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

Tracy L. Vrablik, Li Huang, Stephanie E. Lange, Wendy Hanna-Rose

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3637-3646
Number of pages10
JournalDevelopment
Volume136
Issue number21
DOIs
StatePublished - Nov 1 2009

Fingerprint

Nicotinamidase
Niacinamide
NAD
Cell Survival
Nicotinamide Phosphoribosyltransferase
Gonads
Enzymes
Ovum
Necrosis
Biological Phenomena
Caenorhabditis elegans
Recycling
Invertebrates
Vertebrates
Protein Isoforms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

Cite this

@article{8b210498536840e9a4727667d464dd29,
title = "Nicotinamidase modulation of NAD+ biosynthesis and nicotinamide levels separately affect reproductive development and cell survival in C. elegans",
abstract = "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.",
author = "Vrablik, {Tracy L.} and Li Huang and Lange, {Stephanie E.} and Wendy Hanna-Rose",
year = "2009",
month = "11",
day = "1",
doi = "10.1242/dev.028431",
language = "English (US)",
volume = "136",
pages = "3637--3646",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "21",

}

Nicotinamidase modulation of NAD+ biosynthesis and nicotinamide levels separately affect reproductive development and cell survival in C. elegans. / Vrablik, Tracy L.; Huang, Li; Lange, Stephanie E.; Hanna-Rose, Wendy.

In: Development, Vol. 136, No. 21, 01.11.2009, p. 3637-3646.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nicotinamidase modulation of NAD+ biosynthesis and nicotinamide levels separately affect reproductive development and cell survival in C. elegans

AU - Vrablik, Tracy L.

AU - Huang, Li

AU - Lange, Stephanie E.

AU - Hanna-Rose, Wendy

PY - 2009/11/1

Y1 - 2009/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70350179627&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350179627&partnerID=8YFLogxK

U2 - 10.1242/dev.028431

DO - 10.1242/dev.028431

M3 - Article

C2 - 19820182

AN - SCOPUS:70350179627

VL - 136

SP - 3637

EP - 3646

JO - Development (Cambridge)

JF - Development (Cambridge)

SN - 0950-1991

IS - 21

ER -