Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells. / Kropotov, Andrey ; Kulikova, Veronika; Solovjeva, Ljudmila; Yakimov1, Alexander; Nerinovski, Kirill; Svetlova, Maria; Sudnitsyna, Julia; Plusnina, Alena; Antipova, Maria; Khodorkovskiy, Mikhail; Migaud, Marie E. ; Gambaryan, Stepan; Ziegler, Mathias; Nikiforov, Andrey.
в: Journal of Biological Chemistry, Том 298, № 12, 102615, 01.12.2022.Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
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TY - JOUR
T1 - Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells
AU - Kropotov, Andrey
AU - Kulikova, Veronika
AU - Solovjeva, Ljudmila
AU - Yakimov1, Alexander
AU - Nerinovski, Kirill
AU - Svetlova, Maria
AU - Sudnitsyna, Julia
AU - Plusnina, Alena
AU - Antipova, Maria
AU - Khodorkovskiy, Mikhail
AU - Migaud, Marie E.
AU - Gambaryan, Stepan
AU - Ziegler, Mathias
AU - Nikiforov, Andrey
N1 - Publisher Copyright: © 2022 The Authors
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Nicotinamide riboside (NR) is an effective precursor of nicotinamide adenine dinucleotide (NAD) in human and animal cells. NR supplementation can increase the level of NAD in various tissues and thereby improve physiological functions that are weakened or lost in experimental models of aging or various human pathologies. However, there are also reports questioning the efficacy of NR supplementation. Indeed, the mechanisms of its utilization by cells are not fully understood. Herein, we investigated the role of purine nucleoside phosphorylase (PNP) in NR metabolism in mammalian cells. Using both PNP overexpression and genetic knockout, we show that after being imported into cells by members of the equilibrative nucleoside transporter family, NR is predominantly metabolized by PNP, resulting in nicotinamide (Nam) accumulation. Intracellular cleavage of NR to Nam is prevented by the potent PNP inhibitor Immucillin H in various types of mammalian cells. In turn, suppression of PNP activity potentiates NAD synthesis from NR. Combining pharmacological inhibition of PNP with NR supplementation in mice, we demonstrate that the cleavage of the riboside to Nam is strongly diminished, maintaining high levels of NR in blood, kidney and liver. Moreover, we show that PNP inhibition stimulates Nam mononucleotide and NAD+ synthesis from NR in vivo, in particular, in the kidney. Thus, we establish PNP as a major regulator of NR metabolism in mammals and provide evidence that the health benefits of NR supplementation could be greatly enhanced by concomitant downregulation of PNP activity.
AB - Nicotinamide riboside (NR) is an effective precursor of nicotinamide adenine dinucleotide (NAD) in human and animal cells. NR supplementation can increase the level of NAD in various tissues and thereby improve physiological functions that are weakened or lost in experimental models of aging or various human pathologies. However, there are also reports questioning the efficacy of NR supplementation. Indeed, the mechanisms of its utilization by cells are not fully understood. Herein, we investigated the role of purine nucleoside phosphorylase (PNP) in NR metabolism in mammalian cells. Using both PNP overexpression and genetic knockout, we show that after being imported into cells by members of the equilibrative nucleoside transporter family, NR is predominantly metabolized by PNP, resulting in nicotinamide (Nam) accumulation. Intracellular cleavage of NR to Nam is prevented by the potent PNP inhibitor Immucillin H in various types of mammalian cells. In turn, suppression of PNP activity potentiates NAD synthesis from NR. Combining pharmacological inhibition of PNP with NR supplementation in mice, we demonstrate that the cleavage of the riboside to Nam is strongly diminished, maintaining high levels of NR in blood, kidney and liver. Moreover, we show that PNP inhibition stimulates Nam mononucleotide and NAD+ synthesis from NR in vivo, in particular, in the kidney. Thus, we establish PNP as a major regulator of NR metabolism in mammals and provide evidence that the health benefits of NR supplementation could be greatly enhanced by concomitant downregulation of PNP activity.
KW - NAD biosynthesis
KW - human
KW - metabolism
KW - mouse
KW - nicotinamide adenine dinucleotide (NAD)
KW - nicotinamide riboside
KW - purine nucleoside phosphorylase
UR - https://linkinghub.elsevier.com/retrieve/pii/S0021925822010584
UR - https://www.mendeley.com/catalogue/8243261c-71c8-3b33-979d-b3c832a15af3/
UR - http://www.scopus.com/inward/record.url?scp=85141795200&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2022.102615
DO - 10.1016/j.jbc.2022.102615
M3 - Article
C2 - 36265580
VL - 298
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 12
M1 - 102615
ER -
ID: 99501151