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Since the discovery of the sirtuin family founding member (i.e., the yeast silent information regulator 2 (sir2) protein) in 2000, more and more sirtuin proteins have been identified and are currently known to be present in organisms from all the three kingdoms of life (i.e., bacteria, archaea, and eukarya). Seven sirtuin proteins have been identified in mammals including humans, that is, SIRT1/2/3/4/5/6/7. Sirtuin proteins are a class of enzymes with primary catalytic activity being the β‐nicotinamide adenine dinucleotide (β‐NAD+ or NAD+)‐dependent deacylation from the Nε‐acyl‐lysine residues on cellular proteins. Many sirtuins (e.g., human SIRT1/2/3/4/5/6/7) have been found to each possess multiple individual deacylase activities acting on Nε‐acyl‐lysine substrates with different acyl groups ranging from the simple formyl and acetyl to the more complex groups like succinyl and myristoyl; however, our current knowledge on the (patho)physiological roles of these individual deacylase activities is still limited, which could be due to the currently still thin research toolbox for investigation (i.e., the deacylase‐selective sirtuin mutant and inhibitor/activator). In this article, an updated account on the subject matter will be presented with biochemical and medicinal chemistry perspectives. [ABSTRACT FROM AUTHOR] more...

The sirtuin family of enzymes are able to catalyze the Nε-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Over the past years since the discovery of its founding member (i.e. the yeast silent information regulator 2 (sir2) protein) in 2000, the sirtuin-catalyzed deacylation reaction has been demonstrated to play an important regulatory role in multiple crucial cellular processes such as transcription, DNA damage repair, and metabolism. This reaction has also been regarded as a current therapeutic target for human diseases such as cancer, and metabolic and neurodegenerative diseases. The unique β-nicotinamide adenine dinucleotide (β-NAD+ or NAD+)-dependent nature of the sirtuin-catalyzed deacylation reaction has also engendered extensive mechanistic studies, resulting in a mechanistic view of the enzyme chemistry supported by several lines of experimental evidence. On the journey toward these knowledge advances, chemical biological means have constituted an important functional arsenal; technically, a variety of chemical probes and modulators (inhibitors and activators) have been developed and some of them have been employed toward an enhanced mechanistic and functional (pharmacological) understanding of the sirtuin-catalyzed deacylation reaction. On the other hand, an enhanced mechanistic understanding has also facilitated the development of a variety of chemical probes and modulators. This article will review the tremendous accomplishments achieved during the past few years in the field of sirtuin chemical biology. It is hoped that this would also help to set a stage for how outstanding mechanistic and functional questions for the sirtuin-catalyzed deacylation reaction could be addressed in the future from the chemical biology perspective. [ABSTRACT FROM AUTHOR] more...

• The first dedicated review on the subfamily of eukaryotic sirtuins present in plants. • Many plant sirtuins have been identified with following demonstrated features. • Subcellular compartment-/organ-/tissue-/developmental stage-specific distributions. • Able to catalyze the acyl-lysine deacylation on histone and non-histone proteins. • Important in regulating plants' growth, development, and stress responses. The sirtuin family of intracellular enzymes are able to catalyze a unique β-nicotinamide adenine dinucleotide (β-NAD+)-dependent Nε-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Since 2000, the sirtuin family members have been identified in both prokaryotes and eukaryotes; tremendous accomplishments have also been achieved on the mechanistic and functional (pharmacological) understanding of the sirtuin-catalyzed deacylation reaction. Among the eukaryotic organisms, past research has been focused more on the yeast and mammalian sirtuins than on the plant sirtuins, however, the very presence of sirtuins in various plant species and the functional studies on plant sirtuins published thus far attest to the importance of this particular subfamily of eukaryotic sirtuins in regulating the growth and development of plants and their responses to biotic and abiotic stresses. In this review, an integrated and updated account will be presented on the biochemical, cellular, and functional profiles of all the plant sirtuins identified thus far. It is hoped that this article will also set a stage for expanded efforts in the identification, characterization, and functional interrogation of plant sirtuins; and the development and exploration of their chemical modulators (activators and inhibitors) in plant research and agriculture. [ABSTRACT FROM AUTHOR] more...

In the current study, four side chain-to-side chain cyclic peptides (three 5-mers and one 4-mer) harboring Nε-acetyl-lysine or Nε-myristoyl-lysine were found to be in vitro substrates of the human SIRT1/2/3-catalyzed deacylation with good substrate activities, as judged by the kcat/KM ratios. [ABSTRACT FROM AUTHOR] more...

The β-NAD + -dependent N ε -acyl-lysine deacylation reaction catalyzed by sirtuin family members has been increasingly demonstrated to be important in regulating multiple crucial cellular processes and has also been proposed to be a therapeutic target for multiple human diseases. Accordingly, its inhibitors have been actively pursued over the past few years. In addition, we have also seen the pharmacological assessment of sirtuin inhibitory compounds, although to a lesser extent. In this review, we first discuss how sirtuin inhibitors were discovered with the use of various approaches. We then follow with a discussion of pharmacological studies using sirtuin inhibitors. Our aim here is to set a stage for developing future superior sirtuin inhibitors and for an expanded effort in exploiting inhibitors to explore and/or validate the therapeutic potential stemming from the inhibition of the sirtuin-catalyzed deacylation reaction. [ABSTRACT FROM AUTHOR] more...

Built upon our lead pan-SIRT1/2/3 tripeptidic inhibitors that contain the catalytic mechanism-based sirtuin inhibitory warhead N ε -thioacetyl-lysine, three of their analogs (i.e., 7 , 9 , and 19 ) were discovered in the current study to exhibit a significantly enhanced SIRT3 inhibitory selectivity while maintaining the SIRT3 inhibitory potency. These compounds represent novel lead compounds for developing more potent and selective SIRT3 inhibitors of the catalytic mechanism-based type. [ABSTRACT FROM AUTHOR] more...

N ε -Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism-based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared analogs of N ε -thiocarbamoyl-lysine with its terminal NH 2 mono-substituted with alkyl and aryl groups, we found that N ε -methyl-thiocarbamoyl-lysine and N ε -carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, N ε -methyl-thiocarbamoyl-lysine was found in the study to be a ∼2.5–18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead N ε -thiocarbamoyl-lysine. [ABSTRACT FROM AUTHOR] more...

Bicyclic pentapeptide 10 harboring the catalytic mechanism-based SIRT1/2/3 inhibitory warhead Nε-thioacetyl-lysine at its central position was found to be a highly potent/selective (versus SIRT5/6/7), proteolytically stable, and cell permeable pan-SIRT1/2/3 inhibitor which also exhibited an anti-proliferative effect on the human SK-MEL-2 melanoma cells. Past few years have seen an active pursuit of the inhibitors for the deacylation catalyzed by the seven human sirtuins (i.e. SIRT1-7) as valuable chemical biological/pharmacological probes of this enzymatic deacylation and lead compounds for developing novel therapeutics for human diseases. In the current study, we prepared eight monocyclic and one bicyclic analogs of a linear pentapeptide-based potent (sub-μM IC 50 's) pan-SIRT1/2/3 inhibitor Zheng laboratory discovered recently that harbors the catalytic mechanism-based SIRT1/2/3 inhibitory warhead Nε-thioacetyl-lysine at its central position. We found that the bicyclic analog exhibited largely comparable SIRT1/2/3 inhibitory potencies to those of the parent linear pentapeptide, however, the former is proteolytically much more stable than the latter. Moreover, the bicyclic analog displayed very weak inhibition against SIRT5/6/7, was cell permeable, and exhibited an anti-proliferative effect on the human SK-MEL-2 melanoma cells. This bicyclic analog could be a lead for the future development of more potent and still selective pan-SIRT1/2/3 inhibitors whose use in studies on human sirtuin biology, pharmacology, and medicinal chemistry could complement with the use of the potent inhibitors selective for a single human sirtuin. [ABSTRACT FROM AUTHOR] more...