(R)-2-HG ---a-KG-dependent dioxygenases inhibitor

D-α-Hydroxyglutaric acid ((R)-2-Hydroxyglutarate) is the principal metabolite accumulating in neurometabolic disease D-2-hydroxyglutaric aciduria. D-α-Hydroxyglutaric acid is a weak competitive antagonist of α-ketoglutarate (α-KG) and inhibits multiple α-KG-dependent dioxygenases with a Ki of 10.87 mM. D-α-Hydroxyglutaric acid increases reactive oxygen species (ROS) production. D-α-Hydroxyglutaric acid binds and inhibits ATP synthase and inhibits mTOR signaling.

Product information

CAS Number: 103404-90-6

Molecular Weight: 192.08

Formula: C5H6Na2O5

Synonym:

D-alpha-Hydroxyglutaric acid disodium

D-2-Hydroxypentanedioic acid disodium salt

Disodium (R)-2-Hydroxyglutarate

2R-hydroxy-pentanedioic acid, disodium salt

D-alpha-Hydroxyglutaric acid disodium salt

Pentanedioic acid, 2-hydroxy-, disodium salt, (R)-

D-2-Hydroxypentanedioic acid-2Na+

disodium (2R)-2-hydroxypentanedioate

r-2-hydroxyglutaric acid disodium salt

D-A-HYDROXYGLUTARIC ACID DISODIUM

MDK4906

[R, (+)]-2-Hydroxyglutaric acid disodium salt

Chemical Name: sodium (R)-2-hydroxypentanedioate

Smiles: [Na+].[Na+].[O-]C(=O)CC[C@@H](O)C([O-])=O

InChiKey: DZHFTEDSQFPDPP-HWYNEVGZSA-L

InChi: InChI=1S/C5H8O5.2Na/c6-3(5(9)10)1-2-4(7)8;;/h3,6H,1-2H2,(H,7,8)(H,9,10);;/q;2*+1/p-2/t3-;;/m1../s1

Technical Data

Appearance: Solid powder

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Water up to 100 mM.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Powder: 4^oC for 1 year, -20^oC for 3 years. DMSO: 4^oC for 3 month.

Shelf Life: ≥1080 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

D-α-Hydroxyglutaric acid ((R)-2-hydroxyglutarate) accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. A partial inhibition of KDM7A toward both H3K9me2 and H3K27me2 peptides is observed in the presence of 50 mM D-2-HG and 100 μM α-ketoglutarate (α-KG). Addition of 300 μM α-KG is capable of reversing the inhibition of Caenorhabditis elegans KDM7A (CeKDM7A) by 50 mM D-2-HG, indicating that D-2-HG is a weak competitive inhibitor against α-KG toward the CeKDM7A demethylase. D-α-Hydroxyglutaric acid is a weak inhibitor of TET hydroxylases. In the presence of 0.1 mM of α-KG, addition of 10 mM D-α-Hydroxyglutaric acid results in a partial (33%) inhibition of TET2 and addition of 50 mM D-α-Hydroxyglutaric acid results in more inhibition (83%) of TET2. D-α-Hydroxyglutaric acid exhibits a less pronounced inhibitory effect toward TET1.

In Vivo:

D-α-Hydroxyglutaric acid ((R)-2-hydroxyglutarate) accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. A partial inhibition of KDM7A toward both H3K9me2 and H3K27me2 peptides is observed in the presence of 50 mM D-2-HG and 100 μM α-ketoglutarate (α-KG). Addition of 300 μM α-KG is capable of reversing the inhibition of Caenorhabditis elegans KDM7A (CeKDM7A) by 50 mM D-2-HG, indicating that D-2-HG is a weak competitive inhibitor against α-KG toward the CeKDM7A demethylase. D-α-Hydroxyglutaric acid is a weak inhibitor of TET hydroxylases. In the presence of 0.1 mM of α-KG, addition of 10 mM D-α-Hydroxyglutaric acid results in a partial (33%) inhibition of TET2 and addition of 50 mM D-α-Hydroxyglutaric acid results in more inhibition (83%) of TET2. D-α-Hydroxyglutaric acid exhibits a less pronounced inhibitory effect toward TET1.

References:

1. Xu W, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011 Jan 18;19(1):17-30.
2. Fu X, et al. 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab. 2015 Sep 1;22(3):508-15.
3. Martijn Kranendijk, et al. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis. 2012 Jul;35(4):571-87.
4. Martin Böttcher, et al. D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunology. 2018 Mar 26;7(7):e1445454.
5. Alexandra Latini , et al. D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur J Neurosci. 2003 May;17(10):2017-22.

Products are for research use only. Not for human use.