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J. Am. Chem. Soc., Nov 29 2024, | https://doi.org/10.1021/jacs.4c11809 Biosynthesis-Encoded Lipogenic Acetyl-CoA Measurement Using NMR Reveals Glucose-Driven Lipogenesis and Glutamine's Alternative Roles in Kidney Cancer

Sihyang Jo ¹, Munjun Seo ¹, Thi Ha Nguyen¹, Jin Wook Cha ², Yong Jin An ¹, Sunghyouk Park ¹

¹Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea.
²KIST Gangneung Institute of Natural Products, Natural Product Drug Development Division, Center for Natural Product Systems Biology, Gangneung 25451, Korea.

Corresponding Authors : Yong Jin An, Sunghyouk Park

Abstract

Fatty acid de novo synthesis (FADNS) is a critical process in lipogenesis that is characteristically altered in clear cell renal cell carcinoma (ccRCC), which is the major type of kidney cancer. An important challenge in studying the FADNS process has been the accurate measurement of cytosolic lipogenic acetyl-CoA (AcCoA), the precursor in FADNS, due to its compartmentalization within cells. Here, we describe a novel NMR-based method to decode the isotopic enrichment of lipogenic AcCoA, which, as we demonstrated, is encoded in the simple signal ratios of the geminal methyl groups of lanosterol during its biosynthesis. The approach was validated based on the independence of the tracer enrichment and species along with the expected FADNS modulation using differentially enriched tracers and a well-studied drug. Application of this technique to 786-O ccRCC cells showed that glucose may serve as a major carbon source for lipogenic AcCoA in FADNS at physiological nutrient concentrations, at odds with previous studies that indicated glutamine's dominant role through reductive carboxylation under higher nutrient conditions. Further investigation into glutamine's alternative roles in ccRCC cells suggested its major involvement in the bioenergetic TCA cycle, pyrimidine synthesis, and glutathione synthesis, which is also critical in ccRCC growth. The glutamine-dependent glutathione synthesis was also suggested as a possible metabolic vulnerability compared to normal kidney cells using a glutathione synthesis inhibitor. The current study provides a simple tool for studying an important aspect of lipid metabolism and suggests translational implications for targeting glucose-driven lipogenesis and glutamine-supported glutathione synthesis in ccRCC.

논문정보

형식Research article
게재일2024년 11월 (BRIC 등록일 2024-12-02)
연구진국내 연구진
분야 생명과학 > 생화학

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