Soluble Uric Acid Regulates NAD+ Availability and Innate Immunity through Direct Inhibition of CD38

Core Concepts

Soluble uric acid directly inhibits the hydrolase and cyclase activities of CD38, thereby limiting NAD+ degradation and excessive inflammation.

Abstract

The study demonstrates that soluble uric acid (sUA) is an endogenous, reversible, and non-competitive inhibitor of the enzyme CD38. CD38 plays a key role in degrading nicotinamide adenine dinucleotide (NAD+), an essential cofactor for various metabolic reactions, and regulating inflammation.
The key findings are:

sUA directly inhibits the hydrolase and cyclase activities of human and murine CD38 in the micromolar range, with the 1,3-dihydroimidazol-2-one functional group being essential for this inhibition.

sUA at physiological levels limits NAD+ degradation by inhibiting CD38 activity, thereby increasing NAD+ availability in cells and tissues.

sUA at physiological levels suppresses crude lipopolysaccharide-induced systemic inflammation and monosodium urate crystal-induced peritonitis in mice by interacting with CD38. This anti-inflammatory effect of sUA is abrogated in CD38 knockout mice.

The study provides the molecular basis for the physiological functions of sUA in regulating NAD+ availability and innate immunity, and suggests that abnormal sUA levels may impact health and disease independent of monosodium urate crystal formation.

Stats

Soluble uric acid has a Ki of 57.1-93.3 μM for inhibiting the hydrolase and cyclase activities of CD38.
Plasma soluble uric acid levels in humans are about 120-420 μM, which are higher than the Ki values.
Moderate supplementation of soluble uric acid increased whole blood NAD+ levels by 10-20% in wild-type mice, but not in CD38 knockout mice.

Quotes

"sUA directly inhibits the hydrolase and cyclase activities of human (Figures 1B and S1B) and murine (Figure 1E) CD38 as a non-competitive inhibitor (Figures 1C, 1D, and S1A) with a Ki in the micromolar range (57.1-93.3 μM), demonstrating its binding to the allosteric sites of CD38."
"sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38."

Key Insights Distilled From

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

by Wen,S., Arak... at www.biorxiv.org 06-06-2023

https://www.biorxiv.org/content/10.1101/2023.06.03.543541v2

Deeper Inquiries

How might abnormal sUA levels, independent of monosodium urate crystal formation, impact other physiological processes and disease states?

Abnormal soluble uric acid (sUA) levels, independent of monosodium urate crystal formation, can have significant impacts on various physiological processes and disease states. Firstly, high sUA levels, known as hyperuricemia, have been associated with an increased risk of gout, a painful form of arthritis caused by the deposition of urate crystals in joints. However, beyond gout, abnormal sUA levels have been linked to several other disease states. For example, elevated sUA levels have been correlated with an increased risk of cardiovascular diseases, including hypertension, coronary artery disease, and stroke. Additionally, hyperuricemia has been implicated in the development of kidney diseases, such as chronic kidney disease and kidney stones.
On the other hand, low sUA levels, known as hypouricemia, can also have detrimental effects on health. Hypouricemia has been associated with an increased risk of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Furthermore, low sUA levels have been linked to an increased risk of metabolic disorders, including obesity and diabetes. Abnormal reduction of sUA levels may also impact immune function, leading to increased susceptibility to infections and inflammatory conditions.
Overall, maintaining the balance of sUA within physiological levels is crucial for the proper functioning of various physiological processes and the prevention of disease states. Disruption of sUA homeostasis, whether through excessive elevation or reduction, can have far-reaching consequences on health and well-being.

What are the potential therapeutic implications of targeting the sUA-CD38 interaction for regulating NAD+ availability and inflammation?

Targeting the soluble uric acid (sUA)-CD38 interaction for regulating nicotinamide adenine dinucleotide (NAD+) availability and inflammation holds significant therapeutic implications for various health conditions. By inhibiting CD38 through the interaction with sUA, it is possible to limit NAD+ degradation, thereby increasing NAD+ availability in cells. NAD+ is a crucial cofactor involved in various metabolic reactions that sustain life, regulate inflammation, and impact aging and disease processes. Therefore, modulating NAD+ levels through the sUA-CD38 interaction can have broad therapeutic implications.
One potential therapeutic application of targeting the sUA-CD38 interaction is in the treatment of inflammatory conditions. By inhibiting CD38 activity through sUA, it is possible to limit excessive inflammation by modulating NAD+ levels and downstream inflammatory pathways. This approach could be particularly beneficial in conditions where inflammation plays a central role, such as autoimmune diseases, neuroinflammatory disorders, and chronic inflammatory conditions.
Moreover, the sUA-CD38 interaction could be targeted for the treatment of age-related diseases and conditions associated with NAD+ decline. By preserving NAD+ levels through CD38 inhibition, it may be possible to slow down the aging process, improve cellular function, and mitigate age-related diseases such as neurodegenerative disorders, cardiovascular diseases, and metabolic conditions.
Overall, targeting the sUA-CD38 interaction for regulating NAD+ availability and inflammation represents a promising therapeutic strategy with the potential to impact a wide range of health conditions and improve overall well-being.

Could the structural insights into the sUA-CD38 interaction be leveraged to develop more potent and selective CD38 inhibitors for various applications?

The structural insights into the soluble uric acid (sUA)-CD38 interaction provide valuable information that could be leveraged to develop more potent and selective CD38 inhibitors for various applications. Understanding the specific binding sites and mechanisms of sUA inhibition of CD38 can guide the design and optimization of novel CD38 inhibitors with improved efficacy and specificity.
By utilizing the structural features identified in the sUA-CD38 interaction, researchers can design small molecules or compounds that target the allosteric sites of CD38, mimicking the inhibitory effects of sUA. These novel inhibitors can be optimized to enhance their binding affinity, potency, and selectivity for CD38, leading to more effective modulation of NAD+ availability and downstream biological processes.
Furthermore, the structural insights can aid in the development of CD38 inhibitors with tailored pharmacokinetic properties, such as improved bioavailability, stability, and tissue distribution. This optimization can enhance the therapeutic potential of CD38 inhibitors for various applications, including the treatment of inflammatory conditions, age-related diseases, and metabolic disorders.
Overall, leveraging the structural insights into the sUA-CD38 interaction holds great promise for the development of more potent and selective CD38 inhibitors with diverse applications in biomedical research and clinical practice.