BDH2

Last update 08 May 2025

Basic Info

Synonyms

3-hydroxybutyrate dehydrogenase 2, 3-hydroxybutyrate dehydrogenase type 2, 4-oxo-L-proline reductase

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Introduction

NAD(H)-dependent dehydrogenase/reductase with a preference for cyclic substrates (By similarity) (PubMed:35150746). Catalyzes stereoselective conversion of 4-oxo-L-proline to cis-4-hydroxy-L-proline, likely a detoxification mechanism for ketoprolines (PubMed:35150746). Mediates the formation of 2,5-dihydroxybenzoate (2,5-DHBA), a siderophore that chelates free cytoplasmic iron and associates with LCN2, thereby regulating iron transport and homeostasis while protecting cells against free radical-induced oxidative stress. The iron-siderophore complex is imported into mitochondria, providing an iron source for mitochondrial metabolic processes in particular heme synthesis (By similarity). May act as a 3-hydroxybutyrate dehydrogenase (PubMed:16380372).

100 Clinical Results associated with BDH2

100 Translational Medicine associated with BDH2

0 Patents (Medical) associated with BDH2

Literatures (Medical) associated with BDH2

01 Mar 2025·The Spine Journal

Transcriptomic imputation identifies tissue-specific genes associated with cervical myelopathy

Article

Author: Margetis, Konstantinos ; Seah, Carina ; Karabacak, Mert

BACKGROUND CONTEXTDegenerative cervical myelopathy (DCM) is a progressive spinal condition that can lead to severe neurological dysfunction. Despite its degenerative pathophysiology, family history has shown to be a largely important factor in incidence and progression, suggesting that inherent genetic predisposition may play a role in pathophysiology.PURPOSETo determine the tissue-specific, functional genetic basis of hereditary predisposition to cervical myelopathy.STUDY DESIGNRetrospective case-control study using patient genetics and matched EHR from the Mount Sinai BioMe Biobank.METHODSIn a large, diverse, urban biobank of 32,031 individuals, with 558 individuals with cervical myopathy, we applied transcriptomic imputation to identify genetically regulated gene expression signatures associated with DCM. We performed drug-repurposing analysis using the CMAP database to identify candidate therapeutic interventions to reverse the cervical myelopathy-associated gene signature.RESULTSWe identified 16 genes significantly associated with DCM across 5 different tissues, suggesting tissue-specific manifestations of inherited genetic risk (upregulated: HES6, PI16, TMEM183A, BDH2, LINC00937, CLEC4D, USP43, SPATA1; downregulated: TTC12, CDK5, PAFAH1B2, RCSD1, KLHL29, PTPRG, RP11-620J15.3, C1RL). Drug repurposing identified 22 compounds with the potential to reverse the DCM-associated signature, suggesting points of therapeutic intervention.CONCLUSIONSThe inherited genetic risk for cervical myelopathy is functionally associated with genes involved in tissue-specific nociceptive and proliferative processes. These signatures may be reversed by candidate therapeutics with nociceptive, calcium channel modulating, and antiproliferative effects.CLINICAL SIGNIFICANCEUnderstanding the genetic basis of DCM provides critical insights into the hereditary factors contributing to the disease, allowing for more personalized and targeted therapeutic approaches. The identification of candidate drugs through transcriptomic imputation and drug repurposing analysis offers potential new treatments that could significantly improve patient outcomes and quality of life by addressing the underlying genetic mechanisms of DCM.

18 Feb 2025·Biochemistry

Kinetic and Thermodynamic Characterization of Human 4-Oxo-l-proline Reductase Catalysis

Article

Author: Pečaver, Ennio ; Harrison, David J. ; da Silva, Rafael G. ; Machado, Teresa F. G. ; Zickuhr, Greice M.

The enzyme 4-oxo-l-proline reductase (BDH2) has recently been identified in humans. BDH2, previously thought to be a cytosolic (R)-3-hydroxybutyrate dehydrogenase, actually catalyzes the NADH-dependent reduction of 4-oxo-l-proline to cis-4-hydroxy-l-proline, a compound with known anticancer activity. Here we provide an initial mechanistic characterization of the BDH2-catalyzed reaction. Haldane relationships show the reaction equilibrium strongly favors the formation of cis-4-hydroxy-l-proline. Stereospecific deuteration of NADH C4 coupled with mass spectrometry analysis of the reaction established that the pro-S hydrogen is transferred. NADH is co-purified with the enzyme, and a binding kinetics competition assays with NAD⁺ defined dissociation rate constants for NADH of 0.13 s^-1 at 5 °C and 7.2 s^-1 at 25 °C. Isothermal titration calorimetry at 25 °C defined equilibrium dissociation constants of 0.48 and 29 μM for the BDH2:NADH and BDH2:NAD⁺ complexes, respectively. Differential scanning fluorimetry showed BDH2 is highly thermostabilized by NADH and NAD⁺. The k_cat/K_M pH-rate profile indicates that a group with a pK_a of 7.3 and possibly another with a pK_a of 8.7 must be deprotonated and protonated, respectively, for maximum binding of 4-oxo-l-proline and/or catalysis, while the k_cat profile is largely insensitive to pH in the pH range used. The single-turnover rate constant is only 2-fold higher than k_cat. This agrees with a pre-steady-state burst of substrate consumption, suggesting that a step after chemistry, possibly product release, contributes to limit k_cat. A modest solvent viscosity effect on k_cat indicates that this step is only partially diffusional. Taken together, these data suggest chemistry does not limit the reaction rate but may contribute to it.

01 Feb 2025·Current Medical Science

Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes

Article

Author: Chen, Li-Zhen ; Ling, Shuang ; Xu, Jin-Wen ; Chen, Hong-Qing ; Zhang, Xin-Yuan

OBJECTIVEHypoxia plays a critical role in the pathophysiology of cardiomyopathy, myocardial infarction, and heart failure. Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic conditions. However, the expression and regulatory mechanisms of key enzymes in the ketone pathway under hypoxic conditions are still unclear. This study aimed to investigate the effects of hypoxia on the expression of key enzymes in the ketone metabolic pathway and the underlying regulatory mechanisms involved.METHODSH9C2 myocardial cells were cultured for 6 h in an oxygen-glucose-deprived state, and the expression of various genes was detected by quantitative real-time PCR. ELISA and lactate dehydrogenase (LDH) cytotoxicity assay were used to measure CoAs, itaconic acid, and LDH levels, respectively, and the dependence of gene expression on hypoxia-inducible factor-1 alpha (HIF-1α) was evaluated using the inhibitor LW6.RESULTSH9C2 cardiomyocytes exhibited increased ketone body metabolism in response to hypoxia. Hypoxia induced the expression of the ketone body enzymes succinyl-CoA:3-oxoacid CoA transferase (SCOT/OXCT1), 3-hydroxybutyrate dehydrogenase 2 (BDH2), and acyl-CoA: cholesterol acyltransferase 1 (ACAT1) in cardiomyocytes, with a concomitant increase in the level of acyl-CoA and a decrease in the level of succinyl-CoA. The HIF-1α inhibitor LW6 could partially reverse the expression of BDH2 and ACAT1, as well as the levels of succinyl-CoA. Interestingly, however, hypoxia-induced SCOT/OXCT1 expression was not regulated by the HIF-1α inhibitor. In addition, hypoxia promoted the expression of inflammatory factors.CONCLUSIONThese data confirm the critical role of ketone metabolism in myocardial hypoxia and help to elucidate the pathophysiology of cardiomyopathy, myocardial infarction and heart failure.

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BDH2

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