Nicotinamide adenine dinucleotide (
NAD(+)) is a central molecule in cellular metabolism and an obligate co-substrate for
NAD(+)-consuming
enzymes, which regulate key biological processes such as longevity and stress responses. Although
NAD(+) biosynthesis has been intensely studied, little analysis has been done in developmental models. We have uncovered novel developmental roles for a
nicotinamidase (PNC), the first
enzyme in the
NAD(+) salvage pathway of invertebrates. Mutations in the Caenorhabditis elegans
nicotinamidase PNC-1 cause developmental and functional defects in the reproductive system; the development of the gonad is delayed, four uterine cells die by
necrosis and the mutant animals are egg-laying defective. The temporal delay in gonad development results from depletion of the salvage pathway product
NAD(+), whereas the uv1 cell
necrosis and egg-laying defects result from accumulation of the substrate
nicotinamide. Thus, regulation of both substrate and product level is key to the
biological activity of PNC-1. We also find that diet probably affects the levels of these metabolites, as it affects phenotypes. Finally, we identified a secreted
isoform of PNC-1 and confirmed its extracellular localization and functional activity in vivo. We demonstrate that
nicotinamide phosphoribosyltransferase (Nampt), the equivalent
enzyme in
nicotinamide recycling to
NAD(+) in vertebrates, can functionally substitute for PNC-1. As Nampt is also secreted, we postulate an evolutionarily conserved extracellular role for
NAD(+) biosynthetic
enzymes during development and physiology.