Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production
by Peter Belenky, Rebecca Stebbins, Katrina L. Bogan, Charles R. Evans, Charles Brenner
NAD+ is both a co-enzyme for hydride transfer enzymes and a
substrate of sirtuins and other NAD+ consuming enzymes.
NAD+ biosynthesis is required for two different regimens
that extend lifespan in yeast. NAD+ is synthesized from
tryptophan and the three vitamin precursors of NAD+: nicotinic
acid, nicotinamide and nicotinamide riboside. Supplementation of yeast cells
with NAD+ precursors increases intracellular
NAD+ levels and extends replicative lifespan. Here we show
that both nicotinamide riboside and nicotinic acid are not only vitamins but are
also exported metabolites. We found that the deletion of the nicotinamide
riboside transporter, Nrt1, leads to increased export of nicotinamide riboside.
This discovery was exploited to engineer a strain to produce high levels of
extracellular nicotinamide riboside, which was recovered in purified form. We
further demonstrate that extracellular nicotinamide is readily converted to
extracellular nicotinic acid in a manner that requires intracellular
nicotinamidase activity. Like nicotinamide riboside, export of nicotinic acid is
elevated by the deletion of the nicotinic acid transporter, Tna1. The data
indicate that NAD+ metabolism has a critical extracellular
element in the yeast system and suggest that cells regulate intracellular
NAD+ metabolism by balancing import and export of
NAD+ precursor vitamins.
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Nrt1 and Tna1-Independent Export of NAD+ Precursor
Vitamins Promotes NAD+ Homeostasis and Allows Engineering of
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