8DSH

Human NAMPT in complex with quercitrin and AMPcP

Summary for 8DSH

• Entry DOI: 10.2210/pdb8dsh/pdb
• Related: 8DSC 8DSD 8DSE
• Descriptor: Nicotinamide phosphoribosyltransferase, PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl 6-deoxy-alpha-L-mannopyranoside, ... (4 entities in total)
• Functional Keywords: nad biosynthesis enzyme:activator complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 115079.37

Authors

Ratia, K.,Xiong, R.,Shen, Z.,Thatcher, G.R. (deposition date: 2022-07-22, release date: 2023-03-08, Last modification date: 2023-10-25)

Primary citation

Ratia, K.M.,Shen, Z.,Gordon-Blake, J.,Lee, H.,Laham, M.S.,Krider, I.S.,Christie, N.,Ackerman-Berrier, M.,Penton, C.,Knowles, N.G.,Musku, S.R.,Fu, J.,Velma, G.R.,Xiong, R.,Thatcher, G.R.J.
Mechanism of Allosteric Modulation of Nicotinamide Phosphoribosyltransferase to Elevate Cellular NAD.
Biochemistry, 62:923-933, 2023

PubMed 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 measurements in human cells. The mechanism of action of N-PAMs identifies, for the first time, the role of the rear channel in the regulation of NAMPT turnover coupled to productive and nonproductive NAM binding. The tight regulation of cellular NAMPT via feedback inhibition by NAM, NAD, and adenosine 5'-triphosphate (ATP) is differentially regulated by N-PAMs and other activators, indicating that different classes of pharmacological activators may be engineered to restore or enhance NAD levels in affected tissues.

PubMed: 36746631
DOI: 10.1021/acs.biochem.2c00655

Experimental method

X-RAY DIFFRACTION (2.2 Å)