L-2-hydroxyglutarate production arises from noncanonical enzyme function at acidic pH Journal Article

   


Authors: Intlekofer, A. M.; Wang, B.; Liu, H.; Shah, H.; Carmona-Fontaine, C.; Rustenburg, A. S.; Salah, S.; Gunner, M. R.; Chodera, J. D.; Cross, J. R.; Thompson, C. B.
Article Title: L-2-hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
Abstract: The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function. © The Author(s) 2017.
Journal Title: Nature Chemical Biology
Volume: 13
Issue: 5
ISSN: 1552-4450
Publisher: Nature Publishing Group  
Date Published: 2017-05-01
Start Page: 494
End Page: 500
Language: English
DOI: 10.1038/nchembio.2307
PROVIDER: scopus
PUBMED: 28263965
PMCID: PMC5516644
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85014514282&doi=10.1038%2fnchembio.2307&partnerID=40&md5=f3d177a630bf57474f89f4dd167e213a
Notes: Article -- Export Date: 2 May 2017 -- Source: Scopus
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MSK Authors
  1. Justin Robert Cross
    111 Cross
  2. Carlos Manuel Carmona Fontaine
    8 Carmona Fontaine
  3. Craig Bernie Thompson
    153 Thompson
  4. Andrew Michael Intlekofer
    88 Intlekofer
  5. John Damon Chodera
    118 Chodera
  6. Hui Liu
    8 Liu
  7. Arien S Rustenburg
    14 Rustenburg
  8. Bo Wang
    4 Wang
  9. Hardik Shah
    4 Shah
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