Abstract
The sirtuins form a superfamily of evolutionarily conserved NAD+-dependent protein N-ϵ-acyl-lysine (AcK) deacylases with roles in a variety of key cellular processes. Sirtuins have a broadly conserved overall structure with a catalytic site formed by a hydrophobic channel between the NAD+-binding Rossmann fold domain and a smaller Zn2+-binding domain. Schistosomes express five members of the sirtuin family and generic sirtuin inhibitors induce apoptosis and death in schistosome larvae, the disruption of adult worm pairs, inhibition of egg laying and damage to the male and female worm reproductive systems. Sirtuins in schistosomes and other parasitic flatworms present structural differences from their human orthologues that should allow the development of selective inhibitors that can be developed as drug leads.
Papers of special note have been highlighted as: • of interest; •• of considerable interest.
References
- 1 The Schistosomiasis Control Initiative (SCI): rationale, development and implementation from 2002–2008. Parasitology 136(13), 1719–1730 (2009).
- 2 . Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr. Opin. Infect. Dis. 21(6), 659–667 (2008).
- 3 The genome of the blood fluke Schistosoma mansoni. Nature 460(7253), 352–358 (2009).
- 4 The Schistosoma japonicum genome reveals features of host-parasite interplay. Nature 460(7253), 345–351(2009).
- 5 Whole-genome sequence of Schistosoma haematobium. Nat. Genet. 44(2), 221–225 (2012).
- 6 . Epigenetic control of gene function in schistosomes: a source of therapeutic targets? Front. Genet. 5, 317 (2014).• Reviews current knowledge of epigenetic mechanisms in schistosomes and evaluates their potential as therapeutic targets.
- 7 Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 1, 3 (2010).
- 8 . Lessons on longevity from budding yeast. Nature 464(7288), 513–519 (2010).
- 9 . Metabolic and neuropsychiatric effects of calorie restriction and sirtuins. Annu. Rev. Physiol. 10, 669–684 (2013).
- 10 . The emerging and diverse roles of sirtuins in cancer: a clinical perspective. Onco Targets Ther. 6, 1399–1416 (2013).•• A comprehensive and recent review of the roles of human sirtuins as cancer promoters or repressors and the potential for therapeutic intervention.
- 11 . Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation. Mol. Cells 28(5), 407–415 (2009).• Revises the phylogeny of the sirtuins and highlights the differences in the complement of sirtuins in different species.
- 12 . Genealogy of an ancient protein family: the sirtuins, a family of disordered members. BMC Evol. Biol. 13, 1–19 (2013).
- 13 . Sirtuins of parasitic protozoa: in search of function(s). Mol. Biochem. Parasitol. 185(2), 71–88 (2012).• Explores the roles of sirtuins in parasitic protozoa and emphasizes their interest as drug targets.
- 14 . Sirtuins as emerging anti-parasitic targets. Eur. J. Med. Chem. 59, 132–140 (2013).
- 15 . Targeting schistosome histone modifying enzymes for drug development. Curr. Pharm. Des. 18(24), 3567–3578 (2012).
- 16 Schistosoma mansoni sirtuins: characterization and potential as chemotherapeutic targets. PLoS Negl. Trop. Dis. 7, e2428 (2013).•• Characterizes the sirtuins of S. mansoni and shows that sirtuin inhibitors induce apoptosis and death of the parasites, emphasizing their potential as anti-schistosomal drugs.
- 17 . Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273(2), 793–798 (2000).
- 18 . “The origin of Fungi and pseudofungi”. In: Evolutionary biology of the fungi: symposium of the british mycological society. Rayner ADM, Brasier CM, Moore D (Eds). Cambridge Univ. Press, Cambridge, UK, 339–353 (1987).
- 19 . Evolutionarily conserved and nonconserved cellular localizationos and functions of human SIRT proteins. Mol. Biol. Cell. 16(10), 4623–4635 (2005).
- 20 . Interphase nuleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS ONE 2(8), e784, (2007).
- 21 SirT2 is a histone deacetylase with preference for histone H4Lys 16 during mitosis. Genes Dev. 20(10), 1256–1261 (2006).
- 22 . SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 21(8), 920–928, (2007).
- 23 SIRT5 –mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell. 50(6), 919–930 (2013).
- 24 Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms. Genes Cells 16(2), 190–202 (2011).
- 25 New and continuing developments at PROSITE. Nucl. Acids Res. 41, D344–D347 (2013).
- 26 . Sirtuins, metabolism and DNA repair. Curr. Opin. Genet. Dev. 26, 24–32 (2014).•• Comprehensive and recent review of the crucial roles of sirtuins in the control of metabolism, and the link with their role in the DNA repair response.
- 27 . The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13(19), 2570–2580 (1999).
- 28 . Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410(6825), 227–230 (2001).
- 29 Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430(7000), 686–689 (2004).
- 30 . A therapeutic role for sirtuins in diseases of aging? Trends Biochem. Sci. 32(12), 555–560 (2007).
- 31 . Calorie restriction and sirtuins revisited. Genes Dev. 27(19), 2072–2085 (2013).
- 32 . NAD+ as a signaling molecule modulating metabolism. Cold Spring Harb. Symp. Quant. Biol. 76, 291–298 (2011).
- 33 . How does SIRT1 affect metabolism, senescence and cancer? Nat. Rev. Cancer 9(2), 123–128 (2009).
- 34 A role for mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105(38), 4447–4452 (2008).
- 35 SIRT3 deacetylates ATP synthase FA complex proteins in response to nutrient- and exercise-induced stress. Antioxid. Redox Signal. 21(4), 551–564 (2014).
- 36 Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 62(10), 3404–3417 (2013).
- 37 Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334(6057), 806–809 (2011).
- 38 Sirt5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell 50(6), 919–930 (2013).
- 39 Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124(2), 315–329 (2006).
- 40 The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140(2), 280–293 (2010).
- 41 . On the origin of cancer cells. Science 123(3191), 309–314 (1956).
- 42 . The reversible effect on the energy metabolism of Schistosoma mansoni cercariae and schistosomula. Mol. Biochem. Parasitol. 51(1), 73–80 (1992).
- 43 . Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20(9), 1075–1080 (2006).
- 44 Sirt7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep. 5(3), 654–665 (2013).
- 45 SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin proteasome pathway. Cell Metab. 19(4), 712–721 (2014).
- 46 A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. Cell Metab. 20(5), 856–869 (2014).
- 47 . Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl Acad. Sci. USA 104(31), 12861–12866 (2007)
- 48 . Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9(4), 327–338 (2009).
- 49 SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464(7285), 121–125 (2010).
- 50 SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol. Cell 50(5), 686–698 (2013).
- 51 . ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J. 30(3), 546–555 (2010).
- 52 SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamate metabolism. Cancer Cell 23(4), 450–463 (2013).
- 53 A high fat diet and NAD(+) activate Sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab. 20(5), 840–855 (2014).
- 54 . SIRT3 functions in the nucleus in the control of stress-related gene expression. Mol. Cell. Biol. 32(24), 5022–5034 (2012).
- 55 Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni. PLoS Pathog. 9(9), e1003645 (2013).•• Validates schistosome HDAC8 as an epigenetic drug target and shows that schistosome-specific changes in the catalytic pocket should allow the development of selective inhibitors as drug leads.
- 56 . Structure of the histone deacetylase SIRT2. Nat. Struct. Biol. 8(7), 621–625 (2001).
- 57 Crystal structures of human SIRT3 displaying substrate-induced conformational changes. J. Biol. Chem. 284(36), 24394–24405 (2009).
- 58 Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Structure 15(3), 377–389 (2007).
- 59 . Structure and biochemical functions of SIRT6. J. Biol. Chem. 286(16), 14575–14587 (2011).
- 60 The 2.5Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition. J. Med. Chem. 56(3), 963–969 (2013).
- 61 Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc. Natl Acad. Sci. USA 110(30), E2772–2781 (2013).
- 62 SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126(5), 941–954 (2006).
- 63 . Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogs and 32P-NAD. Biochemistry 48(13), 2878–2890 (2009).
- 64 Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 159(7), 1615–1625 (2014).
- 65 SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496(7443), 110–113 (2013).
- 66 . Zinc-dependent erasers of protein acetylation in schistosomes: on the track of HDAC inhibitors as new antiparasitic drugs. Future Med. Chem. (2014) (In Press).
- 67 . Sorting out functions of sirtuins in cancer. Oncogene 33(13), 1609–1620 (2014).
- 68 . Emerging roles of SIRT1 in cancer drug resistance. Genes Cancer 4(3–4), 82–90 (2013).
- 69 . Sirtuin1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol. Cell 38(6), 864–878 (2010).
- 70 SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20(4), 487–499 (2011).
- 71 SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17(1), 41–52 (2010).
- 72 SIRT3 opposes reprogramming of cancer cell metabolism through HIF1 alpha destabilization. Cancer Cell 19(3), 416–428 (2011).
- 73 The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153(4), 840–854 (2013).
- 74 The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151(6), 1185–1199 (2012).
- 75 . SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumour Biol. 35(11), 10699–10705 (2014).
- 76 SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487(7405), 114–118 (2012).
- 77 . Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11(5), 384–400 (2012).
- 78 Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues. Biochem. J. 335(Pt 3) 631–636 (1998).
- 79 . Inhibition of NAD glycohydrolase and ADP-ribosyltransferases by carbocyclic analogues of oxidized nicotinamide adenine dinucleotide. Biochemistry 28(19), 7688–7694 (1989).
- 80 . New assays and approaches for discovery and design of Sirtuin modulators. Expert Opin. Drug Discov. 9(2), 183–199 (2014).
- 81 Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells. Int. J. Oncol. 41(3), 1101–1109 (2012).
- 82 Salermide, a sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene 28(6), 781–791 (2009).
- 83 . Inhibitors of NAD+-dependent histone deacetylases (sirtuins). Curr. Pharm. Des. 14(6), 562–573 (2008).
- 84 . Sirtuin inhibitors: the approach to affinity and selectivity. Biochim. Biophys. Acta 1804(8), 1635–1644 (2010).
- 85 . Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry. Biochemistry 42(19), 9249–9256 (2003).
- 86 . Coenzyme specificity of Sir2 protein deacetylases: implications for physiological regulation. J. Biol. Chem. 279(38), 40122–40129 (2004).
- 87 Antitumor activity of a small molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66(8), 4368–4377 (2006).
- 88 . 2-Anilobenzamides as SIRT inhibitors. ChemMedChem 1(10), 1059–1062 (2006).
- 89 Identification and characterization of novel sirtuin inhibitor scaffolds. Bioorg Med. Chem. 17(19), 7031–7041 (2009).
- 90 . Structure-activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem 2(10), 1419–1434 (2007).
- 91 Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition. J. Med. Chem. 49(25), 7307–7316 (2006).
- 92 Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem. 48(25), 8045–8054 (2005).
- 93 Thiobarbiturates as sirtuin inhibitors: virtual screening, free-energy calculations and biological testing. ChemMedChem 3(12), 1965–1976 (2008).
- 94 Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science 317(5837), 516–519 (2007).
- 95 Design, synthesis and structure-activity relationship studies of novel sirtuin 2(SIRT2) inhibitors with a benzamide skeleton. Bioorg. Med. Chem. 23(2), 328–339 (2015).
- 96 The discovery of a highly selective 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one SIRT2 inhibitor that is neuroprotective in and in vitro Parkinson's disease model. ChemMedChem 10(1), 69–82 (2015).
- 97 Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach. J. Med. Chem. 57(20), 8340–8357 (2014).
- 98 Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast. J. Biol. Chem. 278(52), 52773–52782 (2003).
- 99 . Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276(42), 38837–38843 (2001).
- 100 Design, synthesis and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J. Med. Chem. 48(24), 7789–7795 (2005).
- 101 N(epsilon)-thioacetyl-lysine-containing tri-, tetra- and pentapeptides as SIRT1 and SIRT2 inhibitors. J. Med. Chem. 52(7), 2153–2156 (2009).
- 102 . Inhibition of the human deacylase Sirtuin 5 by the indole GW5074. Bioorg. Med. Chem. Lett. 23(1), 143–146 (2013).
- 103 Chemical probing of the human sirtuin 5 active site reveals its substrate acyl specificity and peptide-based inhibitors. Angew. Chem. Int. Ed. Engl. 53(40), 10728–10732 (2014).
- 104 Inhibitors of the NAD(+)-dependent protein desuccinylase and demalonylase Sirt5. ACS Med. Chem. Lett. 3(12), 1050–1053 (2012).
- 105 Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3. J. Med. Chem. 56(9), 3666–3679 (2013).
- 106 Fluorescence-based screening assays for the NAD+-dependent histone deacetylase smSirt2 from Schistosoma mansoni. J. Biomol. Screen. 20(1), 112–121 (2015).• Describes assay methods developed for the high-throughput screening of a recombinant schistosome sirtuin.
- 107 Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium falciparum. Cell 121(1), 13–24 (2005).
- 108 Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum. PLoS Biol. 7(4), e84 (2009).
- 109 Targeted disruption of cytosolic SIR2 deacetylase discloses its essential role in Leishmania survival and proliferation. Gene 363, 85–96 (2005).
- 110 . Stage-specific antileishmanial activity of an inhibitor of SIR2 histone deacetylase. Acta Trop. 94(2), 107–115 (2005).
- 111 Bisnaphthalimidopropyl derivatives as inhibitors of Leishmania SIR2 related protein 1. ChemMedChem 5(1), 140–147 (2010).
- 112 . Anti-parasitic drug discovery. Pan Europ. Networks Sci. Technol. 11, 192–193 (2014).