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

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.

Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects

“…It has been reported that orally administered NAM was converted to NA through deamidation by intestinal microbiota, and was absorbed from large intestine as NA ( 54 ). Recently, we demonstrated that orally administered NR was cleaved to NAM by BST1 followed by conversion to NA by microbiota ( 55 ). The absorbed NA contributed to NAD + synthesis through the Preiss-Handler pathway generating NAMN as an intermediate.…”

Maintenance of NAD+ Homeostasis in Skeletal Muscle during Aging and Exercise

“…When NMNAT was knocked out in mice, supplementation of NR failed to protect muscle deterioration with aging, demonstrating the crucial role of NMNAT in NAD+ salvage. Recently, Yaku et al [ 48 ] demonstrated in an elegantly executed study that in C57BL/6N mice, oral gavage of NR increased NAD+ levels in several tissues via two distinct pathways. In the early phase, NR was directly absorbed and boosted NAD+ generation through the salvage pathway.…”

“…A recent review by Khaidizar et al [ 51 ] also reviewed the efficacy of NAD+ and NAD+ precursor supplementation and highlighted the benefits of NR over other compounds in ameliorating aging and age-related diseases. The comparisons among various NAD+ precursors may be complicated by the recent finding that gut microbiota is capable of converting NAM to NA and utilizing multiple pathways to synthesize NAD+ [ 48 , 52 ].…”

NAD+ Precursors: A Questionable Redundancy

“…This was confirmed in a third study, which also examined earlier time points. Interestingly, this study reported how orally administered NR and NAM increased NAD + levels in a biphasic manner [ 29 ]. In an early phase (within 1 h after administration), NR and NAM were directly taken up by the small intestine and utilized for NAD + synthesis in the liver [ 29 ].…”