| Structural highlights
Disease
PGDH_HUMAN Defects in HPGD are the cause of hypertrophic osteoarthropathy, primary, autosomal recessive, type 1 (PHOAR1) [MIM:259100. A disease characterized by digital clubbing, periostosis, acroosteolysis, painful joint enlargement, and variable features of pachydermia that include thickened facial skin and a thickened scalp. Other developmental anomalies include delayed closure of the cranial sutures and congenital heart disease.[1] Defects in HPGD are the cause of cranioosteoarthropathy (COA) [MIM:259100. A form of osterarthropathy characterized by swelling of the joints, digital clubbing, hyperhidrosis, delayed closure of the fontanels, periostosis, and variable patent ductus arteriosus. Pachydermia is not a prominent feature.[2] Defects in HPGD are a cause of isolated congenital nail clubbing (ICNC) [MIM:119900; also called clubbing of digits or hereditary acropachy. ICNC is a rare genodermatosis characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx. It is usually symmetrical and bilateral (in some cases unilateral). In nail clubbing usually the distal end of the nail matrix is relatively high compared to the proximal end, while the nail plate is complete but its dimensions and diameter more or less vary in comparison to normal. There may be different fingers and toes involved to varying degrees. Some fingers or toes are spared, but the thumbs are almost always involved.[3]
Function
PGDH_HUMAN Prostaglandin inactivation. Contributes to the regulation of events that are under the control of prostaglandin levels. Catalyzes the NAD-dependent dehydrogenation of lipoxin A4 to form 15-oxo-lipoxin A4. Inhibits in vivo proliferation of colon cancer cells.[4] [5] [6]
Publication Abstract from PubMed
15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine.
Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system.,Huang W, Li H, Kiselar J, Fink SP, Regmi S, Day A, Yuan Y, Chance M, Ready JM, Markowitz SD, Taylor DJ Nat Commun. 2023 Feb 11;14(1):784. doi: 10.1038/s41467-023-36463-7. PMID:36774348[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008 Jun;40(6):789-93. doi: 10.1038/ng.153. Epub 2008 May 25. PMID:18500342 doi:10.1038/ng.153
- ↑ Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008 Jun;40(6):789-93. doi: 10.1038/ng.153. Epub 2008 May 25. PMID:18500342 doi:10.1038/ng.153
- ↑ Tariq M, Azeem Z, Ali G, Chishti MS, Ahmad W. Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J Med Genet. 2009 Jan;46(1):14-20. doi: 10.1136/jmg.2008.061234. Epub 2008 Sep, 19. PMID:18805827 doi:10.1136/jmg.2008.061234
- ↑ Clish CB, Levy BD, Chiang N, Tai HH, Serhan CN. Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J Biol Chem. 2000 Aug 18;275(33):25372-80. PMID:10837478 doi:10.1074/jbc.M002863200
- ↑ Yan M, Rerko RM, Platzer P, Dawson D, Willis J, Tong M, Lawrence E, Lutterbaugh J, Lu S, Willson JK, Luo G, Hensold J, Tai HH, Wilson K, Markowitz SD. 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17468-73. Epub 2004 Dec 1. PMID:15574495 doi:10.1073/pnas.0406142101
- ↑ Cho H, Huang L, Hamza A, Gao D, Zhan CG, Tai HH. Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2. Bioorg Med Chem. 2006 Oct 1;14(19):6486-91. Epub 2006 Jul 7. PMID:16828555 doi:10.1016/j.bmc.2006.06.030
- ↑ Huang W, Li H, Kiselar J, Fink SP, Regmi S, Day A, Yuan Y, Chance M, Ready JM, Markowitz SD, Taylor DJ. Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system. Nat Commun. 2023 Feb 11;14(1):784. PMID:36774348 doi:10.1038/s41467-023-36463-7
|
