Mechanism of Allosteric Modulation of Nicotinamide Phosphoribosyltransferase to Elevate Cellular NAD

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2023 Feb 6

PMID 36746631

Authors

Kiira M Ratia

Zhengnan Shen

Jesse Gordon-Blake

Hyun Lee

Megan S Laham

Isabella S Krider

Nicholas Christie

Martha Ackerman-Berrier

Christopher Penton

Natalie G Knowles

Soumya Reddy Musku

Jiqiang Fu

Ganga Reddy Velma

Rui Xiong

Gregory R J Thatcher

Affiliations

Soon will be listed here.

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.

Citing Articles

Pathobiochemistry of Aging and Neurodegeneration: Deregulation of NAD+ Metabolism in Brain Cells.

Kolotyeva N, Groshkov A, Rozanova N, Berdnikov A, Novikova S, Komleva Y Biomolecules. 2025; 14(12.

PMID: 39766263 PMC: 11673498. DOI: 10.3390/biom14121556.

Mechanisms of the NAD salvage pathway in enhancing skeletal muscle function.

Su M, Qiu F, Li Y, Che T, Li N, Zhang S Front Cell Dev Biol. 2024; 12:1464815.

PMID: 39372950 PMC: 11450036. DOI: 10.3389/fcell.2024.1464815.

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.

Velma G, Krider I, Alves E, Courey J, Laham M, Thatcher G J Med Chem. 2024; 67(8):5999-6026.

PMID: 38580317 PMC: 11056997. DOI: 10.1021/acs.jmedchem.3c02112.

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress.

Gordon-Blake J, Ratia K, Weidig V, Velma G, Ackerman-Berrier M, Penton C ACS Med Chem Lett. 2024; 15(2):205-214.

PMID: 38352833 PMC: 10860701. DOI: 10.1021/acsmedchemlett.3c00391.

Synthesis, Optimization, and Structure-Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs).

Shen Z, Ratia K, Krider I, Ackerman-Berrier M, Penton C, Musku S J Med Chem. 2023; 66(24):16704-16727.

PMID: 38096366 PMC: 10758216. DOI: 10.1021/acs.jmedchem.3c01406.

References

Camp S, Ceco E, Evenoski C, Danilov S, Zhou T, Chiang E . Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury. Sci Rep. 2015; 5:13135. PMC: 4536637. DOI: 10.1038/srep13135. View

Stromsdorfer K, Yamaguchi S, Yoon M, Moseley A, Franczyk M, Kelly S . NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice. Cell Rep. 2016; 16(7):1851-60. PMC: 5094180. DOI: 10.1016/j.celrep.2016.07.027. View

Oh A, Ho Y, Zak M, Liu Y, Chen X, Yuen P . Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase. Chembiochem. 2014; 15(8):1121-30. DOI: 10.1002/cbic.201402023. View

Yoshino J, Baur J, Imai S . NAD Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2017; 27(3):513-528. PMC: 5842119. DOI: 10.1016/j.cmet.2017.11.002. View

Imai S, Guarente L . NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24(8):464-71. PMC: 4112140. DOI: 10.1016/j.tcb.2014.04.002. View

Burgos E, Vetticatt M, Schramm V . Recycling nicotinamide. The transition-state structure of human nicotinamide phosphoribosyltransferase. J Am Chem Soc. 2013; 135(9):3485-93. PMC: 3627370. DOI: 10.1021/ja310180c. View

Fang E, Scheibye-Knudsen M, Brace L, Kassahun H, SenGupta T, Nilsen H . Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014; 157(4):882-896. PMC: 4625837. DOI: 10.1016/j.cell.2014.03.026. View

Chini C, Peclat T, Warner G, Kashyap S, Espindola-Netto J, de Oliveira G . CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD and NMN levels. Nat Metab. 2020; 2(11):1284-1304. PMC: 8752031. DOI: 10.1038/s42255-020-00298-z. View

Burgos E, Ho M, Almo S, Schramm V . A phosphoenzyme mimic, overlapping catalytic sites and reaction coordinate motion for human NAMPT. Proc Natl Acad Sci U S A. 2009; 106(33):13748-53. PMC: 2728965. DOI: 10.1073/pnas.0903898106. View

10.

Liu L, Su X, Quinn 3rd W, Hui S, Krukenberg K, Frederick D . Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab. 2018; 27(5):1067-1080.e5. PMC: 5932087. DOI: 10.1016/j.cmet.2018.03.018. View

11.

Hug C, Lodish H . Medicine. Visfatin: a new adipokine. Science. 2004; 307(5708):366-7. DOI: 10.1126/science.1106933. View

12.

Yoshino J, Mills K, Yoon M, Imai S . Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011; 14(4):528-36. PMC: 3204926. DOI: 10.1016/j.cmet.2011.08.014. View

13.

Camacho-Pereira J, Tarrago M, Chini C, Nin V, Escande C, Warner G . CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016; 23(6):1127-1139. PMC: 4911708. DOI: 10.1016/j.cmet.2016.05.006. View

14.

Uddin G, Youngson N, Doyle B, Sinclair D, Morris M . Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Sci Rep. 2017; 7(1):15063. PMC: 5678092. DOI: 10.1038/s41598-017-14866-z. View

15.

Essuman K, Summers D, Sasaki Y, Mao X, DiAntonio A, Milbrandt J . The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017; 93(6):1334-1343.e5. PMC: 6284238. DOI: 10.1016/j.neuron.2017.02.022. View

16.

Gardell S, Hopf M, Khan A, Dispagna M, Sessions E, Falter R . Boosting NAD with a small molecule that activates NAMPT. Nat Commun. 2019; 10(1):3241. PMC: 6642140. DOI: 10.1038/s41467-019-11078-z. View

17.

Gorman M, Feigl E, Buffington C . Human plasma ATP concentration. Clin Chem. 2006; 53(2):318-25. DOI: 10.1373/clinchem.2006.076364. View

18.

Zhang R, Qin Y, Lv X, Wang P, Xu T, Zhang L . A fluorometric assay for high-throughput screening targeting nicotinamide phosphoribosyltransferase. Anal Biochem. 2011; 412(1):18-25. DOI: 10.1016/j.ab.2010.12.035. View

19.

Parihar M, Brewer G . Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol. 2006; 292(1):C8-23. DOI: 10.1152/ajpcell.00232.2006. View

20.

Pieper A, McKnight S . Benefits of Enhancing Nicotinamide Adenine Dinucleotide Levels in Damaged or Diseased Nerve Cells. Cold Spring Harb Symp Quant Biol. 2019; 83:207-217. DOI: 10.1101/sqb.2018.83.037622. View