Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria

The primary hyperoxalurias (PH), types 1-3, are disorders of glyoxylate metabolism that result in increased oxalate production and calcium oxalate stone formation. The breakdown of trans-4-hydroxy-L-proline (Hyp) from endogenous and dietary sources of collagen makes a significant contribution to the...

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Bibliographic Details
Published in:	Biochemical journal Vol. 466; no. 2; p. 273
Main Authors:	Summitt, Candice B, Johnson, Lynnette C, Jönsson, Thomas J, Parsonage, Derek, Holmes, Ross P, Lowther, W Todd
Format:	Journal Article
Language:	English
Published:	England 01-03-2015
Subjects:	Biocatalysis Catalytic Domain Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Flavin-Adenine Dinucleotide - chemistry Flavin-Adenine Dinucleotide - metabolism Flavoproteins - chemistry Flavoproteins - genetics Flavoproteins - isolation & purification Flavoproteins - metabolism Furans - pharmacology Furans - therapeutic use Humans Hydroxyproline - chemistry Hydroxyproline - metabolism Hyperoxaluria, Primary - drug therapy Hyperoxaluria, Primary - enzymology Ligands Models, Molecular Mutant Proteins - antagonists & inhibitors Mutant Proteins - chemistry Mutant Proteins - isolation & purification Mutant Proteins - metabolism Peptide Fragments - antagonists & inhibitors Peptide Fragments - genetics Peptide Fragments - isolation & purification Peptide Fragments - metabolism Proline - metabolism Proline Oxidase - chemistry Proline Oxidase - genetics Proline Oxidase - isolation & purification Proline Oxidase - metabolism Protein Conformation Recombinant Proteins - chemistry Recombinant Proteins - isolation & purification Recombinant Proteins - metabolism Substrate Specificity Terminology as Topic Ubiquinone - analogs & derivatives Ubiquinone - chemistry Ubiquinone - metabolism
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Summary:	The primary hyperoxalurias (PH), types 1-3, are disorders of glyoxylate metabolism that result in increased oxalate production and calcium oxalate stone formation. The breakdown of trans-4-hydroxy-L-proline (Hyp) from endogenous and dietary sources of collagen makes a significant contribution to the cellular glyoxylate pool. Proline dehydrogenase 2 (PRODH2), historically known as hydroxyproline oxidase, is the first step in the hydroxyproline catabolic pathway and represents a drug target to reduce the glyoxylate and oxalate burden of PH patients. This study is the first report of the expression, purification, and biochemical characterization of human PRODH2. Evaluation of a panel of N-terminal and C-terminal truncation variants indicated that residues 157-515 contain the catalytic core with one FAD molecule. The 12-fold higher k(cat)/K(m) value of 0.93 M⁻¹·s⁻¹ for Hyp over Pro demonstrates the preference for Hyp as substrate. Moreover, an anaerobic titration determined a K(d) value of 125 μM for Hyp, a value ~1600-fold lower than the K(m) value. A survey of ubiquinone analogues revealed that menadione, duroquinone, and CoQ₁ reacted more efficiently than oxygen as the terminal electron acceptor during catalysis. Taken together, these data and the slow reactivity with sodium sulfite support that PRODH2 functions as a dehydrogenase and most likely utilizes CoQ₁₀ as the terminal electron acceptor in vivo. Thus, we propose that the name of PRODH2 be changed to hydroxyproline dehydrogenase (HYPDH). Three Hyp analogues were also identified to inhibit the activity of HYPDH, representing the first steps toward the development of a novel approach to treat all forms of PH.
ISSN:	1470-8728
DOI:	10.1042/BJ20141159