BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities

Keisuke Yaku; Sailesh Palikhe; Hironori Izumi; Tomoyuki Yoshida; Keisuke Hikosaka; Faisal Hayat; Mariam Karim; Tooba Iqbal; Yasuhito Nitta; Atsushi Sato; Marie E Migaud; Katsuhiko Ishihara; Hisashi Mori; Takashi Nakagawa

doi:10.1038/s41467-021-27080-3

BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities

Nat Commun. 2021 Nov 19;12(1):6767. doi: 10.1038/s41467-021-27080-3.

Authors

Keisuke Yaku^#¹, Sailesh Palikhe^#¹, Hironori Izumi^{2

3}, Tomoyuki Yoshida^{2

3}, Keisuke Hikosaka¹, Faisal Hayat⁴, Mariam Karim¹, Tooba Iqbal¹, Yasuhito Nitta¹, Atsushi Sato⁵, Marie E Migaud⁴, Katsuhiko Ishihara⁶, Hisashi Mori^{2

3

7}, Takashi Nakagawa^{8

9}

Affiliations

¹ Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
² Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
³ Research Center for Idling Brain Science (RCIBS), University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
⁴ Mitchell Cancer Institute, Department of Pharmacology, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36693, USA.
⁵ School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
⁶ Department of Immunology and Molecular Genetics, Kawasaki Medical University, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
⁷ Research Center for Pre-Disease Science, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
⁸ Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan. nakagawa@med.u-toyama.ac.jp.
⁹ Research Center for Pre-Disease Science, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan. nakagawa@med.u-toyama.ac.jp.

^# Contributed equally.

Abstract

Nicotinamide riboside (NR) is one of the orally bioavailable NAD⁺ precursors and has been demonstrated to exhibit beneficial effects against aging and aging-associated diseases. However, the metabolic pathway of NR in vivo is not yet fully understood. Here, we demonstrate that orally administered NR increases NAD⁺ level via two different pathways. In the early phase, NR was directly absorbed and contributed to NAD⁺ generation through the NR salvage pathway, while in the late phase, NR was hydrolyzed to nicotinamide (NAM) by bone marrow stromal cell antigen 1 (BST1), and was further metabolized by the gut microbiota to nicotinic acid, contributing to generate NAD⁺ through the Preiss-Handler pathway. Furthermore, we report BST1 has a base-exchange activity against both NR and nicotinic acid riboside (NAR) to generate NAR and NR, respectively, connecting amidated and deamidated pathways. Thus, we conclude that BST1 plays a dual role as glycohydrolase and base-exchange enzyme during oral NR supplementation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
ADP-ribosyl Cyclase / genetics
ADP-ribosyl Cyclase / metabolism*
Administration, Oral
Aging / drug effects
Animals
Antigens, CD / genetics
Antigens, CD / metabolism*
Dietary Supplements
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Gastrointestinal Microbiome
Glycoside Hydrolases / genetics
Glycoside Hydrolases / metabolism*
Humans
Intestinal Mucosa / metabolism
Intestinal Mucosa / microbiology
Intestine, Small / metabolism
Intestine, Small / microbiology
Mice
Mice, Knockout
Niacin / metabolism
Niacinamide / administration & dosage
Niacinamide / analogs & derivatives*
Niacinamide / metabolism
Niacinamide / pharmacokinetics
Pentosyltransferases / genetics
Pentosyltransferases / metabolism
Pyridinium Compounds / administration & dosage
Pyridinium Compounds / pharmacokinetics*

Substances

Antigens, CD
GPI-Linked Proteins
Pyridinium Compounds
nicotinamide-beta-riboside
Niacinamide
Niacin
Pentosyltransferases
Glycoside Hydrolases
ADP-ribosyl Cyclase
ADP-ribosyl cyclase 2
nicotinate phosphoribosyltransferase