2. Academic Validation
  3. Identification and characterization of bioactive metabolites of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2

Identification and characterization of bioactive metabolites of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2

  • J Biochem. 2022 Dec 20;mvac105. doi: 10.1093/jb/mvac105.
Ken Yasukawa 1 2,  Toshiaki Okuno 1,  Narihito Ogawa 3,  Yuichi Kobayashi 4,  Takehiko Yokomizo 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
  • 2 Drug Discovery Research Department, Sato Pharmaceutical Co., Ltd., Tokyo 140-0011, Japan.
  • 3 Department of Applied Chemistry, Meiji University, Kanagawa 214-8571, Japan.
  • 4 Organization for the Strategic Coordination of Research and Intellectual Properties, Meiji University, Kanagawa 214-8571, Japan.
PMID: 36539331 DOI: 10.1093/jb/mvac105
Abstract

12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH Inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together,12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity.

Keywords

12-HHT; 15-PGDH; Arachidonic acid; BLT2; Prostaglandins.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16968
    99.74%, 15-PGDH Inhibitor