Mechanism of Allosteric Modulation of Nicotinamide Phosphoribosyltransferase to Elevate Cellular NAD.

ABSTRACT: In aging and disease, cellular nicotinamide adenine dinucleotide (NAD⁺) is depleted by catabolism to nicotinamide (NAM). NAD⁺ supplementation is being pursued to enhance human healthspan and lifespan. Activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD⁺ biosynthesis, has the potential to increase the salvage of NAM. Novel NAMPT-positive allosteric modulators (N-PAMs) were discovered in addition to the demonstration of NAMPT activation by biogenic phenols. The mechanism of activation was revealed through the synthesis of novel chemical probes, new NAMPT co-crystal structures, and enzyme kinetics. Binding to a rear channel in NAMPT regulates NAM binding and turnover, with biochemical observations being replicated by NAD

SUBMITTER: Ratia KM 

PROVIDER: S-EPMC10935581 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature