Functional identification of soluble uric acid as an endogenous inhibitor of CD38.

Autor:	Wen S; Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan., Arakawa H; Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan., Yokoyama S; Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan.; Division of Socio-Cognitive-Neuroscience, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Kanazawa, Japan., Shirasaka Y; Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan., Higashida H; Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan., Tamai I; Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Nov 11; Vol. 13. Date of Electronic Publication: 2024 Nov 11.
DOI:	10.7554/eLife.96962
Abstrakt:	Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD + ) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD + availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism. Competing Interests: SW, HA, SY, YS, HH, IT No competing interests declared (© 2024, Wen et al.)
Databáze:	MEDLINE
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