Sirtuin enzymes depend on NAD to catalyze protein deacetylation. Therefore, the lowering of NAD during aging leads to decreased sirtuin activity and may speed up aging processes in laboratory animals and humans. In this study, we used a genetic screen to identify two mutations in the catalytic domain of yeast Sir2 that allow the enzyme to function in an NAD-depleted environment. These mutant enzymes give rise to a significant increase of yeast replicative lifespan and increase deacetylation by the Sir2 ortholog, SIRT1, in mammalian cells. Our data suggest that these mutations increase the stability of the conserved catalytic sirtuin domain, thereby increasing the catalytic efficiency of the mutant enzymes. Our approach to identifying sirtuin mutants that permit function in NAD-limited environments may inform the design of small molecules that can maintain sirtuin activity in aging organisms.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407064 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2017.02.031 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Accounting for NAD Concentrations in Genome-Scale Metabolic Models Captures Important Metabolic Alterations in NAD-Depleted Systems.
Biomolecules
May 2024
Department of Arctic and Marine Biology, UiT The Arctic University of Norway, 9019 Tromsø, Norway.
Nicotinamide adenine dinucleotide (NAD) is a ubiquitous molecule found within all cells, acting as a crucial coenzyme in numerous metabolic reactions. It plays a vital role in energy metabolism, cellular signaling, and DNA repair. Notably, NAD levels decline naturally with age, and this decline is associated with the development of various age-related diseases.
View Article and Find Full Text PDFLow NAD Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice.
Front Endocrinol (Lausanne)
May 2022
School of Veterinary Medicine, Utah State University, Logan, UT, United States.
Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD levels can be lowered experimentally in chronologically young adult males.
View Article and Find Full Text PDFIntracellular NAD Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.
Front Immunol
February 2022
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Nicotinamide adenine dinucleotide (NAD) is an important cofactor in many redox and non-redox NAD-consuming enzyme reactions. Intracellular NAD level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages.
View Article and Find Full Text PDFA single amino acid substitution (H451Y) in Leishmania calcium-dependent kinase SCAMK confers high tolerance and resistance to antimony.
J Antimicrob Chemother
November 2019
MIVEGEC, IRD, CNRS, Univ. Montpellier, Montpellier, France.
Background: For almost a century, antimonials have remained the first-line drugs for the treatment of leishmaniasis. However, little is known about their mode of action and clinical resistance mechanisms.
Objectives: We have previously shown that Leishmania nicotinamidase (PNC1) is an essential enzyme for parasite NAD+ homeostasis and virulence in vivo.
Mutations that Allow SIR2 Orthologs to Function in a NAD-Depleted Environment.
Cell Rep
March 2017
Glenn Center for the Science of Aging, Department of Biology, Koch Institute, MIT, Cambridge, MA 02139, USA. Electronic address:
Sirtuin enzymes depend on NAD to catalyze protein deacetylation. Therefore, the lowering of NAD during aging leads to decreased sirtuin activity and may speed up aging processes in laboratory animals and humans. In this study, we used a genetic screen to identify two mutations in the catalytic domain of yeast Sir2 that allow the enzyme to function in an NAD-depleted environment.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!