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Preclinical mechanistic study

CD38 mediates nicotinamide mononucleotide base exchange to yield nicotinic acid mononucleotide

Romanthi Madawala, Jasmine L Banks, Sarah E Hancock, Lake-Ee Quek, Nigel Turner, Lindsay E Wu

Journal of Biological Chemistry · 2025 · 301(3):108248

Original publication PubMed Full text on PMC

Study at a glance

Design
Mechanistic biochemical and metabolomics study combining recombinant human CD38 assays, stable-isotope tracing, and an acute 2×2 mouse intervention with a CD38 inhibitor.
Population or model
Recombinant-enzyme systems and 9-week-old male C57BL/6J mice; no human participants.
Sample size
In-vivo 2×2 experiment used n=5 mice per group; biochemical experiments were repeated across defined reaction conditions.
Intervention
In vitro NMN/nicotinic-acid substrate experiments with recombinant CD38; in vivo single oral NMN 500 mg/kg with or without oral CD38 inhibitor 78c 10 mg/kg, followed by tissue collection 2 hours later.
Publication type
Mechanistic biochemical and animal study
Evidence class
preclinical-mechanistic
Research area
NMN metabolism and CD38
Trial registration
Not applicable (preclinical mechanistic study)

Study endpoints

  • CD38-dependent conversion of NMN plus nicotinic acid to NaMN
  • Stable-isotope confirmation of base exchange
  • Selectivity versus NR/NaR and reverse exchange
  • Liver, muscle, and kidney NaMN and NaAD after NMN
  • Effect of CD38 inhibition on NMN-induced deamidated metabolites

Plain-language summary

This mechanistic study investigated why administering NMN can raise metabolites from the deamidated Preiss-Handler pathway even though NMN belongs to the amidated salvage pathway.

The authors showed that CD38 can exchange NMN's nicotinamide group for free nicotinic acid, generating nicotinic acid mononucleotide (NaMN). Stable-isotope experiments supported the chemical identity of the reaction, and the reaction was not reproduced with NR or NaR in the same way.

In mice, oral NMN increased NaMN and NaAD in liver and muscle, while coadministration of a CD38 inhibitor abolished those increases. The work identifies a metabolic route but does not quantify how important it is after oral NMN in humans.

Key findings

  • Recombinant CD38 converted NMN plus nicotinic acid into NaMN through a base-exchange reaction.
  • Stable-isotope labeling confirmed that the nicotinic-acid ring was incorporated into newly formed NaMN.
  • The base-exchange reaction was selective for NMN in the tested comparisons and was not detected for NR/NaR under the same experimental framework.
  • A single oral NMN dose increased NaMN and NaAD in mouse liver and muscle.
  • The CD38 inhibitor 78c abolished the NMN-induced rise in NaMN and NaAD in liver and muscle, supporting in-vivo relevance of the mechanism.

Limitations

  • The in-vivo evidence was an acute high-dose mouse experiment, not chronic human oral supplementation.
  • The study identifies a pathway but does not establish what fraction of orally administered NMN follows this route in people.
  • Tissue effects differed, including lack of the same NMN-induced deamidated-metabolite spike in kidney.
  • Biochemical enzyme systems simplify the cellular environment and do not alone define whole-body precursor handling.
  • One author disclosed advisory and equity interests in companies developing NAD+-related products or technologies.

Funding and transparency

Funding

Lindsay E. Wu was funded by a Hevolution/American Federation for Aging Research New Investigator Award in Aging Biology. The work was also supported by National Health and Medical Research Council Development Grant APP2000211, National Health and Medical Research Council Project Grant APP1128351, and a project grant from the Diabetes Australia Research Program.

Competing interests

Lindsay E. Wu is a scientific advisor to Metro International Biotech, which is developing NAD+ precursors and derivatives as therapies for age-related disease, and is a shareholder in EdenRoc Sciences, the parent company of Metro Biotech. He is also a cofounder, advisor, and shareholder in Jumpstart Fertility Inc., which is targeting the NAD+ metabolome to improve embryo culture media in assisted reproduction. The other authors declared no conflicts of interest with the article.

HealthspanX observation

This paper adds a direct enzymatic mechanism to the broader evidence that oral NMN metabolism is more complex than simple intact incorporation into NAD+.

Interpretive weight

Mechanistic context

Biochemical, isotope-labeling, and mouse inhibitor experiments identify a specific CD38-mediated NMN base-exchange mechanism, but they do not establish the quantitative importance of this pathway in humans.

This record summarizes a publication; it is not medical advice or a claim that a HealthspanX product reproduces the study's results. Report a correction.

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