Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.

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 phy...

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Autores principales:	Xiangying Guan, Ping Lin, Eric Knoll, Raj Chakrabarti
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ec9dc8416664c44acf8982b3e5ade89
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spelling	oai:doaj.org-article:6ec9dc8416664c44acf8982b3e5ade892021-11-25T06:00:44ZMechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.1932-620310.1371/journal.pone.0107729https://doaj.org/article/6ec9dc8416664c44acf8982b3e5ade892014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0107729https://doaj.org/toc/1932-6203Sirtuins 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.Xiangying GuanPing LinEric KnollRaj ChakrabartiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e107729 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiangying Guan Ping Lin Eric Knoll Raj Chakrabarti Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
description	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.
format	article
author	Xiangying Guan Ping Lin Eric Knoll Raj Chakrabarti
author_facet	Xiangying Guan Ping Lin Eric Knoll Raj Chakrabarti
author_sort	Xiangying Guan
title	Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
title_short	Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
title_full	Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
title_fullStr	Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
title_full_unstemmed	Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.
title_sort	mechanism of inhibition of the human sirtuin enzyme sirt3 by nicotinamide: computational and experimental studies.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/6ec9dc8416664c44acf8982b3e5ade89
work_keys_str_mv	AT xiangyingguan mechanismofinhibitionofthehumansirtuinenzymesirt3bynicotinamidecomputationalandexperimentalstudies AT pinglin mechanismofinhibitionofthehumansirtuinenzymesirt3bynicotinamidecomputationalandexperimentalstudies AT ericknoll mechanismofinhibitionofthehumansirtuinenzymesirt3bynicotinamidecomputationalandexperimentalstudies AT rajchakrabarti mechanismofinhibitionofthehumansirtuinenzymesirt3bynicotinamidecomputationalandexperimentalstudies
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Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.

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