alpha-Hydroxyglutaric acid

α-Hydroxyglutaric acid
Names
	IUPAC name 2-Hydroxypentanedioic acid
	Other names 2-Hydroxyglutaric acid
Identifiers
CAS Number	2889-31-8 ;
3D model (JSmol)	Interactive image; Interactive image;
ChEBI	CHEBI:17084 ;
ChemSpider	42 ;
KEGG	C02630 ;
MeSH	Alpha-hydroxyglutarate
PubChem CID	43;
	InChI InChI=1S/C5H8O5/c6-3(5(9)10)1-2-4(7)8/h3,6H,1-2H2,(H,7,8)(H,9,10) Key: HWXBTNAVRSUOJR-UHFFFAOYSA-N ; InChI=1/C5H8O5/c6-3(5(9)10)1-2-4(7)8/h3,6H,1-2H2,(H,7,8)(H,9,10) Key: HWXBTNAVRSUOJR-UHFFFAOYAI;
	SMILES C(CC(=O)O)C(C(=O)O)O; O=C(O)C(O)CCC(=O)O;
Properties
Chemical formula	C5H8O5
Molar mass	148.114 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	verify (what is ?)
	Infobox references

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 to high levels in low oxygen conditions, including cells of the immune system.[10]

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References

Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A (November 2009). "Monoclonal antibody specific for IDH1 R132H mutation". Acta Neuropathol. 118 (5): 599–601. doi:10.1007/s00401-009-0595-z. PMID 19798509.
Ward PS, Patel J, Wise DR, et al. (March 2010). "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. doi:10.1016/j.ccr.2010.01.020. PMC 2849316. PMID 20171147.
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 (Feb 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Molecular Cell. 57 (4): 662–73. doi:10.1016/j.molcel.2014.12.023. PMC 4336627. PMID 25601757.
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 (Jun 2010). "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate". Nature. 465 (7300): 966. doi:10.1038/nature09132. PMC 3766976. PMID 20559394.
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 (May 2011). "The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases". EMBO Rep. 12 (5): 463–9. doi:10.1038/embor.2011.43. PMC 3090014. PMID 21460794.
Wang YP, Lei QY. "Metabolic recoding of epigenetics in cancer". Cancer Commun (Lond). 38 (1): 25. doi:10.1186/s40880-018-0302-3. PMC 5993135. PMID 29784032.
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 (Jan 2011). "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases". Cancer Cell. 19 (1): 17–30. doi:10.1016/j.ccr.2010.12.014. PMC 3229304. PMID 21251613.
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 (Feb 2012). "Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation" (PDF). Nature. 483 (7390): 484–8. doi:10.1038/nature10898. PMC 3656605. PMID 22343896.
Tarhonskaya H, Rydzik AM, Leung IK, Loik ND, Chan MC, Kawamura A, McCullagh JS, Claridge TD, Flashman E, Schofield CJ (Mar 2014). "Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases". Nat Commun. 5: 3423. doi:10.1038/ncomms4423. PMC 3959194. PMID 24594748.
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 (Dec 2016). "S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate". Nature. 540 (7632): 236–241. doi:10.1038/nature20165. PMC 5149074. PMID 27798602.

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[1] Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A (November 2009). "Monoclonal antibody specific for IDH1 R132H mutation". Acta Neuropathol. 118 (5): 599–601. doi:10.1007/s00401-009-0595-z. PMID 19798509.

[pmid20171147-2] Ward PS, Patel J, Wise DR, et al. (March 2010). "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. doi:10.1016/j.ccr.2010.01.020. PMC 2849316. PMID 20171147.

[pmid25601757-3] 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 (Feb 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Molecular Cell. 57 (4): 662–73. doi:10.1016/j.molcel.2014.12.023. PMC 4336627. PMID 25601757.

[pmid20559394-4] 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 (Jun 2010). "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate". Nature. 465 (7300): 966. doi:10.1038/nature09132. PMC 3766976. PMID 20559394.

[pmid21460794-5] 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 (May 2011). "The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases". EMBO Rep. 12 (5): 463–9. doi:10.1038/embor.2011.43. PMC 3090014. PMID 21460794.

[6] Wang YP, Lei QY. "Metabolic recoding of epigenetics in cancer". Cancer Commun (Lond). 38 (1): 25. doi:10.1186/s40880-018-0302-3. PMC 5993135. PMID 29784032.

[pmid21251613-7] 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 (Jan 2011). "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases". Cancer Cell. 19 (1): 17–30. doi:10.1016/j.ccr.2010.12.014. PMC 3229304. PMID 21251613.

[pmid22343896-8] 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 (Feb 2012). "Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation" (PDF). Nature. 483 (7390): 484–8. doi:10.1038/nature10898. PMC 3656605. PMID 22343896.

[pmid24594748-9] Tarhonskaya H, Rydzik AM, Leung IK, Loik ND, Chan MC, Kawamura A, McCullagh JS, Claridge TD, Flashman E, Schofield CJ (Mar 2014). "Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases". Nat Commun. 5: 3423. doi:10.1038/ncomms4423. PMC 3959194. PMID 24594748.

[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 (Dec 2016). "S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate". Nature. 540 (7632): 236–241. doi:10.1038/nature20165. PMC 5149074. PMID 27798602.