FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1569008313> ?p ?o ?g. }

• W1569008313 endingPage "200" @default.
• W1569008313 startingPage "198" @default.
• W1569008313 abstract "Two articles in this issue (Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar) show a new metabolic pathway regulated by hypoxia, but independently of HIF1 or HIF2. L-2-hydroxyglutarate, produced in hypoxia by malate dehydrogenases and LDHA, is a potent inhibitor of KDM4C, and through redox stress reduces glycolysis. Two articles in this issue (Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar) show a new metabolic pathway regulated by hypoxia, but independently of HIF1 or HIF2. L-2-hydroxyglutarate, produced in hypoxia by malate dehydrogenases and LDHA, is a potent inhibitor of KDM4C, and through redox stress reduces glycolysis. A key step in the Krebs cycle is the conversion of isocitrate to 2-oxoglutarate, and thereafter to succinate. Mutations in isocitrate dehydogenases IDH1 and IDH2 result in conversion of 2-oxoglutarate (also known as alpha-ketoglutarate) to D(R)-2-hydroxyglutarate, an oncometabolite that can inhibit enzymes that use 2-oxoglutarate as a cofactor with oxygen (Losman and Kaelin, 2013Losman J.A. Kaelin Jr., W.G. Genes Dev. 2013; 27: 836-852Crossref PubMed Scopus (432) Google Scholar). These are dioxygenases, which include TET1 and TET2, enzymes that modify 5-methylcytosine residues in DNA and hence gene transcription (Figure 1). Two papers published in this issue (Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar) describe another metabolite, a normal product of 2-oxoglutarate metabolism, the L(S)-2-hydroxyglutarate isomer. This metabolite was previously noted as a product of IDH in hypoxia, but its role was unknown. These papers present evidence of increased production of L-2-hydroxyglutarate in hypoxia. The accumulation of the metabolite is several fold and there is also a small induction of D-2-hydroxyglutarate. Both reports use cancer cell lines, but in particular, Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar focuses on endothelial cells and normal cell populations. This is not a cancer-specific effect, but may be more marked in cancer cell lines. Surprisingly, both papers showed that HIF1α had only minor effect on this hypoxia-induced metabolite change, and if anything, there was a small increase in the pathway when HIF1α was inhibited, and there was no effect of HIF2α knockdown (Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar). It is very surprising that HIF1α has little effect because one of the major mechanisms of this shift in Krebs cycle in hypoxia is regulation of pyruvate dehydrogenase kinase and phosphorylation of pyruvate dehydrogenase, which causes almost immediate rapid reduction in flux through the Krebs cycle. Thus, the mechanisms by which hypoxia induces the upregulation of this metabolite need further elucidation. Both articles showed that 2-oxoglutarate membrane permeable precursors could enhance the effect, although in the case of the Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar report, this is achieved by the precursor alone (dimethyl-alpha-ketoglutarate), whereas Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar required an inhibitor of an enzyme that degrades 2-oxoglutarate (OGDHC and alpha-keto-beta-methylvaleric acid), perhaps because of a different precursor, 3-trifluoromethylbenzyl-α-ketoglutarate ester (TFMB-2OG). Major differences between the D and the L isoforms exist in that the D form inhibits the TET enzymes, but it is also a substrate for the prolyl hydroxylase domain 2 (PHD2) or EGLN1 enzymes, preventing HIF upregulation. In contrast, the L metabolite inhibits PHD2 and TET1 and is indeed more potent than the D isoform against TET enzymes, producing a rather different biological effect, and potentially affecting HIF1α driven gene regulation (Chowdhury et al., 2011Chowdhury R. Yeoh K.K. Tian Y.M. Hillringhaus L. Bagg E.A. Rose N.R. Leung I.K. Li X.S. Woon E.C. Yang M. et al.EMBO Rep. 2011; 12: 463-469Crossref PubMed Scopus (738) Google Scholar). However, the downstream pathways investigated in the two papers differ markedly. Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar focused on the effects on histone demethylation, whereas Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar described effects on transcription of genes downstream of HIF1α, but in particular, changes in the redox regulation in the cells. L-2-hydroxyglutarate inhibited the H3K9me3 demethylase KDM4C. Considering the number of dioxygenases and that many have roles in chromatin modification (Salminen et al., 2015Salminen A. Kauppinen A. Kaarniranta K. Cell Mol. Life Sci. 2015; (Published online June 29, 2015)PubMed Google Scholar), this provides an important further mechanism for fine-tuning the hypoxia response in different cells and tissues. Depending on the fold induction of this metabolite, there may be far greater heterogeneity and adaptation than previously realized (Choudhry et al., 2014Choudhry H. Schödel J. Oikonomopoulos S. Camps C. Grampp S. Harris A.L. Ratcliffe P.J. Ragoussis J. Mole D.R. EMBO Rep. 2014; 15: 70-76Crossref PubMed Scopus (125) Google Scholar). The redox changes were associated with reduction of glycolysis and the shift in Krebs cycle to glycolysis. However, most of the latter effects were generated by manipulating L-2-hydroxyglutarate levels, rather than by hypoxia. Both reports agree that the source of L-2-hydroxyglutarate is not IDH1 and IDH2, but metabolism by MDH1 and MDH2. In Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, a much more important role of LDHA is shown and no effect of LDHB. Since the majority of the effects could be attributed to LDHA in the Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar report and to MDH2 in the Oldham et al., 2015Oldham W.M. Clish C. Yang Y. Loscalzo J. Cell Met. 2015; 22 (this issue): 291-303Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar report, the relevant roles of these enzymes in different cell types needs further clarification. Successful inhibition of mutant IDH1 and IDH2 has shown the continued dependence on cells that grown in the presence of these mutations for R-2-hydroxyglutarate. It would be much harder to make inhibitors that would be successful for the L-2-hydroxyglutarate, since attempts to produce useful inhibitors of LDHA have not been successful, and there are major concerns about producing inhibitors of mitochondrial enzymes and normal tissue toxicity. However, the glutamine pathway is clearly important under hypoxia, feeding into this metabolic process, and, with the availability of small molecule inhibitors of glutaminase (Xiang et al., 2015Xiang Y. Stine Z.E. Xia J. Lu Y. O’Connor R.S. Altman B.J. Hsieh A.L. Gouw A.M. Thomas A.G. Gao P. et al.J. Clin. Invest. 2015; 125: 2293-2306Crossref PubMed Scopus (273) Google Scholar) combined with the ability to deprive tumor cells of glutamate, may be an important therapeutic approach (Emadi et al., 2014Emadi A. Jun S.A. Tsukamoto T. Fathi A.T. Minden M.D. Dang C.V. Exp. Hematol. 2014; 42: 247-251Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). MYC also drives this pathway, although in those studies another enzyme was responsible, the mitochondrial aldehyde dehydrogenase iron-containing enzyme 1 (ADHFE1) and IDH2 (Terunuma et al., 2014Terunuma A. Putluri N. Mishra P. Mathé E.A. Dorsey T.H. Yi M. Wallace T.A. Issaq H.J. Zhou M. Killian J.K. et al.J. Clin. Invest. 2014; 124: 398-412Crossref PubMed Scopus (278) Google Scholar). Whether both L and D isoforms were present is not clear, as knockdown of D2HGDH did not affect levels, yet IDH2 knockdown prevented their generation. Tumors with high 2-hydroxyglutarate or DNA methylation patterns had a worse prognosis and high glutaminase expression. It was also shown that glutamine was the main precursor for the 2-hydroxyglutarate. The studies need to be repeated in hypoxia now. The levels of L-2-hydroxyglutarate or the indirect effects on H3K9me3 methylation could be useful monitors of in vivo hypoxia metabolism and could help classify hypoxia areas of tumors in a different way to using HIF1 or carbonic anhydrase 9 staining or pimonidazole binding (Jubb et al., 2010Jubb A.M. Buffa F.M. Harris A.L. J. Cell. Mol. Med. 2010; 14: 18-29Crossref PubMed Scopus (125) Google Scholar). Classification of hypoxia in tumors may be helpful for future personalization of radiotherapy and hypoxia-activated prodrugs. Intlekofer et al., 2015Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W.S. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Cell Met. 2015; 22 (this issue): 304-311Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar indeed showed that upregulation of H3K9me3 correlated with HIF1 in glioblastoma, but the time course of reversal of L-2-hydroxyglutarate after reoxygenation or demethylation of H3K9me3 is unclear and needs further investigation. For example, if there is discordance of overlap between HIF1α and these pathways in other tumor types, deciphering which of the biological pathways is active in a tumor is important. Individual tumors show great heterogeneity in the extent of hypoxic areas and genes expressed in them, and some with low HIF1α expression could potentially be driven by this metabolic pathway and would produce different types of hypoxia biology, relevant to interaction with drugs and radiation. Funding by the Breast Cancer Research Foundation to A.L.H." @default.
• W1569008313 created "2016-06-24" @default.
• W1569008313 creator A5079633934 @default.
• W1569008313 date "2015-08-01" @default.
• W1569008313 modified "2023-10-11" @default.
• W1569008313 title "A New Hydroxy Metabolite of 2-Oxoglutarate Regulates Metabolism in Hypoxia" @default.
• W1569008313 cites W1900467627 @default.
• W1569008313 cites W1916910865 @default.
• W1569008313 cites W1969697457 @default.
• W1569008313 cites W2004574994 @default.
• W1569008313 cites W2015755329 @default.
• W1569008313 cites W2044055595 @default.
• W1569008313 cites W2061122794 @default.
• W1569008313 cites W2149898004 @default.
• W1569008313 cites W2164219809 @default.
• W1569008313 doi "https://doi.org/10.1016/j.cmet.2015.07.016" @default.
• W1569008313 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26244928" @default.
• W1569008313 hasPublicationYear "2015" @default.
• W1569008313 type Work @default.
• W1569008313 sameAs 1569008313 @default.
• W1569008313 citedByCount "12" @default.
• W1569008313 countsByYear W15690083132016 @default.
• W1569008313 countsByYear W15690083132017 @default.
• W1569008313 countsByYear W15690083132018 @default.
• W1569008313 countsByYear W15690083132019 @default.
• W1569008313 countsByYear W15690083132020 @default.
• W1569008313 countsByYear W15690083132021 @default.
• W1569008313 countsByYear W15690083132023 @default.
• W1569008313 crossrefType "journal-article" @default.
• W1569008313 hasAuthorship W1569008313A5079633934 @default.
• W1569008313 hasBestOaLocation W15690083131 @default.
• W1569008313 hasConcept C178790620 @default.
• W1569008313 hasConcept C185592680 @default.
• W1569008313 hasConcept C2777477808 @default.
• W1569008313 hasConcept C540031477 @default.
• W1569008313 hasConcept C55493867 @default.
• W1569008313 hasConcept C62231903 @default.
• W1569008313 hasConcept C7836513 @default.
• W1569008313 hasConcept C86803240 @default.
• W1569008313 hasConcept C95444343 @default.
• W1569008313 hasConceptScore W1569008313C178790620 @default.
• W1569008313 hasConceptScore W1569008313C185592680 @default.
• W1569008313 hasConceptScore W1569008313C2777477808 @default.
• W1569008313 hasConceptScore W1569008313C540031477 @default.
• W1569008313 hasConceptScore W1569008313C55493867 @default.
• W1569008313 hasConceptScore W1569008313C62231903 @default.
• W1569008313 hasConceptScore W1569008313C7836513 @default.
• W1569008313 hasConceptScore W1569008313C86803240 @default.
• W1569008313 hasConceptScore W1569008313C95444343 @default.
• W1569008313 hasIssue "2" @default.
• W1569008313 hasLocation W15690083131 @default.
• W1569008313 hasLocation W15690083132 @default.
• W1569008313 hasOpenAccess W1569008313 @default.
• W1569008313 hasPrimaryLocation W15690083131 @default.
• W1569008313 hasRelatedWork W2003655561 @default.
• W1569008313 hasRelatedWork W2040035525 @default.
• W1569008313 hasRelatedWork W2045138402 @default.
• W1569008313 hasRelatedWork W2052493351 @default.
• W1569008313 hasRelatedWork W2126584409 @default.
• W1569008313 hasRelatedWork W2315955885 @default.
• W1569008313 hasRelatedWork W2351373426 @default.
• W1569008313 hasRelatedWork W2585431625 @default.
• W1569008313 hasRelatedWork W3169423050 @default.
• W1569008313 hasRelatedWork W3173417825 @default.
• W1569008313 hasVolume "22" @default.
• W1569008313 isParatext "false" @default.
• W1569008313 isRetracted "false" @default.
• W1569008313 magId "1569008313" @default.
• W1569008313 workType "article" @default.