Nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and reduced nicotinamide mononucleotide (NMNH) are all precursors in the biosynthesis of nicotinamide adenine dinucleotide (NAD⁺), a crucial coenzyme in cellular metabolism. Each of these compounds contributes to NAD⁺ biosynthesis through distinct biochemical pathways and exhibits different efficiencies and effects on cellular processes. NMNH, in particular, has been identified as a potent NAD⁺ precursor with unique properties compared to NMN and NR. The following sections detail the biochemical differences between these compounds in terms of NAD⁺ biosynthesis.
NMN and NR in NAD⁺ Biosynthesis
- Pathways: NMN and NR are both precursors in the NAD⁺ biosynthesis pathway. NMN is directly converted to NAD⁺ by nicotinamide mononucleotide adenylyltransferase (NMNAT), while NR is first phosphorylated to NMN by nicotinamide riboside kinase (NRK) before being converted to NAD⁺ (Wang et al., 2024) (Pastore, 2023).
- Efficiency: Both NMN and NR have been shown to increase NAD⁺ levels, but their effects are relatively mild, requiring higher doses for significant impact (Zapata-Pérez et al., 2021).
- Health Benefits: Supplementation with NMN and NR has been associated with various health benefits, including protection against age-related diseases and metabolic disorders (Wang et al., 2024) (Pastore, 2023).
NMNH as a Potent NAD⁺ Precursor
- Pathway: NMNH is metabolized through a novel, NRK and NAMPT-independent pathway, which distinguishes it from NMN and NR. This pathway allows for a more rapid and substantial increase in NAD⁺ levels (Zapata-Pérez et al., 2021).
- Efficiency: NMNH has been demonstrated to enhance NAD⁺ levels more effectively than NMN and NR, both in vitro and in vivo. This is mediated by NMNAT, which also increases NADH levels, contributing to cellular reductive stress (Liu et al., 2021) (Liu et al., 2020).
- Cellular Effects: NMNH has been shown to suppress glycolysis and the TCA cycle, induce cell cycle arrest, and inhibit cell growth, which are effects not observed with NMN or NR (Liu et al., 2021) (Liu et al., 2020) (Liu et al., 2020).
Comparative Biochemical Implications
- Metabolic Impact: While NMN and NR primarily serve to replenish NAD⁺ levels, NMNH not only enhances NAD⁺ but also affects cellular metabolism by altering glycolytic and TCA cycle activities. This suggests a broader impact on cellular energy homeostasis and stress responses (Liu et al., 2021) (Liu et al., 2020).
- Therapeutic Potential: The unique properties of NMNH, such as its rapid NAD⁺ enhancement and metabolic effects, highlight its potential as a therapeutic agent, particularly in conditions like acute kidney injury where rapid NAD⁺ replenishment is beneficial (Zapata-Pérez et al., 2021).
While NMNH shows promise as a more effective NAD⁺ precursor, it is important to consider the broader implications of its use. The induction of reductive stress and suppression of metabolic pathways by NMNH could have unintended consequences, particularly in long-term applications. Further research is needed to fully understand the safety and efficacy of NMNH compared to NMN and NR, especially in clinical settings.
