Α-Hydroxyglutaric acid explained

α-Hydroxyglutaric acid (2-hydroxyglutaric acid) is an alpha hydroxy acid form of glutaric acid.

In biology

In humans the compound is formed by a hydroxyacid-oxoacid transhydrogenase whereas in bacteria is formed by a 2-hydroxyglutarate synthase. The compound can be converted to α-ketoglutaric acid through the action of a 2-hydroxyglutarate dehydrogenase which, in humans, are two enzymes called D2HGDH and L2HGDH. Deficiency in either of these two enzymes lead to a disease known as 2-hydroxyglutaric aciduria.

D-2-hydroxyglutarate

Mutations in isocitrate dehydrogenase (IDH1 and IDH2), which frequently occur in glioma and AML,[1] [2] [3] produce D-2-hydroxyglutarate from alpha-ketoglutarate.[4] D-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate, including histone lysine demethylases.[5] [6] This leads to a hypermethylated state of DNA and histones,[7] which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. Studies have also shown that 2-hydroxyglutarate may be converted back to alpha-ketoglutarate either enzymatically or non-enzymatically.[8] [9] Further studies are required to fully understand the dynamics between 2-hydroxyglutarate and alpha-ketoglutarate.

L-2-hydroxyglutarate

On the other hand, L-2-hydroxyglutarate is produced at high levels in low oxygen conditions, including cells of the immune system.[10]

Notes and References

  1. Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A . Monoclonal antibody specific for IDH1 R132H mutation . Acta Neuropathol. . 118 . 5 . 599–601 . November 2009 . 19798509 . 10.1007/s00401-009-0595-z . 36093146 .
  2. Ward PS, Patel J, Wise DR, etal . The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate . Cancer Cell . 17 . 3 . 225–34 . March 2010 . 20171147 . 2849316 . 10.1016/j.ccr.2010.01.020 .
  3. Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, Wang P, Yang H, Ma S, Lin H, Jiao B, Ren R, Ye D, Guan KL, Xiong Y . WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation . Molecular Cell . 57 . 4 . 662–73 . Feb 2015 . 25601757 . 10.1016/j.molcel.2014.12.023 . 4336627.
  4. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM . Cancer-associated IDH1 mutations produce 2-hydroxyglutarate . Nature . 465 . 7300 . 966 . Jun 2010 . 20559394 . 3766976 . 10.1038/nature09132 . 2010Natur.465..966D .
  5. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, McDonough MA, King ON, Clifton IJ, Klose RJ, Claridge TD, Ratcliffe PJ, Schofield CJ, Kawamura A . The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases . EMBO Rep . 12 . 5 . 463–9 . May 2011 . 21460794 . 3090014 . 10.1038/embor.2011.43 .
  6. Wang YP, Lei QY . Metabolic recoding of epigenetics in cancer . Cancer Commun (Lond) . 2018 . 38 . 1 . 1–8 . 29784032 . 10.1186/s40880-018-0302-3 . free . 5993135 .
  7. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases . Cancer Cell . 19 . 1 . 17–30 . Jan 2011 . 21251613 . 10.1016/j.ccr.2010.12.014 . 3229304.
  8. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RG, Yan H, Kaelin WG Jr . Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation . Nature . 483 . 7390 . 484–8 . Feb 2012 . 22343896 . 3656605 . 10.1038/nature10898 . 2012Natur.483..484K .
  9. Tarhonskaya H, Rydzik AM, Leung IK, Loik ND, Chan MC, Kawamura A, McCullagh JS, Claridge TD, Flashman E, Schofield CJ . Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases . Nat Commun . 5 . 3423 . Mar 2014 . 24594748 . 3959194 . 10.1038/ncomms4423 . 2014NatCo...5.3423T .
  10. Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Veliça P, You J, Chia GS, Sim J, Doedens A, Abelanet A, Evans CE, Griffiths JR, Poellinger L, Goldrath AW, Johnson RS . S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature . 540 . 7632 . 236–241 . Dec 2016 . 27798602 . 10.1038/nature20165 . 5149074. 2016Natur.540..236T.

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