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• W4307282670 abstract "ABSTRACT In aging and disease, cellular NAD + is depleted by catabolism to nicotinamide (NAM) and NAD + supple-mentation is being pursued to enhance human healthspan and lifespan. Activation of nicoti namide phosphoribosyl -transferase (NAMPT), the rate-limiting step in NAD + biosynthesis, has potential to increase salvage of NAM. Novel NAMPT positive allosteric modulators (N-PAMs) were discovered in addition to demonstration of NAMPT activati on by biogenic phenols. The mechanism of activation was revealed through 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 + measurements in human cells. The mechanism of action of N-PAMs identifies, for the first time, the role of the rear channel in regulation of NAMPT turnover coupled to feedback inhibition by NAM. N-PAM inhibition of low affinity, non-productive NAM binding via the rear channel, causes a right-shif t in K I (NAM) that accompanies an increase in enzyme activity. Conversion of an N-PAM to a high-affinity l igand blocks both high and low affinity NAM binding, ablating enzyme activity. In the presence of an N-PAM, NAMPT boosts NAD + biosynthesis at higher NAM concentrations, in addition to relieving inhibition by NAD + . Since cellular stress often leads to enhanced catabolism of NAD + to NAM, this mechanism is relevant to supporting cellular N AD + levels in aging and disease. The tight regulation of cellular NAMPT is differentially regulated by N-PAMs and other activators, indicating that different classes of pharmacological activators may be engineered for cell and tissue selectivity." @default.
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• W4307282670 date "2022-10-22" @default.
• W4307282670 modified "2023-09-30" @default.
• W4307282670 title "The mechanism of nicotinamide phosphoribosyltransferase whereby positive allosteric modulation elevates cellular NAD⁺" @default.
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• W4307282670 doi "https://doi.org/10.1101/2022.10.21.513220" @default.
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