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

Abstract

Excessive elevation of soluble uric acid (sUA) is associated with the risk of various diseases. However, evolutionary biology implies that sUA has unassigned physiological functions and targets. Here, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38, a major enzyme responsible for NAD+ degradation, via a reversible non-competitive mechanism, thereby increasing NAD+ availability. CD38 inhibition is restricted to sUA in purine metabolic pathways. A structural comparison using analogs shows that 1,3-dihydroimidazol-2-one is the main functional group for CD38 inhibition, while the adjacent uracil-like heterocycles are also essential. Moreover, mild and short-term elevation of plasma sUA prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis by interacting with CD38. Taken together, this study reveals that sUA functions as an endogenous inhibitor of CD38 to physiologically limit NAD+ degradation and innate immunity.