PRODH2

Last update 08 May 2025

Basic Info

Synonyms

HSPOX1, Hydroxyproline dehydrogenase, HYPDH

+ [5]

Introduction

Dehydrogenase that converts trans-4-L-hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate (Hyp) using ubiquinone-10 as the terminal electron acceptor. Can also use proline as a substrate but with a very much lower efficiency. Does not react with other diastereomers of Hyp: trans-4-D-hydroxyproline and cis-4-L-hydroxyproline. Ubiquininone analogs such as menadione, duroquinone and ubiquinone-1 react more efficiently than oxygen as the terminal electron acceptor during catalysis.

100 Clinical Results associated with PRODH2

100 Translational Medicine associated with PRODH2

0 Patents (Medical) associated with PRODH2

Literatures (Medical) associated with PRODH2

01 Mar 2025·Archives of Biochemistry and Biophysics

Biochemical, structural, and cellular characterization of S-but-3-yn-2-ylglycine as a mechanism-based covalent inactivator of the flavoenzyme proline dehydrogenase

Article

Author: Ji, Juan ; Campbell, Ashley C ; Tadeo, Ada ; Benz, Christopher C ; Scott, Gary K ; Meeks, Kaylen R ; Nix, Jay C ; Tanner, John J ; Ellerby, Lisa M

The mitochondrial flavoenzymes proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (PRODH2) catalyze the first steps of proline and hydroxyproline catabolism, respectively. The enzymes are targets for chemical probe development because of their roles in cancer cell metabolism (PRODH) and primary hyperoxaluria (PRODH2). Mechanism-based inactivators of PRODH target the FAD by covalently modifying the N5 atom, with N-propargylglycine (NPPG) being the current best-in-class of this type of probe. Here we investigated a close analog of NPPG, but-3-yn-2-ylglycine (B32G), distinguished by having a methyl group adjacent to the ethynyl group of the propargyl warhead. UV-visible spectroscopy shows that a bacterial PRODH catalyzes the oxidation of the S-enantiomer of B32G, a necessary first step in mechanism-based inactivation. In contrast, the enzyme does not react with the R-enantiomer. Enzyme activity assays show that S-B32G inhibits bacterial PRODH in a time-dependent manner consistent with covalent inactivation; however, the inactivation efficiency is ∼600-times lower than NPPG. We generated the crystal structure of PRODH inactivated by S-B32G at 1.68 Å resolution and found that inactivation induces a covalent link between the FAD N5 and the ε-nitrogen of an active site lysine, confirming that S-B32G follows the same mechanism as NPPG. Despite its lower inactivation efficiency at the purified bacterial enzyme, S-B32G exhibited comparable activity to NPPG against PRODH and PRODH2 in human cells and mouse livers. Molecular modeling is used to rationalize the stereospecificity of B32G.

01 Jan 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Therapeutic targeting of HYPDH/PRODH2 with N-propargylglycine offers a Hyperoxaluria treatment opportunity

Article

Author: Tanner, John J ; Bons, Joanna ; Schilling, Birgit ; Benz, Christopher C ; Tadeo, Ada ; Ellerby, Lisa M ; Scott, Gary K ; Teramayi, Fadzai

N-propargylglycine prevents 4-hydroxyproline catabolism in mouse liver and kidney. N-propargylglycine is a novel suicide inhibitor of PRODH2 and induces mitochondrial degradation of PRODH2. PRODH2 is selectively expressed in liver and kidney and contributes to primary hyperoxaluria (PH). Preclinical evaluation of N-propargylglycine efficacy as a new PH therapeutic is warranted.

01 Jun 2023·iScience

Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis

Article

Author: Lu, Li ; Chen, Faling ; Gao, Tingting ; Lv, Zhibao ; Chen, Feng ; Xu, Weijue ; Qu, Wenqian ; Hu, Shaohua ; Guo, Ting ; Zhou, Jin

Epigenetic alterations are especially important in necrotizing enterocolitis (NEC). Here, we reported that histone deacetylase 8 (HDAC8) plays a previously unknown role in modulating arginine metabolism via acetylation of histone 3 lysine 9 (acetyl-H3K9) regulation during the pathogenesis of NEC. We found that HDAC8 was upregulated in humans and mice intestinal samples with NEC, while selective inhibition of HDAC8 expression ameliorated NEC. HDAC8 regulates enzymes involved in the metabolic conversion of proline to arginine (PRODH, PRODH2, OAT, and OTC) and arginine to ornithine (ARG1). The results showed that H3K9ac signal in the PRODH/PRODH2 promoter region was mediated by HDAC8. Additionally, the decreased concentration of butyric acid was strongly correlated with elevated HDAC8 levels and circulating arginine, which may result from an unbalanced Firmicutes/Bacteroidetes ratio. These results reveal previously underappreciated roles of microbial metabolites and HDAC8 to coordinate the arginine metabolism during NEC development.

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PRODH2

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