The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress

Yumeng Zu; Chou Wu; Feifei Li; Hong Yao; Yuyue Xia; Ruoxi Zhang; Lulu Li; Shuangquan Chen; Qi Shi; Shuang Xi; Huanhuan Pang; Minghui Liu; Leibo Wang; Sandi Terpack; Weihua Wang; She Chen; Hong Zhang; Yibing Wang; Maojun Yang; Shanjin Huang; Fuling Zhou; Yu Tang; Zeping Hu; Shilong Fan; Yefeng Tang; Young Sam Lee; Gelin Wang

doi:10.1016/j.molcel.2025.05.022

The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress

Yumeng Zu
, Chou Wu
, Feifei Li
, Hong Yao
, Yuyue Xia
, Ruoxi Zhang
, Lulu Li
, Shuangquan Chen
, Qi Shi
, Shuang Xi
, Huanhuan Pang
, Minghui Liu
, Leibo Wang
, Sandi Terpack
, Weihua Wang
, She Chen
, Hong Zhang
, Yibing Wang
, Maojun Yang
, Shanjin Huang

Fuling Zhou, Yu Tang, Zeping Hu, Shilong Fan, Yefeng Tang, Young Sam Lee, Gelin Wang

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD⁺ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD⁺ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.

Original language	English
Pages (from-to)	2271-2286.e6
Journal	Molecular Cell
Volume	85
Issue number	12
DOIs	https://doi.org/10.1016/j.molcel.2025.05.022
State	Published - Jun 19 2025

Bibliographical note

Publisher Copyright:
© 2025 Elsevier Inc.

Funding

We thank Steven McKnight for initiating this project and critical reading of the manuscript; Xiaodong Wang and Sheng-Cai Lin for the critical reading of the manuscript; Haiteng Deng, Xiaohui Liu, and Guofang Tian for their assistance in metabolite analysis; Masato Kato and Zhe Chen for their assistance in X-ray crystallography; Hui Jiang and Yijun Qi for assistance in protein phosphorylation assays; and Kosaku Uyeda and Yi Lin for helpful input. We thank the Metabolomics Facility Center of Metabolomics and Lipidomics in the National Protein Science Technology Center of Tsinghua University for liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments. This work was supported by grants to G.W. from the National Natural Science Foundation of China ( 91949101 and 81872874 ), the Tsinghua-Toyota Joint Research Fund , the Tsinghua University Initiative Scientific Research Program , the Tsinghua-Peking Center for Life Sciences , the Beijing Advanced Innovation Center for Structural Biology , and the SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine .

Funders	Funder number
Guofang Tian
Metabolomics Facility Center of Metabolomics and Lipidomics
Tsinghua University
Center for Agricultural and Life Sciences Metabolomics
Kosaku Uyeda
Beijing Frontier Research Center for Biological Structure, Tsinghua University
Tsinghua-Toyota Joint Research Fund
National Natural Science Foundation of China (NSFC)	91949101, 81872874

Keywords

AMP
ATP
NAD biosynthesis
NAMPT
energy stress
fasting
ischemia
purine synthesis

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2025.05.022

Cite this

Zu, Y., Wu, C., Li, F., Yao, H., Xia, Y., Zhang, R., Li, L., Chen, S., Shi, Q., Xi, S., Pang, H., Liu, M., Wang, L., Terpack, S., Wang, W., Chen, S., Zhang, H., Wang, Y., Yang, M., ... Wang, G. (2025). The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress. Molecular Cell, 85(12), 2271-2286.e6. https://doi.org/10.1016/j.molcel.2025.05.022

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title = "The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress",

abstract = "Nicotinamide adenine dinucleotide (NAD+) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD+ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD+ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.",

keywords = "AMP, ATP, NAD biosynthesis, NAMPT, energy stress, fasting, ischemia, purine synthesis",

author = "Yumeng Zu and Chou Wu and Feifei Li and Hong Yao and Yuyue Xia and Ruoxi Zhang and Lulu Li and Shuangquan Chen and Qi Shi and Shuang Xi and Huanhuan Pang and Minghui Liu and Leibo Wang and Sandi Terpack and Weihua Wang and She Chen and Hong Zhang and Yibing Wang and Maojun Yang and Shanjin Huang and Fuling Zhou and Yu Tang and Zeping Hu and Shilong Fan and Yefeng Tang and Lee, \{Young Sam\} and Gelin Wang",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = jun,

day = "19",

doi = "10.1016/j.molcel.2025.05.022",

language = "English",

volume = "85",

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Zu, Y, Wu, C, Li, F, Yao, H, Xia, Y, Zhang, R, Li, L, Chen, S, Shi, Q, Xi, S, Pang, H, Liu, M, Wang, L, Terpack, S, Wang, W, Chen, S, Zhang, H, Wang, Y, Yang, M, Huang, S, Zhou, F, Tang, Y, Hu, Z, Fan, S, Tang, Y, Lee, YS & Wang, G 2025, 'The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress', Molecular Cell, vol. 85, no. 12, pp. 2271-2286.e6. https://doi.org/10.1016/j.molcel.2025.05.022

TY - JOUR

T1 - The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress

AU - Zu, Yumeng

AU - Wu, Chou

AU - Li, Feifei

AU - Yao, Hong

AU - Xia, Yuyue

AU - Zhang, Ruoxi

AU - Li, Lulu

AU - Chen, Shuangquan

AU - Shi, Qi

AU - Xi, Shuang

AU - Pang, Huanhuan

AU - Liu, Minghui

AU - Wang, Leibo

AU - Terpack, Sandi

AU - Wang, Weihua

AU - Chen, She

AU - Zhang, Hong

AU - Wang, Yibing

AU - Yang, Maojun

AU - Huang, Shanjin

AU - Zhou, Fuling

AU - Tang, Yu

AU - Hu, Zeping

AU - Fan, Shilong

AU - Tang, Yefeng

AU - Lee, Young Sam

AU - Wang, Gelin

PY - 2025/6/19

Y1 - 2025/6/19

N2 - Nicotinamide adenine dinucleotide (NAD+) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD+ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD+ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.

AB - Nicotinamide adenine dinucleotide (NAD+) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD+ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD+ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.

KW - AMP

KW - ATP

KW - NAD biosynthesis

KW - NAMPT

KW - energy stress

KW - fasting

KW - ischemia

KW - purine synthesis

UR - https://www.scopus.com/pages/publications/105008082027

UR - https://www.scopus.com/pages/publications/105008082027#tab=citedBy

U2 - 10.1016/j.molcel.2025.05.022

DO - 10.1016/j.molcel.2025.05.022

M3 - Article

C2 - 40505662

AN - SCOPUS:105008082027

SN - 1097-2765

VL - 85

SP - 2271-2286.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 12

ER -

The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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