15-hydroxyprostaglandin dehydrogenase (NAD+)

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

Function

It catalyzes the NAD⁺-dependent oxidation of the 15-hydroxyl group of prostaglandins (primarily prostaglandin E₂ or PGE₂, but also others like PGD₂ and PGF_2α) 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.:

Biological Role

• 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.
• 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.
• 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.
• Other roles — It is involved in wound healing, obesity-related inflammation, and pregnancy maintenance.

Therapeutic interest

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).

Ligands

Inhibitors

• SW033291
• SW209415
• SW222746
• ML148
• 15-PGDH-IN-4
• HW201877

Substrates

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.

Class

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.

Structural studies

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

References