi
dc.contributor.authorBian, Ke
dc.contributor.authorTang, Qi
dc.contributor.authorHumulock, Zachary T.
dc.contributor.authorLi, Deyu
dc.contributor.authorFedeles, Bogdan I
dc.contributor.authorSingh, Vipender
dc.contributor.authorEssigmann, John M
dc.date.accessioned2018-09-17T16:16:25Z
dc.date.available2018-09-17T16:16:25Z
dc.date.issued2017-04
dc.identifier.issn0893-228X
dc.identifier.issn1520-5010
dc.identifier.urihttp://hdl.handle.net/1721.1/118110
dc.description.abstractCancer-associated mutations often lead to perturbed cellular energy metabolism and accumulation of potentially harmful oncometabolites. One example is the chiral molecule 2-hydroxyglutarate (2HG); its two stereoisomers (d- and l-2HG) have been found at abnormally high concentrations in tumors featuring anomalous metabolic pathways. 2HG has been demonstrated to competitively inhibit several α-ketoglutarate (αKG)- and non-heme iron-dependent dioxygenases, including some of the AlkB family DNA repair enzymes, such as ALKBH2 and ALKBH3. However, previous studies have only provided the IC50values of d-2HG on the enzymes, and the results have not been correlated to physiologically relevant concentrations of 2HG and αKG in cancer cells. In this work, we performed detailed kinetic analyses of DNA repair reactions catalyzed by ALKBH2, ALKBH3, and the bacterial AlkB in the presence of d- and l-2HG in both double- and single-stranded DNA contexts. We determined the kinetic parameters of inhibition, including kcat, KM, and Ki. We also correlated the relative concentrations of 2HG and αKG previously measured in tumor cells with the inhibitory effect of 2HG on the AlkB family enzymes. Both d- and l-2HG significantly inhibited the human DNA repair enzymes ALKBH2 and ALKBH3 at pathologically relevant concentrations (73-88% for d-2HG and 31-58% for l-2HG inhibition). This work provides a new perspective that the elevation of the d- or l-2HG concentration in cancer cells may contribute to an increased mutation rate by inhibiting the DNA repair performed by the AlkB family enzymes and thus exacerbate the genesis and progression of tumors.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant number 2 P20 GM103430)en_US
dc.description.sponsorshipRhode Island Foundation (Medical Research Funds grant)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant P01 CA2673)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant R01 CA080024)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant P30 ES002109)en_US
dc.publisherAmerican Chemical Society (ACS)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1021/ACS.CHEMRESTOX.7B00009en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePMCen_US
dc.titleOncometabolites D- and L-2-hydroxyglutarate Inhibit the AlkB Family DNA Repair Enzymes under Physiological Conditionsen_US
dc.typeArticleen_US
dc.identifier.citationChen, Fangyi, Ke Bian, Qi Tang, Bogdan I. Fedeles, Vipender Singh, Zachary T. Humulock, John M. Essigmann, and Deyu Li. “Oncometabolites D- and L-2-hydroxyglutarate Inhibit the AlkB Family DNA Repair Enzymes under Physiological Conditions.” Chemical Research in Toxicology 30, no. 4 (March 24, 2017): 1102–1110.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Center for Environmental Health Sciencesen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistryen_US
dc.contributor.mitauthorFedeles, Bogdan I
dc.contributor.mitauthorSingh, Vipender
dc.contributor.mitauthorEssigmann, John M
dc.contributor.mitauthorLi, Deyu
dc.relation.journalChemical Research in Toxicologyen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-08-28T18:18:25Z
dspace.orderedauthorsChen, Fangyi; Bian, Ke; Tang, Qi; Fedeles, Bogdan I.; Singh, Vipender; Humulock, Zachary T.; Essigmann, John M.; Li, Deyuen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-5252-826X
dc.identifier.orcidhttps://orcid.org/0000-0002-8241-4834
dc.identifier.orcidhttps://orcid.org/0000-0002-2196-5691
mit.licensePUBLISHER_POLICYen_US


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