15-hydroxyprostaglandin dehydrogenase (NAD+): Difference between revisions

 

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* [[ML148]] <ref>Niesen FH, Schultz L, Jadhav A, Bhatia C, Guo K, Maloney DJ, Pilka ES, Wang M, Oppermann U, Heightman TD, Simeonov A. High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships. ”PLoS One”. 2010 Nov 2;5(11):e13719. {{doi|10.1371/journal.pone.0013719}} {{pmid|21072165}}</ref>

* [[ML148]] <ref>Niesen FH, Schultz L, Jadhav A, Bhatia C, Guo K, Maloney DJ, Pilka ES, Wang M, Oppermann U, Heightman TD, Simeonov A. High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships. ”PLoS One”. 2010 Nov 2;5(11):e13719. {{doi|10.1371/journal.pone.0013719}} {{pmid|21072165}}</ref>

* 15-PGDH-IN-4 <ref>Dodda LS, Campos S, Ciccone D, Carreiro S, Leit S, Brennan D, Zephyr J, Jacques-O’Hagan S, Kumar S, Kuo FS, Shaik MM, Price DJ, Loh C, Edmondson SD, Tummino P, Kaila N. Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors. ”J Med Chem”. 2025 Sep 11;68(17):18436-18462. {{doi|10.1021/acs.jmedchem.5c01231}} {{pmid|40864846}}</ref>

* 15-PGDH-IN-4 <ref>Dodda LS, Campos S, Ciccone D, Carreiro S, Leit S, Brennan D, Zephyr J, Jacques-O’Hagan S, Kumar S, Kuo FS, Shaik MM, Price DJ, Loh C, Edmondson SD, Tummino P, Kaila N. Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors. ”J Med Chem”. 2025 Sep 11;68(17):18436-18462. {{doi|10.1021/acs.jmedchem.5c01231}} {{pmid|40864846}}</ref>

* [[HW201877]] <ref>Li Q, Zang Y, An D, Yin S, Wu H, Wang M, Li C, Zhou Y, Liu L, Zhang X. Discovery of HW201877: A Highly Potent and Orally Bioavailable Inhibitor of 15-Prostaglandin Dehydrogenase to Potentiate Tissue Repair and Regeneration. ”J Med Chem”. 2025 Jul 10;68(13):14099-14113. {{doi|10.1021/acs.jmedchem.5c01361}} {{pmid|40568827}}</ref>

== Substrates ==

== Substrates ==

Class of enzymes

Hydroxyprostaglandin dehydrogenase 15-(NAD) (the HUGO-approved symbol = HPGD; HGNC ID, HGNC:5154), also called 15-hydroxyprostaglandin dehydrogenase (NAD⁺), (EC 1.1.1.141), is an enzyme produced by the HPGD gene.

It catalyzes the It catalyzes the NAD⁺-dependent oxidation of the 15-hydroxyl group of prostaglandins (primarily prostaglandin E₂ or PGE₂, but also others like PGD₂ and PGF₂α) and related eicosanoids (such as lipoxins), converting them to inactive 15-keto metabolites. This is the rate-limiting step in prostaglandin degradation, reducing their biological activity and regulating processes such as inflammation, cell proliferation, and tissue homeostasis.:^[1][2]

• Downregulation in cancer — Can be reduced in tumors (e.g., colorectal, lung, breast), leading to elevated PGE₂ levels that promote tumorigenesis; it acts as a tumor suppressor.^[3]
• Aging and regeneration — Levels increase with age, contributing to tissue decline (e.g., muscle atrophy, cartilage loss). Inhibiting 15-PGDH elevates PGE₂ and promotes regeneration in muscle, bone, cartilage, liver, colon, and hematopoietic tissues.^[4][5]
• Inflammation and immunity — Degrades pro-inflammatory prostaglandins; inhibition can enhance resolution of inflammation or protect barriers like the blood-brain barrier in conditions such as Alzheimer’s or traumatic brain injury.^[6]
• Other roles — It is involved in wound healing, obesity-related inflammation, and pregnancy maintenance.

Small-molecule inhibitors of 15-PGDH are under investigation for promoting tissue repair, countering sarcopenia, treating osteoarthritis, and supporting recovery after injury or transplantation. Mutations in HPGD can cause rare disorders like primary hypertrophic osteoarthropathy (digital clubbing, bone overgrowth).^[7]

Inhibitors

The two substrates of this enzyme are prostaglandin E2 and oxidised nicotinamide adenine dinucleotide (NAD⁺). Its products are 15-ketoprostaglandin E2, reduced NADH, and a proton.^{[13][14][15][16]}

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor.

The systematic name of this enzyme class is (5Z,13E)-(15S)-11alpha,15-dihydroxy-9-oxoprost-13-enoate:NAD⁺ 15-oxidoreductase. Other names in common use include NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (type I), PGDH, 11alpha,15-dihydroxy-9-oxoprost-13-enoate:NAD⁺ 15-oxidoreductase, 15-OH-PGDH, 15-hydroxyprostaglandin dehydrogenase, 15-hydroxyprostanoic dehydrogenase, NAD⁺-specific 15-hydroxyprostaglandin dehydrogenase, prostaglandin dehydrogenase, 15-hydroxyprostaglandin dehydrogenase (NAD⁺), and 15-PGDH.

As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code 2GDZ.