Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme found throughout the human body. It plays a role in various cellular processes and is involved in maintaining cellular well-being. NAMPT exists in both an intracellular (iNAMPT) and an extracellular (eNAMPT) form, each contributing to different biological functions. Its presence is detected across many tissues, including blood, pericardium, and gastric mucosa.
NAMPT’s Fundamental Role in Cellular Energy
NAMPT’s primary function is its role in the salvage pathway for nicotinamide adenine dinucleotide (NAD+) synthesis. It acts as a rate-limiting enzyme, converting nicotinamide (NAM) into nicotinamide mononucleotide (NMN). This step is the initial and controlling point for most NAD+ formation in mammals. NAD+ is a coenzyme distributed in every cell, involved in hundreds of metabolic processes.
NAD+ is an electron carrier that transfers energy from food molecules to other cellular processes. For instance, it is involved in glycolysis and the citric acid cycle, pathways that generate ATP, the cell’s main energy currency. Without sufficient NAD+, these energy production pathways would be hampered, affecting cell function. The continuous recycling of NAM back into NMN by NAMPT helps maintain stable NAD+ levels, which is important for sustained energy production and metabolic activity.
NAMPT’s Impact on Cellular Regulation
Beyond energy production, NAMPT influences broader cellular regulatory functions. The NAD+ produced through NAMPT’s activity serves as a coenzyme for NAD-dependent enzymes, including sirtuins (SIRTs) and poly (ADP-ribose) polymerases (PARPs). These enzymes are involved in DNA repair, gene expression, and inflammation.
Sirtuins, for example, regulate cellular metabolism, stress resistance, and DNA repair by modifying other proteins. PARPs are involved in DNA repair and maintaining genomic stability. By influencing NAD+ levels, NAMPT indirectly impacts the activity of these regulatory enzymes, affecting cellular resilience and responses to various stresses. This regulatory role allows NAMPT to influence how cells adapt and maintain their function.
NAMPT and Its Link to Health
Research indicates associations between NAMPT levels or activity and various health conditions. In metabolic disorders, altered NAMPT activity has been observed in type 2 diabetes and obesity. Abnormal NAMPT activity has been linked to insulin resistance, a condition where the body’s cells do not respond effectively to insulin.
In neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, connections with NAMPT are being explored. Maintaining NAD+ levels, influenced by NAMPT, is important for neuronal health and function. NAMPT also has a complex, context-dependent role in certain types of cancer. Some cancer cells exhibit increased NAMPT levels, which may support their rapid growth and energy demands due to its effects on glucose and lipid metabolism. These links highlight NAMPT as an area of active investigation for understanding and managing these health challenges.
Strategies to Influence NAMPT Activity
Research is underway to understand how NAMPT activity might be modulated. One approach involves dietary precursors that feed into the NAD+ salvage pathway. Compounds like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are being studied for their potential to increase NAD+ levels, which are synthesized via the NAMPT pathway. Niacin, another form of vitamin B3, also contributes to NAD+ synthesis through a different pathway that complements the NAMPT-dependent salvage route.
Researchers are also investigating molecules that directly activate or inhibit NAMPT. For instance, experimental drugs like APO866 are being tested as NAMPT inhibitors, showing potential in studies for conditions such as advanced melanoma and certain types of leukemia by reducing NAD+ levels in cancer cells. Conversely, some research focuses on identifying NAMPT activators, such as P7C3 analogs, to enhance its activity and support cellular health. These investigations aim to understand how manipulating NAMPT activity could offer new avenues for therapeutic development.