Insights on the Modulation of SIRT5 Activity: A Challenging Balance

Mori, Matteo; Cazzaniga, Giulia; Meneghetti, Fiorella; Villa, Stefania; Gelain, Arianna

doi:10.3390/molecules27144449

Cited by 8 publications

(5 citation statements)

References 75 publications

(140 reference statements)

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“…As class III HDACs, SIRTs require the co-substrate nicotinamide adenine dinucleotide (NAD + ) to exert their catalytic activity. In mammals, there are seven sirtuins (SIRT1-7), each possessing different biological and specific functions in various cell compartments [5][6][7]. Indeed, SIRT1 is mainly nuclear, though shuttling into the cytoplasm, while SIRT2 houses in the cytoplasm, shuttling to the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

Scarano

Abbotto

Musumeci

et al. 2023

IJMS

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Sirtuin isoform 2 (SIRT2) is one of the seven sirtuin isoforms present in humans, being classified as class III histone deacetylases (HDACs). Based on the high sequence similarity among SIRTs, the identification of isoform selective modulators represents a challenging task, especially for the high conservation observed in the catalytic site. Efforts in rationalizing selectivity based on key residues belonging to the SIRT2 enzyme were accompanied in 2015 by the publication of the first X-ray crystallographic structure of the potent and selective SIRT2 inhibitor SirReal2. The subsequent studies led to different experimental data regarding this protein in complex with further different chemo-types as SIRT2 inhibitors. Herein, we reported preliminary Structure-Based Virtual Screening (SBVS) studies using a commercially available library of compounds to identify novel scaffolds for the design of new SIRT2 inhibitors. Biochemical assays involving five selected compounds allowed us to highlight the most effective chemical features supporting the observed SIRT2 inhibitory ability. This information guided the following in silico evaluation and in vitro testing of further compounds from in-house libraries of pyrazolo-pyrimidine derivatives towards novel SIRT2 inhibitors (1–5). The final results indicated the effectiveness of this scaffold for the design of promising and selective SIRT2 inhibitors, featuring the highest inhibition among the tested compounds, and validating the applied strategy.

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Section: Introductionmentioning

confidence: 99%

Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

Scarano

Abbotto

Musumeci

et al. 2023

IJMS

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show abstract

“…Here, it was also noted that DCM modeling contributed to lowered SIRT5 in the myocardial tissues, along with enhanced proteins modified by Mal-Lys. SIRT5 is principally located in the mitochondria and is overexpressed in the brain, heart, testis, and lymphoblasts 26 . Mitochondrial SIRTs coordinate the modulation of gene expression and activities of a myriad of enzymes to orchestrate oxidative metabolism and stress responses 27 .…”

Section: Discussionmentioning

confidence: 99%

SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy

Wei,

Shi,

Dong

et al. 2024

Int. J. Biol. Sci.

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Sirtuin 5 (SIRT5), localized in the mitochondria, has been identified as a protein desuccinylase and demalonylase in the mitochondria since the depletion of SIRT5 boosted the global succinylation and malonylation of mitochondrial proteins. We investigated the role of SIRT5 in diabetic cardiomyopathy (DCM) and identified the mechanism regarding lysine demalonylation in this process. Wild-type and SIRT5 knockout mice were induced with DCM, and primary cardiomyocytes and cardiac fibroblasts extracted from wild-type and SIRT5 knockout mice were subjected to high glucose (HG). SIRT5 deficiency exacerbated myocardial injury in DCM mice, aggravated HG-induced oxidative stress and mitochondrial dysfunction in cardiomyocytes, and intensified cardiomyocyte senescence, pyroptosis, and DNA damage. DCM-induced SIRT5 loss diminished glutathione S-transferase P (GSTP1) protein stability, represented by significantly increased lysine malonylation (Mal-Lys) modification of GSTP1. SIRT5 overexpression alleviated DCM-related myocardial injury, which was reversed by GSTP1 knockdown. Reduced SIRT5 transcription in DCM resulted from the downregulation of SPI1. SPI1 promoted the transcription of SIRT5, thereby ameliorating DCM-associated myocardial injury. However, SIRT5 deletion resulted in a significant reversal of the protective effect of SPI1. These observations suggest that SPI1 activates SIRT5 transcriptionally to mediate GSTP1 Mal-Lys modification and protein stability, thus ameliorating DCM-associated myocardial injury.

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“…SIRT5's ability to remove succinyl, malonyl, and glutaryl groups from lysine residues on proteins influences several key metabolic processes 42 , 43 . For instance, it desuccinylates and activates carbamoyl phosphate synthetase 1 (CPS1), a critical enzyme in the urea cycle, which is essential for ammonia detoxification in the liver 53 . This modification by SIRT5 enhances CPS1 activity, thereby facilitating the efficient removal of ammonia and preventing ammonia toxicity.…”

Section: Mitochondrial Sirtuins Biologymentioning

confidence: 99%

“…This modification by SIRT5 enhances CPS1 activity, thereby facilitating the efficient removal of ammonia and preventing ammonia toxicity. Moreover, SIRT5 has been shown to regulate the activity of enzymes involved in the TCA cycle, fatty acid oxidation, and mitochondrial respiration by removing malonyl and glutaryl groups, which can inhibit these enzymes' activities 53 . By controlling these modifications, SIRT5 ensures optimal mitochondrial function and energy production, which are vital for maintaining cellular energy homeostasis.…”

Section: Mitochondrial Sirtuins Biologymentioning

confidence: 99%

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies

Shen,

Ma,

et al. 2024

Theranostics

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The sirtuin (SIRT) family is well-known as a group of deacetylase enzymes that rely on nicotinamide adenine dinucleotide (NAD + ). Among them, mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) are deacetylases located in mitochondria that regulate the acetylation levels of several key proteins to maintain mitochondrial function and redox homeostasis. Mitochondrial SIRTs are reported to have the Janus role in tumorigenesis, either tumor suppressive or oncogenic functions. Although the multi-faceted roles of mitochondrial SIRTs with tumor-type specificity in tumorigenesis, their critical functions have aroused a rising interest in discovering some small-molecule compounds, including inhibitors and activators for cancer therapy. Herein, we describe the molecular structures of mitochondrial SIRTs, focusing on elucidating their regulatory mechanisms in carcinogenesis, and further discuss the recent advances in developing their targeted small-molecule compounds for cancer therapy. Together, these findings provide a comprehensive understanding of the crucial roles of mitochondrial SIRTs in cancer and potential new therapeutic strategies.

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Insights on the Modulation of SIRT5 Activity: A Challenging Balance

Cited by 8 publications

References 75 publications

Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies

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