Home>>Signaling Pathways>> Proteases>> Endogenous Metabolite>>L-α-Hydroxyglutaric Acid

L-α-Hydroxyglutaric Acid

(Synonyms: S-2-羟基戊二酸,2(S)-HG, 2(S)-Hydroxyglutaric Acid, L-2-HG, L-2-Hydroxyglutaric Acid) 目录号 : GC41478

An α-hydroxy acid

L-α-Hydroxyglutaric Acid Chemical Structure

Cas No.:13095-48-2

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1mg
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5mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

CD8-positive T-lymphocytes

Preparation Method

Cells were activated with anti-CD3 and anti-CD28 antibodies for 48 h, then expanded for an additional 4 days in the presence of IL-2 and then treated with the indicated concentration of L-α-Hydroxyglutaric Acid for 16 h.

Reaction Conditions

300,500 μM L-α-Hydroxyglutaric Acid for 16 h

Applications

L-α-Hydroxyglutaric Acid inhibited the production of effector cytokines and reduced cytotoxicity. In addition, when the dose of L-α-Hydroxyglutaric Acid was more than 300 μM, L-α-Hydroxyglutaric Acid inhibited cell expansion, increased cell apoptosis, decreased IFN-γ secretion, but increased IL-2 secretion.

Animal experiment [2]:

Animal models

Wistar rats

Preparation Method

The homogenates of different mouse tissues were mixed with the corresponding buffer, and L-α-Hydroxyglutaric Acid at a final concentration of 0.25 to 5 mM was also added to the medium.

Dosage form

0.25 to 5 mM L-α-Hydroxyglutaric Acid for 15 min at 37 °C

Applications

When examined the effect of L-α-Hydroxyglutaric Acid, at concentrations varying from 1 to 5 mM, on CK activity in total homogenates from cerebellum, cerebral cortex, skeletal muscle and cardiac muscle. L-α-Hydroxyglutaric Acid did not alter tCK activities from cerebral cortex, skeletal muscle, and cardiac muscle, but significantly inhibited the enzyme activity from cerebellum at all concentrations tested.

References:

[1]. Tyrakis PA, Palazon A, et,al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature. 2016 Dec 8;540(7632):236-241. doi: 10.1038/nature20165. Epub 2016 Oct 26. PMID: 27798602; PMCID: PMC5149074.

[2]. da Silva CG, Bueno AR, et,al. L-2-hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats. Int J Dev Neurosci. 2003 Jun;21(4):217-24. doi: 10.1016/s0736-5748(03)00035-2. PMID: 12781789.

产品描述

L-α-Hydroxyglutaric Acid is an important metabolite in various domains of life. In mammals and plants, it is produced by lactate dehydrogenase (LDH) and malate dehydrogenase (MDH)-mediated 2-ketoglutarate (2-KG) reduction under hypoxic conditions[2]. L-α-Hydroxyglutaric Acid is an inhibitor of 2-KG dependent dioxygenases with specific pro-oncogenic capabilities[3,4].

In CD8-positive T-lymphocytes, L-α-Hydroxyglutaric Acid inhibited the production of effector cytokines and reduced cytotoxicity. In addition, when the dose of L-α-Hydroxyglutaric Acid was more than 300 μM, L-α-Hydroxyglutaric Acid inhibited cell expansion, increased cell apoptosis, decreased IFN-γ secretion, but increased IL-2 secretion[6].This compound was identified to aid the proliferation and antitumorigenic abilities of CD8+ T-lymphocytes, to contribute to relieving the cellular reductive stress[5].

When examined the effect of L-α-Hydroxyglutaric Acid, at concentrations varying from 1 to 5 mM, on CK activity in total homogenates from cerebellum, cerebral cortex, skeletal muscle and cardiac muscle. L-α-Hydroxyglutaric Acid did not alter tCK activities from cerebral cortex, skeletal muscle, and cardiac muscle, but significantly inhibited the enzyme activity from cerebellum at all concentrations tested. The inhibition of Mi-CK activity by L-α-Hydroxyglutaric Acid is non-competitive. The Km calculated was 2.52±0.74 mM. The Ki value was calculated by the method of which provides a simple way of determining the inhibition constant (Ki) for non-competitive inhibitors. The Ki value calculated was 11.13±3.71 mM for L-α-Hydroxyglutaric Acid [1].

Besides, in Zebrafish, L-α-Hydroxyglutaric Acid-induced apoptosis was caused by oxidation[7].

References:
[1]: da Silva CG, Bueno AR, et,al. L-2-hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats. Int J Dev Neurosci. 2003 Jun;21(4):217-24. doi: 10.1016/s0736-5748(03)00035-2. PMID: 12781789.
[2]: Oldham WM, Clish CB, et,al. Hypoxia-Mediated Increases in L-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress. Cell Metab. 2015 Aug 4;22(2):291-303. doi: 10.1016/j.cmet.2015.06.021. Epub 2015 Jul 23. PMID: 26212716; PMCID: PMC4526408.
[3]: Xu W, Yang H, et,al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011 Jan 18;19(1):17-30. doi: 10.1016/j.ccr.2010.12.014. PMID: 21251613; PMCID: PMC3229304.
[4]: Chowdhury R, Yeoh KK, et,al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011 May;12(5):463-9. doi: 10.1038/embor.2011.43. Epub 2011 Apr 1. PMID: 21460794; PMCID: PMC3090014.
[5]: Tyrakis PA, Palazon A, et,al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature. 2016 Dec 8;540(7632):236-241. doi: 10.1038/nature20165. Epub 2016 Oct 26. PMID: 27798602; PMCID: PMC5149074.
[6]: Tyrakis PA, Palazon A, et,al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature. 2016 Dec 8;540(7632):236-241. doi: 10.1038/nature20165. Epub 2016 Oct 26. PMID: 27798602; PMCID: PMC5149074.
[7]:Parng C, Ton C, et,al. A zebrafish assay for identifying neuroprotectants in vivo. Neurotoxicol Teratol. 2006 Jul-Aug;28(4):509-16. doi: 10.1016/j.ntt.2006.04.003. Epub 2006 Jun 30. PMID: 16814516.

L-α-羟基戊二酸是生命各个领域的重要代谢产物。在哺乳动物和植物中,它是在低氧条件下通过乳酸脱氢酶 (LDH) 和苹果酸脱氢酶 (MDH) 介导的 2-酮戊二酸 (2-KG) 还原产生的[2]。 L-α-Hydroxyglutaric Acid 是一种 2-KG 依赖性双加氧酶抑制剂,具有特定的促癌能力[3,4]

在 CD8 阳性 T 淋巴细胞中,L-α-羟基戊二酸可抑制效应细胞因子的产生并降低细胞毒性。此外,当L-α-羟基戊二酸的剂量大于300 μM时,L-α-羟基戊二酸抑制细胞增殖,增加细胞凋亡,减少IFN-γ分泌,但增加IL-2分泌[6 ].该化合物被鉴定为有助于 CD8+ T 淋巴细胞的增殖和抗肿瘤发生能力,有助于缓解细胞还原应激[5]

当检查浓度从 1 到 5 mM 不等的 L-α-羟基戊二酸对来自小脑、大脑皮层、骨骼肌和心肌的总匀浆中 CK 活性的影响时。 L-α-Hydroxyglutaric Acid 不改变大脑皮层、骨骼肌和心肌的 tCK 活性,但在所有测试浓度下显着抑制小脑的酶活性。 L-α-Hydroxyglutaric Acid 对 Mi-CK 活性的抑制是非竞争性的。计算的 Km 为 2.52±0.74 mM。 Ki 值的计算方法提供了一种简单的方法来确定非竞争性抑制剂的抑制常数 (Ki)。 L-α-羟基戊二酸[1]的Ki值为11.13±3.71 mM。

此外,在斑马鱼中,L-α-羟基戊二酸诱导的细胞凋亡是由氧化引起的[7]

Chemical Properties

Cas No. 13095-48-2 SDF
别名 S-2-羟基戊二酸,2(S)-HG, 2(S)-Hydroxyglutaric Acid, L-2-HG, L-2-Hydroxyglutaric Acid
化学名 2S-hydroxy-pentanedioic acid
Canonical SMILES OC(CC[C@H](O)C(O)=O)=O
分子式 C5H8O5 分子量 148.1
溶解度 10mg/mL in PBS, pH 7.2 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 6.7522 mL 33.761 mL 67.5219 mL
5 mM 1.3504 mL 6.7522 mL 13.5044 mL
10 mM 0.6752 mL 3.3761 mL 6.7522 mL
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Research Update

Enantioseparation of d,l-2-hydroxyglutaric acid by capillary electrophoresis with tandem mass spectrometry-Fast and efficient tool for d- and l-2-hydroxyglutaracidurias diagnosis

J Chromatogr A2016 Oct 7;1467:383-390.PMID: 27295961DOI: 10.1016/j.chroma.2016.05.095

A novel capillary electrophoresis-tandem mass spectrometry method for the enantioseparation and identification of 2-hydroxyglutaric acid enantiomers without derivatization for clinical purposes was described. Vancomycin chloride was used as an efficient chiral selector for the discrimination of 2-hydroxyglutaric acid enantiomers by capillary electrophoresis employed complete capillary filling method. The obtained resolution was 2.05. Hyphenation of CE with tandem mass spectrometry allows a reliable identification of separated enantiomers as well as their quantification. The method was validated and applied for the separation, identification and determination of 2-hydroxyglutaric enantiomers in urine samples obtained from healthy patients and two urine samples obtained from child patients suffering from high urine excretion of 2-hydroxyglutaric acid. Abnormal excretion of d-hydroxyglutaric acid was found in both child urine samples (104.5±2.1 and 2200.0±12.6mmol/mol of creatinine, respectively). The limits of detection for d- and L-Hydroxyglutaric Acid were 31 and 38nmol/L, respectively.

A zebrafish assay for identifying neuroprotectants in vivo

Neurotoxicol Teratol2006 Jul-Aug;28(4):509-16.PMID: 16814516DOI: 10.1016/j.ntt.2006.04.003

In this study, we developed an in vivo method to determine drug effects on oxidation-induced apoptosis in the zebrafish brain caused by treatment with L-Hydroxyglutaric Acid (LGA). We confirmed that LGA-induced apoptosis was caused by oxidation by examining the presence of an oxidative product, nitrotyrosine. Next, we examined the effects of 14 characterized neuroprotectants on LGA-treated zebrafish, including: D-methionine (D-Met), Indole-3-carbinol, deferoxamine (DFO), dihydroxybenzoate (DHB), deprenyl, L-NAME (N(G)-nitro-L-arginine methyl ester), n-acetyl L-cysteine (L-NAC), 2-oxothiazolidine-4-carboxylate (OTC), lipoic acid, minocycline, isatin, cortisone, ascorbic acid and alpha-tocopherol. Eleven of 14 neuroprotectants and 7 of 7 synthetic anti-oxidants exhibit significant protection in zebrafish. Buthionine sulfoximine (BSO), used as a negative control, exhibited no significant protective effects. In addition, three blood-brain barrier (BBB) impermeable compounds exhibited no significant effects. Our results in zebrafish were similar to results reported in mammals supporting the utility of this in vivo method for identifying potential neuroprotective anti-oxidants.