D2HGDH

Last update 08 May 2025

Basic Info

Synonyms

D-2-hydroxyglutarate dehydrogenase, D-2-hydroxyglutarate dehydrogenase, mitochondrial, D2HGD

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Introduction

Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate (PubMed:15070399, PubMed:15609246, PubMed:16037974, PubMed:20020533, PubMed:33431826). Also catalyzes the oxidation of other D-2-hydroxyacids, such as D-malate (D-MAL) and D-lactate (D-LAC) (PubMed:33431826). Exhibits high activities towards D-2-HG and D-MAL but a very weak activity towards D-LAC (PubMed:33431826).

100 Clinical Results associated with D2HGDH

100 Translational Medicine associated with D2HGDH

0 Patents (Medical) associated with D2HGDH

232

Literatures (Medical) associated with D2HGDH

01 Jul 2025·Archives of Biochemistry and Biophysics

Biophysical investigation of metal-substituted D-2-hydroxyglutarate dehydrogenase

Article

Author: Moni, Bilkis Mehrin ; Quaye, Joanna Afokai ; Gadda, Giovanni

D-2-Hydroxyglutarate dehydrogenase from Pseudomonas aeruginosa PAO1 (EC: 1.1.99.39; Uniprot ID: Q9I6H4) is a metallo-flavoenzyme that utilizes Zn²⁺ and FAD to catalyze the conversion of D-2-hydroxyglutarate to 2-ketoglutarate. The enzyme utilizes Co²⁺, Ni²⁺, Mn²⁺, and Cd²⁺ as alternative metal cofactors. To study how metal substitution impacts flavin properties, the enzyme was purified with different metal ions or treated with EDTA to generate the metallo-apoenzyme (E_FAD-apo). Fluorescence assays revealed distinct metal ion binding sites in the enzyme: concentrations of metal ions up to ∼0.40 mM increased flavin fluorescence at 531 nm, whereas concentrations above ∼0.40 mM quenched flavin fluorescence with a 2-6 nm bathochromic shift. Concomitantly, enzyme-specific activity exhibited a sigmoidal increase, indicating a metal-induced conformational change. CD spectra showed no significant shifts at ∼209 and ∼220 nm but a ≤ 2-fold increase in mean residue ellipticity compared to E_FAD-apo. Metal binding also caused a 2-9 nm bathochromic shift in flavin absorption and emission maxima, indicating stabilization of the excited-state flavin π-electron system. The binding of Zn²⁺, Co²⁺, Mn²⁺, or Cd²⁺ to the enzyme increased by ∼1 unit of the pK_a value of the flavin N₃ atom compared to the E_FAD-apo, consistent with metal-hydrate perturbing flavin electronic properties. In contrast, Ni²⁺ binding decreased the pK_a value, consistent with flavin N₃ atom deprotonating before the Ni²⁺-hydrate in the enzyme active site. These findings reveal that metal ion substitution has minimal impact on the electronic properties of the flavin and the overall structural integrity of the enzyme, highlighting the potential use of metal-substituted variants of the enzyme as biomimetic catalysts.

01 Jun 2025·Cytokine

Novel genetic associations with childhood adipocytokines in Indian adolescents

Article

Author: Bharadwaj, Dwaipayan ; Bandesh, Khushdeep ; Nair, Janaki M ; Chakraborty, Shraddha ; Marwaha, Raman K ; Basu, Analabha ; Prasad, Gauri ; Tandon, Nikhil ; Chauhan, Ganesh ; Giri, Anil K

Adipocytokines, including leptin, adiponectin, and resistin, are key mediators linking adiposity, insulin resistance, and inflammation. We present the first genome-wide association study (GWAS; N = 5258) and exome-wide association study (ExWAS; N = 4578) on leptin, adiponectin, and resistin in South Asian population. We identified novel associations in genes ZNF467, and LEPREL2 for leptin; ZNF467, LEPREL2, CRLF3, ZNF732, SOX30, XIRP1, ATP8B3, SPATA2L, TMCO4, TLN2, ABCA12, and SHB for adiponectin; and D2HGDH for resistin. Additionally, we confirmed known associations of FTO, MC4R, and HOXB3 with leptin and ADIPOQ with adiponectin. Notably, ADIPOQ variants were consistently significant across GWAS, ExWAS, and gene-based analyses, reinforcing their central role in regulating adiponectin levels. Most of these novel associations identified were population-specific, highlighting the importance of studying diverse populations to uncover unique genetic signals. After adjusting for BMI, the associations with adiponectin and resistin remained significant, whereas most associations for leptin weakened in both effect size and significance. Functional annotation revealed that the identified variants were enriched for expression in adipose tissue, the brain (cerebellar hemisphere and cerebral cortex), and the pituitary gland. These variants act as eQTLs and splice-QTLs in adipose, brain, and pancreas, suggesting cross-tissue regulatory mechanisms. ExWAS further implicated rare variant burden in genes such as LONP1, ZNF335, and TTC16 for adiponectin and resistin. These findings enhance our understanding of adipocytokine biology, emphasises the need for population-specific genetic research, and lays foundation for future functional studies.

01 Jun 2025·Archives of Biochemistry and Biophysics

Oxidation of α-hydroxy acids by D-2-hydroxyglutarate dehydrogenase enzymes

Review

Author: Moni, Bilkis Mehrin ; Kugblenu, Jessica Eyram ; Gadda, Giovanni ; Quaye, Joanna Afokai

α-Hydroxy acids are naturally occurring organic molecules with various medical and industrial applications. However, some α-hydroxy acids, like D-2-hydroxyglutarate (D2HG), have been implicated in cancers and neurometabolic disorders such as D2HG aciduria. Several studies on the D2HG oxidizing enzyme D-2-hydroxyglutarate dehydrogenase (D2HGDH) from various eukaryotic and prokaryotic sources focus on the use and application of the enzyme as biosensors for detecting D2HG. A recent gene knockout study on the bacterial D2HGDH homologs from Pseudomonas stutzeri and Pseudomonas aeruginosa identified the D2HGDH to be essential for bacterial survival by driving l-serine biosynthesis. Thus, D2HGDH is a good candidate for a therapeutic target against the multidrug-resistant P. aeruginosa. However, there is no consensus on the D2HGDH catalytic mechanism, and several D2HGDH homologs have not been characterized in their structural properties, which are two crucial features for therapeutic design. P. aeruginosa D2HGDH, the most extensively studied D2HGDH homolog, is emerging as a paradigm for D2HGDH and flavoproteins with metal ions in their active site. In this review, we have explored the structures of all published D2HGDH homologs from 12 species using AlphaFold 3 and highlighted the fully conserved structure and active site topologies of all D2HGDH homologs. Additionally, evolutionary and functional studies coupled with analyses of enzymatic activities reveal that prokaryotic and eukaryotic D2HGDH homologs, diverging from two distinct ancestors, may have differentially evolved to specialize in their α-hydroxy acid catalysis. Additionally, this review identifies all D2HGDH homologs as metal and FAD-dependent enzymes that employ a metal-triggered FAD reduction in their catalysis. Elucidation of the D2HGDH mechanism will allow designing antibiotics that target these enzymes as potential therapeutics against pathogenic bacteria like P. aeruginosa in addition to the application of D2HGDH homologs as biosensors.

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D2HGDH

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