Enzymatic and Chemical Syntheses of Vacor Analogs of Nicotinamide Riboside, NMN and NAD.

Lars Jansen Sverkeli,Mathias Ziegler,Marie E Migaud,Faisal Hayat

doi:10.3390/biom11071044

Lars Jansen Sverkeli, Mathias Ziegler + Show 2 more

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https://doi.org/10.3390/biom11071044

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Abstract

It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by enzymes of the NAD salvage pathway. Thereby, vacor is transformed into the NAD analog vacor adenine dinucleotide (VAD), a molecule that causes cell toxicity. Therefore, vacor may potentially be exploited to kill cancer cells. In this study, we have developed efficient enzymatic and chemical procedures to produce vacor analogs of NAD and nicotinamide riboside (NR). VAD was readily generated by a base-exchange reaction, replacing the nicotinamide moiety of NAD by vacor, catalyzed by Aplysia californica ADP ribosyl cyclase. Additionally, we present the chemical synthesis of the nucleoside version of vacor, vacor riboside (VR). Similar to the physiological NAD precursor, NR, VR was converted to the corresponding mononucleotide (VMN) by nicotinamide riboside kinases (NRKs). This conversion is quantitative and very efficient. Consequently, phosphorylation of VR by NRKs represents a valuable alternative to produce the vacor analog of NMN, compared to its generation from vacor by nicotinamide phosphoribosyltransferase (NamPT).

Highlights

We present the chemical synthesis of vacor riboside (VR) and demonstrate that it acts as an authentic nicotinamide riboside (NR) analogue, as it is converted to vacor mononucleotide (VMN) by nicotinamide riboside kinases (NRKs)
We reasoned that the well-known baseexchange reaction [24,25,32], which is an exceptional feature of ADP-ribosyl cyclases, could be exploited for a simplified route to produce vacor adenine dinucleotide (VAD)
As vacor has gained attention due to its potential to enter the nicotinamide adenine dinucleotide (NAD) biosynthetic pathway, with downstream vacor products acting as toxins, a potential use case for vacor products has emerged

Summary

Introduction

Most NAD is synthesized in a two-step process called the nicotinamide (Nam) salvage pathway (Figure 1). In this process, Nam is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyl transferase (NamPT) in a rate-limiting reaction [10]. Nam is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyl transferase (NamPT) in a rate-limiting reaction [10] This reaction requires phosphoribosyl pyrophosphate (PRPP) as co-substrate. As Nam is the product of most reactions consuming NAD, the salvage pathway lets the cell recycle Nam as its main NAD precursor. The NAD biosynthetic pathways have emerged as a topic of significant research

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