Nicotinamidase modulation of NAD+ biosynthesis and nicotinamide levels separately affect reproductive development and cell survival in C. elegans.

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.
AuthorsTracy L Vrablik, Li Huang, Stephanie E Lange, Wendy Hanna-Rose
JournalDevelopment (Cambridge, England) (Development) Vol. 136 Issue 21 Pg. 3637-46 (Nov 2009) ISSN: 1477-9129 [Electronic] England
PMID19820182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Caenorhabditis elegans Proteins
  • NAD
  • Niacinamide
  • Nicotinamidase
  • Animals
  • Caenorhabditis elegans (cytology, enzymology, physiology)
  • Caenorhabditis elegans Proteins (genetics, metabolism)
  • Cell Survival
  • Female
  • NAD (biosynthesis)
  • Niacinamide (metabolism)
  • Nicotinamidase (genetics, metabolism)
  • Ovum (growth & development)
  • Uterus (cytology, physiology)

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