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https://www.readbyqxmd.com/read/29300832/analysis-of-polymorphisms-in-58-potential-candidate-genes-for-association-with-human-longevity
#1
Timothy A Donlon, Brian J Morris, Randi Chen, Kamal H Masaki, Richard C Allsopp, D Craig Willcox, Maarit Tiirikainen, Bradley J Willcox
Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that amongst genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single nucleotide polymorphisms (SNPs) in 46 genes differentially expressed in calorically-restricted mice and 12 other genes for association with longevity. Subjects were American men of Japanese ancestry, 440 aged ≥95 years and 374 with an average lifespan. Based on a dominant model of inheritance, an association with longevity at the p < 0...
December 30, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/29261224/mitochondrial-sirtuins-in-the-rat-adrenal-gland-location-within-the-glands-of-males-and-females-hormonal-and-developmental-regulation-of-gene-expressions
#2
Piotr Celichowski, Karol Jopek, Marta Szyszka, Marianna Tyczewska, Ludwik K Malendowicz, Marcin Rucinski
INTRODUCTION: Sirtuins are NAD dependent class III histone deacetylases. In adrenal cortex mitochondria are able to transform - via nicotinamide nucleotide transhydrogenase (NNT) - NAD into NADPH, which is required for steroidogenesis. These findings suggest that sirtuins expressed in mitochondria, Sirt3, Sirt4 and Sirt5, may be associated with adrenal steroidogenesis. Therefore, the purpose of this study was to characterize the expression of mitochondrial sirtuins (Sirt3-5) in individual compartments of rat adrenal cortex, their developmental regulation and to demonstrate whether their expression is dependent on adrenocorticotrophic hormone (ACTH) and Nampt (nicotinamide phosphoribosyltransferase also known as visfatin/PBEF), the rate-limiting enzyme in the regulation of mammalian NAD synthesis...
December 20, 2017: Folia Histochemica et Cytobiologica
https://www.readbyqxmd.com/read/29249955/expression-of-sirtuins-in-the-retinal-neurons-of-mice-rats-and-humans
#3
Hongdou Luo, Min Zhou, Kaibao Ji, Jiejie Zhuang, Wenjie Dang, Shiya Fu, Tao Sun, Xu Zhang
Sirtuins are a class of histone deacetylases (HDACs) that have been shown to regulate a range of pathophysiological processes such as cellular aging, inflammation, metabolism, and cell proliferation. There are seven mammalian Sirtuins (SIRT1-7) that play important roles in stress response, aging, and neurodegenerative diseases. However, the location and function of Sirtuins in neurons are not well defined. This study assessed the retinal expression of Sirtuins in mice, rats, and humans and measured the expression of Sirtuins in aged and injured retinas...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29180469/shmt2-desuccinylation-by-sirt5-drives-cancer-cell-proliferation
#4
Xin Yang, Zhe Wang, Xin Li, Boya Liu, Minghui Liu, Lu Liu, Shuaiyi Chen, Mengmeng Ren, Yankun Wang, Miao Yu, Bo Wang, Junhua Zou, Wei-Guo Zhu, Yuxin Yin, Wei Gu, Jianyuan Luo
The mitochondrial serine hydroxymethyltransferase SHMT2 which catalyzes the rate-limiting step in serine catabolism drives cancer cell proliferation, but how this role is regulated is undefined. Here we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2 which was crucial for activating its enzymatic activity. Conversely hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29154835/sirt5-and-post-translational-protein-modifications-a-potential-therapeutic-target-for-myocardial-ischemia-reperfusion-injury-with-regard-to-mitochondrial-dynamics-and-oxidative-metabolism
#5
REVIEW
Rongjun Zou, Wanting Shi, Jun Tao, Hongmu Li, Xifeng Lin, Songran Yang, Ping Hua
SIRT5 is a sirtuin family member that participates in dynamic and reversible protein chemical modification after translation. It has pivotal roles in the regulation of numerous aspects of myocardial energy metabolism and cardiac functions. Recent studies suggest that down-regulation of this regulator significantly increased the extent of myocardial infarction during ischemia-reperfusion injury (IRI). Accordingly, SIRT5 is emerging as a major contributor to the pathogenesis of IRI and may possess therapeutic potential for reversing mitochondrial respiratory chain disturbances and cellular damage attributed to ischemia-reperfusion...
November 14, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29138502/crystal-structures-of-the-mitochondrial-deacylase-sirtuin-4-reveal-isoform-specific-acyl-recognition-and-regulation-features
#6
Martin Pannek, Zeljko Simic, Matthew Fuszard, Marat Meleshin, Dante Rotili, Antonello Mai, Mike Schutkowski, Clemens Steegborn
Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29115436/sirt5-promotes-cell-proliferation-and-invasion-in-hepatocellular-carcinoma-by-targeting-e2f1
#7
Liang Chang, Liang Xi, Yubin Liu, Rui Liu, Zhongshi Wu, Zhixiang Jian
Sirtuin 5 (SIRT5) is a member of the NAD+‑dependent class III protein deacetylases. Although it is known that SIRT5 deacetylates and activates urate oxidase in the liver mitochondria of mice, the mechanism of SIRT5 in the proliferation of hepatocellular carcinoma (HCC) remains to be fully elucidated. The present study investigated the expression and functional significance of SIRT5 in HCC, and examined the relevant mechanism. SIRT5 was found to be upregulated in HCC tissues and cell lines, and the higher expression of SIRT5 indicated poorer overall survival...
January 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29044784/mechanism-based-inhibitors-of-the-human-sirtuin-5-deacylase-structure-activity-relationship-biostructural-and-kinetic-insight
#8
Nima Rajabi, Marina Auth, Kathrin R Troelsen, Martin Pannek, Dhaval P Bhatt, Martin Fontenas, Matthew D Hirschey, Clemens Steegborn, Andreas S Madsen, Christian A Olsen
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties...
October 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29025872/sirtuins-regulate-proteomic-responses-near-thermal-tolerance-limits-in-the-blue-mussels-mytilus-galloprovincialis-and-mytilus-trossulus
#9
M Christina Vasquez, Michelle Beam, Shelley Blackwell, Marcus J Zuzow, Lars Tomanek
The blue mussels Mytilus galloprovincialis and M. trossulus are competing species with biogeographical ranges set in part by environmental exposure to heat and hyposalinity. The underlying cellular mechanisms influencing interspecific differences in stress tolerance are unknown, but are believed to be under regulation by sirtuins, NAD-dependent deacylases that play a critical role in the cellular stress response. A comparison of the proteomic responses of M. galloprovincialis and M. trossulus to an acute heat shock in the presence and absence of the sirtuin inhibitor suramin (SIRT1, 2 and 5), showed that sirtuins affected molecular chaperones, oxidative stress proteins, metabolic enzymes, cytoskeletal and signaling proteins more in the heat-sensitive M...
October 12, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/28972174/sirtuin-5-is-required-for-mouse-survival-in-response-to-cardiac-pressure-overload
#10
Kathleen A Hershberger, Dennis M Abraham, Angelical S Martin, Lan Mao, Juan Liu, Hongbo Gu, Jason W Locasale, Matthew D Hirschey
In mitochondria, the sirtuin SIRT5 is an NAD(+)-dependent protein deacylase that controls several metabolic pathways. While a wide range of SIRT5 targets has been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains unclear. Given that SIRT5 expression is highest in the heart and that sirtuins are commonly stress-response proteins, we used an established model of pressure overload-induced heart muscle hypertrophy caused by transverse aortic constriction (TAC) to determine SIRT5's role in cardiac stress responses...
October 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28891317/the-role-of-sirtuins-in-antioxidant-and-redox-signaling
#11
Chandra K Singh, Gagan Chhabra, Mary Ann Ndiaye, Liz Mariely Garcia-Peterson, Nicholas J Mack, Nihal Ahmad
SIGNIFICANCE: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets...
October 20, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28857557/genetically-encoded-fluorescent-probe-for-detecting-sirtuins-in-living-cells
#12
Weimin Xuan, Anzhi Yao, Peter G Schultz
Sirtuins are NAD(+) dependent protein deacetylases, which are involved in many biological processes. We now report a novel genetically encoded fluorescent probe (EGFP-K85AcK) that responds to sirtuins in living cells. The probe design exploits a lysyl residue in EGFP that is essential for chromophore maturation, and is also an efficient deacetylation substrate for sirtuins. Analysis of activity in Escherichia coli ΔcobB revealed that the probe can respond to various human sirtuins, including SIRT1, SIRT2, SIRT3 and SIRT5...
August 31, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28756638/structure-based-discovery-of-new-selective-small-molecule-sirtuin-5-inhibitors
#13
Sha Liu, Sen Ji, Zhu-Jun Yu, Hua-Li Wang, Xu Cheng, Wei-Jian Li, Li Jing, Yamei Yu, Qiang Chen, Ling-Ling Yang, Guo-Bo Li, Yong Wu
Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses and is implicated in metabolism-related diseases. Small-molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein, we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, six compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of newly synthesized (E)-2-cyano-N-phenyl-3-(5-phenylfuran-2-yl)acrylamide derivatives/analogues were carried out structure-activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5...
July 30, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28739840/mitochondrial-sirtuins-in-cardiometabolic-diseases
#14
REVIEW
Xiaoqiang Tang, Xiao-Feng Chen, Hou-Zao Chen, De-Pei Liu
Mitochondria are heterogeneous and essentially contribute to cellular functions and tissue homeostasis. Mitochondrial dysfunction compromises overall cell functioning, tissue damage, and diseases. The advances in mitochondrion biology increase our understanding of mitochondrial dynamics, bioenergetics, and redox homeostasis, and subsequently, their functions in tissue homeostasis and diseases, including cardiometabolic diseases (CMDs). The functions of mitochondria mainly rely on the enzymes in their matrix...
August 15, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28707980/extranuclear-sirtuins-and-metabolic-stress
#15
Mahmoud-Sobhy Elkhwanky, Jukka Hakkola
SIGNIFICANCE: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation...
August 11, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28707979/emerging-roles-for-sirt5-in-metabolism-and-cancer
#16
Lauren R Bringman-Rodenbarger, Angela H Guo, Costas A Lyssiotis, David B Lombard
SIGNIFICANCE: Developing evidence in the literature suggests that sirtuin 5 (SIRT5) may be involved in metabolic reprogramming, an emerging hallmark of cancer by which neoplastic cells reconfigure their metabolism to support the anabolic demands of rapid cell division. SIRT5 is one of the seven members of the nicotinamide adenine dinucleotide-dependent sirtuin family of lysine deacetylases. It removes succinyl, malonyl, and glutaryl groups from protein targets within the mitochondrial matrix and other subcellular compartments...
October 26, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28631845/mild-metabolic-perturbations-alter-succinylation-of-mitochondrial-proteins
#17
Huanlian Chen, Hui Xu, Samuel Potash, Anatoly Starkov, Vsevolod V Belousov, Dmitry S Bilan, Travis T Denton, Gary E Gibson
Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have 1,190 unique succinylation sites representing multiple metabolic pathways. Succinylation is sensitive to both increases and decreases of the NAD(+) -dependent desuccinylase, SIRT5. Although the succinyl group for succinylation is derived from metabolism, the effects of systematic variation of metabolism on mitochondrial succinylation are not known...
November 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28614718/sirt5-desuccinylates-and-activates-pyruvate-kinase-m2-to-block-macrophage-il-1%C3%AE-production-and-to-prevent-dss-induced-colitis-in-mice
#18
Fang Wang, Ke Wang, Wei Xu, Shimin Zhao, Dan Ye, Yi Wang, Ying Xu, Lisha Zhou, Yiwei Chu, Cuiping Zhang, Xue Qin, Pengyuan Yang, Hongxiu Yu
LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1β gene in LPS-stimulated macrophages...
June 13, 2017: Cell Reports
https://www.readbyqxmd.com/read/28559847/high-sensitivity-of-sirt3-deficient-hearts-to-ischemia-reperfusion-is-associated-with-mitochondrial-abnormalities
#19
Rebecca M Parodi-Rullán, Xavier Chapa-Dubocq, Pedro J Rullán, Sehwan Jang, Sabzali Javadov
Aim: Sirtuins are NAD(+)-dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation, and SIRT3 is the major deacetylase among mitochondrial isoforms. Here, we elucidated the possible role of acetylation of cyclophilin D, a key regulator of the mitochondrial permeability transition pore (mPTP), in mitochondria-mediated cardiac dysfunction induced by ischemia-reperfusion (IR) in wild type (WT) and SIRT3 knockout (SIRT3(-/-)) mice. Materials and Methods: Isolated and Langendorff-mode perfused hearts of WT and SIRT3(-/-) mice were subjected to 25-min global ischemia followed by 60-min of reperfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28514599/a-bioenergetics-systems-evaluation-of-ketogenic-diet-liver-effects
#20
Lewis J Hutfles, Heather M Wilkins, Scott J Koppel, Ian W Weidling, J Eva Selfridge, Eephie Tan, John P Thyfault, Chad Slawson, Aron W Fenton, Hao Zhu, Russell H Swerdlow
Ketogenic diets induce hepatocyte fatty acid oxidation and ketone body production. To further evaluate how ketogenic diets affect hepatocyte bioenergetic infrastructure, we analyzed livers from C57Bl/6J male mice maintained for 1 month on a ketogenic or standard chow diet. Compared with the standard diet, the ketogenic diet increased cytosolic and mitochondrial protein acetylation and also altered protein succinylation patterns. SIRT3 protein decreased while SIRT5 protein increased, and gluconeogenesis, oxidative phosphorylation, and mitochondrial biogenesis pathway proteins were variably and likely strategically altered...
September 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
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