The Substrate Specificity of Sirtuins

Bheda, Poonam; Jing, Hui; Wolberger, Cynthia; Lin, Hening

doi:10.1146/annurev-biochem-060815-014537

Cited by 212 publications

(197 citation statements)

References 154 publications

(275 reference statements)

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“…Sirtuins are protein deacetylases (and deacylases) conserved from bacteria to humans (Bheda et al 2016). Sirtuins have been implicated in the regulation of circadian rhythm, mitochondrial metabolism, aging, and cancer (Imai and Guarente 2014;Chalkiadaki and Guarente 2015).…”

Section: Nadmentioning

confidence: 99%

“…There are seven mammalian sirtuins, which are localized in the mitochondria (SIRT3, SIRT4, and SIRT5), the nucleus (SIRT1, SIRT6, and SIRT7), or both the cytoplasm and nucleus (SIRT2). All nuclear sirtuins can deacetylate histones, but numerous additional substrates have been identified, including transcriptional factors, DNA repair proteins, and metabolic enzymes (Chalkiadaki and Guarente 2015;Bheda et al 2016). Some sirtuins can also remove acyl modifications from histones.…”

Section: Nadmentioning

confidence: 99%

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Undercover: gene control by metabolites and metabolic enzymes

2016

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To make the appropriate developmental decisions or maintain homeostasis, cells and organisms must coordinate the expression of their genome and metabolic state. However, the molecular mechanisms that relay environmental cues such as nutrient availability to the appropriate gene expression response remain poorly understood. There is a growing awareness that central components of intermediary metabolism are cofactors or cosubstrates of chromatin-modifying enzymes. As such, their concentrations constitute a potential regulatory interface between the metabolic and chromatin states. In addition, there is increasing evidence for a direct involvement of classic metabolic enzymes in gene expression control. These dual-function proteins may provide a direct link between metabolic programing and the control of gene expression. Here, we discuss our current understanding of the molecular mechanisms connecting metabolism to gene expression and their implications for development and disease.Metabolism and gene regulation are two fundamental biological processes that are essential to all living organisms. Homeostasis, cell growth, and differentiation all require the coordination of metabolic state and gene expression programs. Nevertheless, how expression of the genome adapts to metabolic state or environmental changes is not well understood. One level of regulation involves signal transduction pathways that control key transcription factors that act as master regulators of gene expression programs. In addition, post-translational modifications (PTMs) of chromatin play a major role in the activation or repression of gene transcription. These include acetylation, methylation, and phosphorylation of the histones and DNA methylation. Some of these chromatin modifications are involved in the maintenance of stable patterns of gene expression, usually referred to as epigenetic regulation. Pertinently, the activity of enzymes that modulate chromatin is critically dependent on central metabolites as cofactors or cosubstrates. Thus, the availability of metabolites that are required for the activity of histone-modifying enzymes may connect metabolism to chromatin structure and gene expression. Finally, selective metabolic enzymes act in the nucleus to adjust gene transcription in response to changes in metabolic state. Here, we review the interface between metabolism and gene transcription. We focus on the molecular mechanisms involved and discuss unresolved issues and implications for development and disease. The basics of metabolism and gene expression controlMetabolism is the total of all chemical reactions in cells and organisms that maintain life. Metabolism can be divided into two classes: catabolic processes (the breakdown of molecules that usually results in the release of energy) and anabolic processes (the synthesis of components such as proteins, lipids, and nucleic acids, which costs energy). Cellular (or intermediary) metabolism is organized in separate chemical pathways formed by a chain of linked enzymatic reactions in wh...

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Section: Nadmentioning

confidence: 99%

Section: Nadmentioning

confidence: 99%

Undercover: gene control by metabolites and metabolic enzymes

2016

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“…[1] The human genome codes for seven different sirtuin isoforms (SIRT1–7), which are classified according to sequence similarity and localize to different cellular compartments. [2] Recently, it has become evident that different enzyme isoforms exhibit preference for different ε- N -acyllysine posttranslational modifications (PTMs).…”

mentioning

confidence: 99%

“…[2] Recently, it has become evident that different enzyme isoforms exhibit preference for different ε- N -acyllysine posttranslational modifications (PTMs). [1c, 3] Thus, ε- N -acetyllysine (Kac) functionalities are targeted primarily by SIRT1 and 6 in the nucleus, SIRT2 in the cytoplasm, and SIRT3 in the mitochondria. [3a] In addition, long chain acyl groups, such as ε- N -myristoyllysine (Kmyr), are also cleaved by SIRT1–3 and 6.…”

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confidence: 99%

Mechanism‐Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight

et al. 2017

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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. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.

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“…8 SIRT1 shuttles between the cell nucleus and cytoplasm and deacetylates both histone proteins, such as H3K9, H3K14, and H4K16, and multiple nonhistone proteins, including PPAR γ , NF-K β , members of the p53 family of proteins, and others. 9 …”

Section: Introductionmentioning

confidence: 99%

Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [¹⁸F]-2-Fluorobenzoylaminohexanoicanilide

et al. 2018

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Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays significant roles in the regulation of lifespan, metabolism, memory, and circadian rhythms and in the mechanisms of many diseases. However, methods of monitoring the pharmacodynamics of SIRT1-targeted drugs are limited to blood sampling because of the invasive nature of biopsies. For the noninvasive monitoring of the spatial and temporal dynamics of SIRT1 expression−activity in vivo by PET−CT−MRI, we developed a novel substrate-type radio-tracer, [18F]-2-fluorobenzoylaminohexanoicanilide (2-[18F]-BzAHA). PET−CT−MRI studies in rats demonstrated increased accumulation of 2-[18F]BzAHA-derived radioactivity in the hypothalamus, hippocampus, nucleus accumbens, and locus coeruleus, consistent with autoradiographic and immunofluorescent (IMF) analyses of brain-tissue sections. Pretreatment with the SIRT1 specific inhibitor, EX-527 (5 mg/kg, ip), resulted in about a 20% reduction of 2-[18F]BzAHA-derived-radioactivity accumulation in these structures. In vivo imaging of SIRT1 expression−activity should facilitate studies that improve the understanding of SIRT1-mediated regulation in the brain and aid in the development and clinical translation of SIRT1-targeted therapies.

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The Substrate Specificity of Sirtuins

Cited by 212 publications

References 154 publications

Undercover: gene control by metabolites and metabolic enzymes

Undercover: gene control by metabolites and metabolic enzymes

Mechanism‐Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight

Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [¹⁸F]-2-Fluorobenzoylaminohexanoicanilide

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The Substrate Specificity of Sirtuins

Cited by 212 publications

References 154 publications

Undercover: gene control by metabolites and metabolic enzymes

Undercover: gene control by metabolites and metabolic enzymes

Mechanism‐Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight

Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide

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Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [¹⁸F]-2-Fluorobenzoylaminohexanoicanilide