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Li, H., Chawla, G., Hurlburt, A.J., Sterrett, M.C., Zaslaver, O., Cox, J., Karty, J.A., Rosebrock, A.P., Caudy, A.A., Tennessen, J.M. (2017). Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth.  Proc. Natl. Acad. Sci. U.S.A. 114(6): 1353--1358.
FlyBase ID
FBrf0234785
Publication Type
Research paper
Abstract

L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification, and cell differentiation. However, despite the ability of L-2HG to interfere with a broad range of cellular processes, this molecule is often characterized as a metabolic waste product. Here, we demonstrate that Drosophila larvae use the metabolic conditions established by aerobic glycolysis to both synthesize and accumulate high concentrations of L-2HG during normal developmental growth. A majority of the larval L-2HG pool is derived from glucose and dependent on the Drosophila estrogen-related receptor (dERR), which promotes L-2HG synthesis by up-regulating expression of the Drosophila homolog of lactate dehydrogenase (dLdh). We also show that dLDH is both necessary and sufficient for directly synthesizing L-2HG and the Drosophila homolog of L-2-hydroxyglutarate dehydrogenase (dL2HGDH), which encodes the enzyme that breaks down L-2HG, is required for stage-specific degradation of the L-2HG pool. In addition, dLDH also indirectly promotes L-2HG accumulation via synthesis of lactate, which activates a metabolic feed-forward mechanism that inhibits dL2HGDH activity and stabilizes L-2HG levels. Finally, we use a genetic approach to demonstrate that dLDH and L-2HG influence position effect variegation and DNA methylation, suggesting that this compound serves to coordinate glycolytic flux with epigenetic modifications. Overall, our studies demonstrate that growing animal tissues synthesize L-2HG in a controlled manner, reveal a mechanism that coordinates glucose catabolism with L-2HG synthesis, and establish the fly as a unique model system for studying the endogenous functions of L-2HG during cell growth and proliferation.

PubMed ID
PubMed Central ID
PMC5307464 (PMC) (EuropePMC)
Related Publication(s)
Personal communication to FlyBase

Genomic mapping data for ImpL3[16], ImpL3[17], and L2HGDH[14].
Tennessen, 2017.8.21, Genomic mapping data for ImpL3[16], ImpL3[17], and L2HGDH[14]. [FBrf0236424]

L2HGDH insertion from J. Tennessen.
Tennessen, 2018.4.27, L2HGDH insertion from J. Tennessen. [FBrf0238672]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Proc. Natl. Acad. Sci. U.S.A.
    Title
    Proceedings of the National Academy of Sciences of the United States of America
    Publication Year
    1915-
    ISBN/ISSN
    0027-8424
    Data From Reference
    Aberrations (1)
    Alleles (12)
    Genes (4)
    Human Disease Models (1)
    Natural transposons (2)
    Insertions (5)
    Experimental Tools (1)
    Transgenic Constructs (6)