Biochemical characterization of Plasmodium falciparum Sir2, a NAD+-dependent deacetylase

Chakrabarty, Subhra Prakash; Saikumari, Y. K.; Bopanna, Monnanda Ponnappa; Balaram, Hemalatha

doi:10.1016/j.molbiopara.2007.12.003

Cited by 45 publications

(53 citation statements)

References 44 publications

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“…Although P. falciparum Sir2 was inhibited by nicotinamide, a natural product of the sirtuin reaction, it was not sensitive to sirtinol or splitomicin [64]. However, recent studies [65,66] have shown that both nicotinamide and the synthetic inhibitor surfactin inhibit PfSir2 activity and are potent inhibitors of intra-erythrocytic growth of the parasite. Chakrabarty et al [67] have also developed lysine-based tripeptide analogues as PfSir2 inhibitors, one of which also markedly inhibited parasite intra-erythrocytic growth.…”

Section: -Sirtuin Inhibitorsmentioning

confidence: 99%

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Pierce

Dubois-Abdesselem²,

Lancelot³

et al. 2012

cpd

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The histone modifying enzymes (HME) represent particularly promising targets for the development of alternatives to praziquantel, the only currently available drug to combat schistosomiasis. The inhibition of these enzymes frequently arrests the cell cycle or induces apoptosis in cancer cells, but not in normal cells and numerous HME inhibitors are under investigation as potential anticancer agents. The recent resolution of the genome sequences of Schistosoma mansoni and Schistosoma japonicum has allowed us to identify all the schistosome genes encoding histone acetyltransferases, deacetylases, methyltransferases and demethylases. We have chosen a strategy using phylogenetic screening with inhibitors of HME classes, screening of individual HME targets by both high-throughput and reasoned (in silico docking using resolved crystal structures) approaches in a project funded by the European Community, named SEtTReND (Schistosome Epigenetics: Targets, Regulation, New Drugs). The initial focus is on the class I histone deacetylase (HDAC) 8 since the comparison of the catalytic site of the schistosome and human enzymes shows crucial differences, rendering possible the development of inhibitors specific for SmHDAC8. However, phenotypic screening shows that inhibitors of all HME classes tested were able to induce apoptosis and death in parasites in vitro, indicating that other enzymes may prove to be viable targets. SCHISTOSOMIASIS: IMPACT OF THE DISEASE AND THE NEED FOR NEW DRUGSThe impact of schistosomiasis on communities in endemic areas extends well beyond the classical signs of morbidity: Symmer's fibrosis leading to hepato-splenomegaly, ascites, oesophageal varices, and culminating in death. These overt and catastrophic symptoms affect only a relatively small percentage of infected individuals, even if absolute numbers of annual deaths (about 280 000) are high. However, more cryptic effects such as anaemia, undernutrition, diarrhoea and chronic pelvic or abdominal pain were consistently underevaluated until a meta-analysis of a large number of previous schistosomiasis morbidity studies by King et al.[1] allowed an objective assessment. This showed that the WHO's previously estimated disability weight for schistosomiasis of 0.5%, based essentially on mortality, should be markedly revised upwards to between 2 and 15% and that the years of life lost to schistosomiasis represented a relatively small proportion of the total of years lost to disability. This reassessment of the true disease burden represented by schistosomiasis has led to the realization of the importance of reinforcing control measures.In the continuing absence of an effective infection-preventing vaccine, the only viable strategy is the mass-treatment of populations in endemic areas using the currently available drug, praziquantel. Thus the Schistosomiasis Control Initiative in Africa [2] had dispensed more than 40 million praziquantel treatments in eight sub-Saharan countries by 2008. This ongoing programme will undoubtedly have a major impact, both on...

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Section: -Sirtuin Inhibitorsmentioning

confidence: 99%

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Pierce

Dubois-Abdesselem²,

Lancelot³

et al. 2012

cpd

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“…Rep20 is the most telomere-distal telomere associated repetitive element (TARE) and is usually adjacent to the subtelomeric var gene promoter. TPE in P. falciparum depends on Sir2 (Duraisingh et al, 2005; Freitas-Junior et al, 2005; Tonkin et al, 2009), which is both a histone deacetylase and an ADP-ribosyltransferase (Merrick and Duraisingh, 2007; Chakrabarty et al, 2008) and is localized at the telomeres, where histones H4 acetylation is absent (Freitas-Junior et al, 2005). By examining subnuclear localization of a number of genetic markers along chromosome 2 by FISH, it is also inferred that chromatin structure is more condensed for telomere-proximal regions than telomere-distal ones (Freitas-Junior et al, 2005).…”

Section: Sir2-mediated Tpe Plays An Essential Role In Manoallelic Expmentioning

confidence: 99%

Telomere components as potential therapeutic targets for treating microbial pathogen infections

Li¹

2012

Front. Oncol.

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In a number of microbial pathogens that undergoes antigenic variation to evade the host’s immune attack, genes encoding surface antigens are located at subtelomeric loci, and recent studies have revealed that telomere components play important roles in regulation of surface antigen expression in several of these pathogens, indicating that telomeres play critical roles in microbial pathogen virulence regulation. Importantly, although telomere protein components and their functions are largely conserved from protozoa to mammals, telomere protein homologs in microbial pathogens and humans have low sequence homology. Therefore, pathogen telomere components are potential drug targets for therapeutic approaches because first, most telomere proteins are essential for pathogens’ survival, and second, disruption of pathogens’ antigenic variation mechanism would facilitate host’s immune system to clear the infection.

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“…TPE in P. falciparum is similar to that in S. cerevisiae in that it depends on Sir2 (Duraisingh et al 2005;Freitas-Junior et al 2005;Tonkin et al 2009). However, PfSir2 is both a histone deacetylase and an ADP-ribosyltransferase (Chakrabarty et al 2008;Merrick & Duraisingh 2007), and the Sir2-dependent TPE spreads much further away along the chromosome in P. falciparum (~55 kb) than in S. cerevisiae (~3 kb). PfSir2 is localized at the telomeres, and histones H4 acetylation is absent from the telomeres (Freitas-Junior et al 2005).…”

Section: Sir2-mediated Tpe Plays An Essential Role In Manoallelic Expmentioning

confidence: 99%

Telomere as an Important Player in Regulation of Microbial Pathogen Virulence

Li¹

2012

Reviews on Selected Topics of Telomere Biology

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Biochemical characterization of Plasmodium falciparum Sir2, a NAD+-dependent deacetylase

Cited by 45 publications

References 44 publications

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Telomere components as potential therapeutic targets for treating microbial pathogen infections

Telomere as an Important Player in Regulation of Microbial Pathogen Virulence

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