D-α-Hydroxyglutaric Acid is a weak competitive antagonist of α‑ketoglutarate (α‑KG) (Ki = 10.87mM) [1]. D-α-Hydroxyglutaric Acid promotes ROS production, binds and inhibits ATP synthase—thus compromising mitochondrial respiration and shifting metabolism toward glycolysis—and suppresses mTOR signaling, impacting energy homeostasis and cell proliferation [2-3]. D-α-Hydroxyglutaric Acid is often used to study the mechanisms related to metabolic diseases and tumor metabolism [4].
In endothelial cells, D-α-Hydroxyglutaric Acid (10mM, 20mM; 8h) inhibits endothelial cell migration, wound healing, and tube formation by inhibiting cell proliferation [5]. In CD8 + T cells, D-α-Hydroxyglutaric Acid (0-20mM; 24h) inhibits cell proliferation in a dose-dependent manner [6]. In U251 cells, cell viability, total cell number, live cell count, and DNA replication decreased after D-α-Hydroxyglutaric Acid (500μM, 1000μM; 24h) treatment [7].
In C57BL/6 mice, D-α-Hydroxyglutaric Acid (50μg/g; ip; single injection) regulates local and systemic inflammatory responses in vivo [8].
References:
[1]. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases[J]. Cancer cell, 2011, 19(1): 17-30.
[2]. Fu X, Chin R M, Vergnes L, et al. 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling[J]. Cell metabolism, 2015, 22(3): 508-515.
[3]. Böttcher M, Renner K, Berger R, et al. D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization[J]. Oncoimmunology, 2018, 7(7): e1445454.
[4]. Ye D, Guan K L, Xiong Y. Metabolism, activity, and targeting of D-and L-2-hydroxyglutarates[J]. Trends in cancer, 2018, 4(2): 151-165.
[5]. Cao C, Zhang L, Sorensen M D, et al. D-2-hydroxyglutarate regulates human brain vascular endothelial cell proliferation and barrier function[J]. Journal of Neuropathology & Experimental Neurology, 2023, 82(11): 921-933.
[6]. Notarangelo G, Spinelli J B, Perez E M, et al. Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function[J]. Science, 2022, 377(6614): 1519-1529.
[7]. Tong S, Wu J, Song Y, et al. IDH1-mutant metabolite D-2-hydroxyglutarate inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT[J]. Cell Death Discovery, 2024, 10(1): 317.
[8]. de Goede K E, Harber K J, Gorki F S, et al. d-2-Hydroxyglutarate is an anti-inflammatory immunometabolite that accumulates in macrophages after TLR4 activation[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2022, 1868(9): 166427.
D-α-Hydroxyglutaric Acid是α-酮戊二酸（α-KG）的弱竞争性拮抗剂（Ki = 10.87mM） [1]。D-α-Hydroxyglutaric Acid促进活性氧（ROS）生成，结合并抑制ATP合酶，从而损害线粒体呼吸作用，使代谢转向糖酵解，并抑制mTOR信号传导，影响能量稳态和细胞增殖 [2-3]。D-α-Hydroxyglutaric Acid常用于研究代谢性疾病和肿瘤代谢相关机制 [4]。
在内皮细胞中，D-α-Hydroxyglutaric Acid（10mM、20mM；8h）通过抑制细胞增殖来抑制内皮细胞迁移、伤口愈合和管腔形成 [5]。在CD8+T细胞中，D-α-Hydroxyglutaric Acid（0-20mM；24h）以剂量依赖性方式抑制细胞增殖 [6]。在U251细胞中，经D-α-Hydroxyglutaric Acid（500μM，1000μM；24h）处理后，细胞活力、细胞总数、活细胞计数和DNA复制均降低 [7]。
在C57BL/6小鼠中，D-α-Hydroxyglutaric Acid（50μg/g；ip；单次注射）调节体内局部和全身炎症反应 [8]。