ArticlePloS one2014
Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 80 citations in OpenAlex.
- Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease.Neurology · 2025Trial
- Chronic nicotinamide riboside supplementation is well-tolerated and elevates NADNature communications · 2018Trial
- NAD+ depletion links metabolic stress to drive innate immune priming and selectively control PANoptosis.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- NAD Metabolism Regulates Proliferation of Macrophages in Atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Review
- Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischaemic injury involves direct activation of mitochondrial sirtuin 3.Cardiovascular research · 2025Article
- Identification of small molecular inhibitors of SIRT3 by computational and biochemical approaches a potential target of breast cancer.Scientific reports · 2024Article
- Mechanistic Insights into the Multiple Functions of Niacinamide: Therapeutic Implications and Cosmeceutical Applications in Functional Skincare Products.Antioxidants (Basel, Switzerland) · 2024Review
- SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process.Journal of medicinal chemistry · 2024Review
- Mitochondrial sirtuins: Energy dynamics and cancer metabolism.Molecules and cells · 2024Review
- SARS-CoV-2 infection dysregulates NAD metabolism.Frontiers in immunology · 2023Article
- Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies.International journal of molecular sciences · 2022Review
- Fumonisin BToxins · 2022Article
- Modulation of sirtuins during monolayer chondrocyte culture influences cartilage regeneration upon transfer to a 3D culture environment.Frontiers in bioengineering and biotechnology · 2022Article
- Histone Modifications and Their Targeting in Lymphoid Malignancies.International journal of molecular sciences · 2021Review
- Molecular Dynamics Simulations Reveal the Modulated Mechanism of STING Conformation.Interdisciplinary sciences, computational life sciences · 2021Article
- Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation.Antioxidants (Basel, Switzerland) · 2021Review
- Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease.Frontiers in immunology · 2021Review
- Impaired nicotinamide adenine dinucleotide (NADJournal of diabetes investigation · 2020Review
- Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway.Oncotarget · 2020Article
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sirtuins are key regulators of many cellular functions including cell growth, apoptosis, metabolism, and genetic control of age-related diseases. Sirtuins are themselves regulated by their cofactor nicotinamide adenine dinucleotide (NAD+) as well as their reaction product nicotinamide (NAM), the physiological concentrations of which vary during the process of aging. Nicotinamide inhibits sirtuins through the so-called base exchange pathway, wherein rebinding of the reaction product to the enzyme accelerates the reverse reaction. We investigated the mechanism of nicotinamide inhibition of human SIRT3, the major mitochondrial sirtuin deacetylase, in vitro and in silico using experimental kinetic analysis and Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB(GB)SA) binding affinity calculations with molecular dynamics sampling. Through experimental kinetic studies, we demonstrate that NAM inhibition of SIRT3 involves apparent competition between the inhibitor and the enzyme cofactor NAD+, contrary to the traditional characterization of base exchange as noncompetitive inhibition. We report a model for base exchange inhibition that relates such kinetic properties to physicochemical properties, including the free energies of enzyme-ligand binding, and estimate the latter through the first reported computational binding affinity calculations for SIRT3:NAD+, SIRT3:NAM, and analogous complexes for Sir2. The computational results support our kinetic model, establishing foundations for quantitative modeling of NAD+/NAM regulation of mammalian sirtuins during aging and the computational design of sirtuin activators that operate through alleviation of base exchange inhibition.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.