Soluble Uric Acid Is an Endogenous Inhibitor of CD38

Shijie Wen¹, Hiroshi Arakawa¹, Shigeru Yokoyama², Yoshiyuki Shirasaka¹, Haruhiro Higashida³ and Ikumi Tamai¹, ¹Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan, ²Research Center for Child Mental Development, Kanazawa University; 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 University, Kanazawa, Japan, ³Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan

Meeting: ACR Convergence 2023

Keywords: gout, Inflammation, innate immunity

Session Information

Date: Sunday, November 12, 2023

Title: (0040–0064) Innate Immunity Poster

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: CD38 is the main NAD⁺-degrading enzyme that plays a key role in innate immunity, aging, cancer, and metabolic disorders. Pharmacological inhibition of CD38 has been proposed as a promising strategy for various diseases, including rheumatic diseases. Recently, we and another laboratory demonstrated that monosodium urate (MSU) crystals upregulate the protein expression of CD38 to promote inflammation. In the present study, we aim to clarify the effect of soluble uric acid (sUA) on CD38 and explore its unique role in purine metabolic pathways.

Methods: In enzyme assays, recombinant hCD38, and homogenates or crude membrane fractions of cells and tissues were used as enzyme sources, nicotinamide guanine dinucleotide (NGD) and epsilon-NAD⁺ were used as substrates for the measurement of CD38 activity. In metabolic assays, NAD⁺ was incubated with recombinant hCD38 in the presence or absence of sUA or other CD38 inhibitors. Then, NAD⁺ concentrations in the reaction buffers were measured by LC-MS/MS.

Results: sUA directly inhibited the hydrolase and cyclase activities of CD38. Kinetic analysis revealed that sUA is a non-competitive inhibitor of CD38, suggesting its binding to the allosteric sites of CD38. The inhibitory effects of sUA on CD38 activity were reversible. The precursors and metabolite of sUA hardly inhibited the enzymatic activity of CD38. A structural comparison using analogs revealed that 1,3-dihydroimidazol-2-one is the main functional group for CD38 inhibition, although the adjacent uracil-like heterocycles are also essential. Metabolic assays using NAD⁺ as substrate also confirmed the direct inhibitory effect of sUA on CD38. In addition, these findings were further verified by several physiological and pathological models in WT and CD38 KO mice.

Conclusion: sUA directly inhibits CD38 via a reversible non-competitive mechanism, and the inhibitory effect is restricted to sUA in purine metabolic pathways. These findings may promote understanding of sUA physiology, and the development of CD38 inhibitors. The opposite effects of sUA and MSU crystals on CD38 may explain why rapid urate lowering increases the risk of gout flares in the initiation of therapy.

Disclosures: S. Wen: None; H. Arakawa: None; S. Yokoyama: None; Y. Shirasaka: None; H. Higashida: None; I. Tamai: None.

To cite this abstract in AMA style:

Wen S, Arakawa H, Yokoyama S, Shirasaka Y, Higashida H, Tamai I. Soluble Uric Acid Is an Endogenous Inhibitor of CD38 [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/soluble-uric-acid-is-an-endogenous-inhibitor-of-cd38/. Accessed .

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