Dudkina Natavan, Park Hyun Bong, Song Deguang, Jain Abhishek, Khan Sajid A, Flavell Richard A, Johnson Caroline H, Palm Noah W, Crawford Jason M
Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT 06516, USA.
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.
Cell Chem Biol. 2025 Jan 16;32(1):126-144.e18. doi: 10.1016/j.chembiol.2024.07.011. Epub 2024 Aug 19.
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.
人醛糖 - 酮糖还原酶家族1成员C3（AKR1C3）表达的改变与多种癌症的不良预后、铁死亡抗性和代谢疾病有关。尽管其具有临床意义，但AKR1C3的内源性生化作用仍未完全明确。利用非靶向代谢组学，我们鉴定出一种由AKR1C3介导的主要转化过程，即精胺氧化产物“精胺醛”被还原为“精胺醇”。精胺醛会导致DNA损伤并激活DNA双链断裂反应，而精胺醇在体外可诱导自噬。AKR1C3还能下拉酰基吡喃酮，且吡喃酮 - 211可抑制AKR1C3活性。通过G蛋白偶联受体配体筛选，我们确定吡喃酮 - 211也是半孤儿受体GPR84的强效激动剂。引人注目的是，哺乳动物脂肪酸合酶在体外可产生酰基吡喃酮，且这种产生受NADPH调节。综上所述，我们的研究支持AKR1C3在扩展的多胺途径中发挥调节作用，以及一个将脂肪酸合成和NADPH水平与GPR84信号传导联系起来的模型。
