Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway

Natavan Dudkina, Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT 06516, USA.
Hyun Bong Park, Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT 06516, USA; Department of Biology, College of Natural Sciences, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea.
Deguang Song, Department of Immunobiology, Yale School of Medicine, New Haven, CT 06536, USA.
Abhishek Jain, Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06536, USA.Follow
Sajid A. Khan, Department of Surgery, Division of Surgical Oncology, Yale School of Medicine, New Haven, CT 06510, USA.Follow
Richard A. Flavell, Department of Immunobiology, Yale School of Medicine, New Haven, CT 06536, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06536, USA.Follow
Caroline H. Johnson, Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06536, USA. Electronic address: caroline.johnson@yale.edu.Follow
Noah W. Palm, Department of Immunobiology, Yale School of Medicine, New Haven, CT 06536, USA. Electronic address: noah.palm@yale.edu.
Jason M. Crawford, Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT 06516, USA; Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA. Electronic address: jason.crawford@yale.edu.

Document Type

Article

Publication Title

Cell chemical biology

Abstract

Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.

DOI

10.1016/j.chembiol.2024.07.011

Publication Date

8-9-2024

Identifier

39163853 (pubmed); 10.1016/j.chembiol.2024.07.011 (doi); S2451-9456(24)00313-1 (pii)

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