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ZunGuo Du, XiuJuan Liu, Tao Chen, WenChao Gao, ZhengMing Wu, ZhiQian Hu, Dong Wei, ChunFang Gao, QingQuan Li
A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate...
March 6, 2018: Cell Reports
Chris Carrico, Jesse G Meyer, Wenjuan He, Brad W Gibson, Eric Verdin
Post-translational modification of lysine residues via reversible acylation occurs on proteins from diverse pathways, functions, and organisms. While nuclear protein acylation reflects the competing activities of enzymatic acyltransferases and deacylases, mitochondrial acylation appears to be driven mostly via a non-enzymatic mechanism. Three protein deacylases, SIRT3, SIRT4, and SIRT5, reside in the mitochondria and remove these modifications from targeted proteins in an NAD+ -dependent manner. Recent proteomic surveys of mitochondrial protein acylation have identified the sites of protein acetylation, succinylation, glutarylation, and malonylation and their regulation by SIRT3 and SIRT5...
March 6, 2018: Cell Metabolism
Xing-Xing He, Chen-Kai Huang, Bu-Shan Xie
The exact molecular mechanism of 5-fluorouracil (5-FU) in human gastric cancer cells remains to be elucidated. Cultured BGC‑823 human gastric carcinoma and AGS cell lines were treated with 5‑FU. Autophagosome formation was investigated through multiple approaches, including the quantification of green fluorescent protein‑microtubule‑associated protein 1A/1B‑light chain 3 (LC3) puncta, LC3 conversion and electron microscopy observations. Additionally, autophagy was inhibited using 3‑methyladenine (3‑MA) and beclin‑1 ablation, to determine its role in 5‑FU‑mediated cell death...
March 1, 2018: Molecular Medicine Reports
Diana Kalbas, Sandra Liebscher, Theresa Nowak, Marat Meleshin, Martin Pannek, Corinna Popp, Zayan Alhalabi, Frank Bordusa, Wolfgang Sippl, Clemens Steegborn, Mike Schutkowski
Sirtuins are protein deacylases regulating metabolism and stress responses and implicated in aging-related diseases. Modula-tors of the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, e.g., for cancer. Selective and po-tent inhibitors are available for Sirt2 but selective inhibitors for Sirt5 with Ki-values in the low nM range are lacking. We syn-thesized and screened 3-Arylthiosuccinylated- and 3-Benzylthiosuccinylated peptide derivatives yielding Sirt5 inhibitors with low nM Ki-values...
March 1, 2018: Journal of Medicinal Chemistry
Xiu-Fei Chen, Meng-Xin Tian, Ren-Qiang Sun, Meng-Li Zhang, Li-Sha Zhou, Lei Jin, Lei-Lei Chen, Wen-Jie Zhou, Kun-Long Duan, Yu-Jia Chen, Chao Gao, Zhou-Li Cheng, Fang Wang, Jin-Ye Zhang, Yi-Ping Sun, Hong-Xiu Yu, Yu-Zheng Zhao, Yi Yang, Wei-Ren Liu, Ying-Hong Shi, Yue Xiong, Kun-Liang Guan, Dan Ye
Peroxisomes account for ~35% of total H2 O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2 O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers...
February 28, 2018: EMBO Reports
Yi Wang, Jing Jin, Matthew Wai Heng Chung, Ling Feng, Hongyan Sun, Quan Hao
Lysine succinylation is a newly discovered posttranslational modification with distinctive physical properties. However, to date rarely have studies reported effectors capable of interpreting this modification on histones. Following our previous study of SIRT5 as an eraser of succinyl-lysine (Ksuc), here we identified the GAS41 YEATS domain as a reader of Ksuc on histones. Biochemical studies showed that the GAS41 YEATS domain presents significant binding affinity toward H3K122suc upon a protonated histidine residue...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kevin B Koronowski, Nathalie Khoury, Kahlilia C Morris-Blanco, Holly M Stradecki-Cohan, Timothy J Garrett, Miguel A Perez-Pinzon
The role of Sirtuins in brain function is emerging, yet little is known about SIRT5 in this domain. Our previous work demonstrates that protein kinase C epsilon (PKCε)-induced protection from focal ischemia is lost in SIRT5-/-mice. Thus, metabolic regulation by SIRT5 contributes significantly to ischemic tolerance. The aim of this study was to identify the SIRT5-regulated metabolic pathways in the brain and determine which of those pathways are linked to PKCε. Our results show SIRT5 is primarily expressed in neurons and endothelial cells in the brain, with mitochondrial and extra-mitochondrial localization...
2018: Frontiers in Neuroscience
Kana Tanabe, Jiaan Liu, Daiki Kato, Hitoshi Kurumizaka, Kenzo Yamatsugu, Motomu Kanai, Shigehiro A Kawashima
Chromatin structure and gene expression are dynamically regulated by posttranslational modifications of histones. Recent advance in mass spectrometry has identified novel types of lysine acylations, such as butyrylation and malonylation, whose functions and regulations are likely different from those of acetylation. Sirtuins, nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, catalyze various deacylations. However, it is poorly understood how distinct sirtuins regulate the histone acylation states of nucleosomes that have many lysine residues...
February 8, 2018: Scientific Reports
Yun-Qian Wang, Hao-Lian Wang, Jie Xu, Juan Tan, Lin-Na Fu, Ji-Lin Wang, Tian-Hui Zou, Dan-Feng Sun, Qin-Yan Gao, Ying-Xuan Chen, Jing-Yuan Fang
Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in 13C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine-derived non-essential amino acids. This reduces the building blocks required for rapid growth...
February 7, 2018: Nature Communications
Morten Dall, Melanie Penke, Karolina Sulek, Madlen Matz-Soja, Birgitte Holst, Antje Garten, Wieland Kiess, Jonas T Treebak
Dietary supplementation of nicotinamide adenine dinucleotide (NAD+) precursors has been suggested as a treatment for non-alcoholic fatty liver disease and obesity. In the liver, NAD+ is primarily generated by nicotinamide phosphoribosyltransferase (NAMPT), and hepatic levels of NAMPT and NAD+ have been reported to be dependent on age and body composition. The aim of the present study was to identify time-course-dependent changes in hepatic NAD content and NAD+ salvage capacity in mice challenged with a high-fat diet (HFD)...
February 1, 2018: Molecular and Cellular Endocrinology
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
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
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
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 Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress...
January 15, 2018: Cancer Research
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...
January 5, 2018: European Journal of Pharmacology
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
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
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
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, nicotinamide adenine dinucleotide (NAD+ )-dependent deacylases that play a critical role in the cellular stress response. A comparison of the proteomic responses of M. galloprovincialis and M...
December 1, 2017: Journal of Experimental Biology
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. Although a wide range of SIRT5 targets have 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...
December 1, 2017: Journal of Biological Chemistry
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