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Biological Background for Bioinformatic Studies on the Trypanothione

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Biological Background for Bioinformatic Studies on the Trypanothione Biological background for bioinformaticstudies on the trypanothione synthase Until now, during our seminar we discussed some elements and approaches of bioinformatics studies, such as search algorithms for recognition between targets and ligands, optimization problems in drug-receptor interactions, the mathematical modeling of activity, affinity, efficacy and selectivity of the drug etc. The main purpose to make an attempt to direct some activities of our seminar and some activities of the participants in the project related with bioinformatics studies in SWU, on a concrete object. The object an enzyme, related with glutathionand an unique metabolic pathway distrubutedin Unicellular Parasitic protozoa (Eukaryota) species discovered by Alan Fairlambbefore 17-18 years. Unicellular Parasitic protozoa (Eukaryota) species Leishmania and Trypanosoma cause serious diseases. Trypanosomabrucei cause -AfricanSleeping sickness in humans or -Naganain animals. Trypanosomacruzi cause -SouthAmerican ChagasDisease Leishmaniamajor cause –leishmaniasis, which affect and destroy skin; Leishmaniadonovani cause –leishmaniasis, which affect the visceral organs. Leishmania currentlyaffects12 millionpeoplein88 countries, including Bulgaria. The current few trypanocidaldrugs used to combat these infections are unsatisfactory due to: • toxicity, • high cost, • poor efficacy and • increasing levels of drug resistance. Fondamental Knowledge of eukaryote biology Detailed proteomic data Detailed genomic data Opportunities to identify and exploit novel aspects of parasite metabolism in drug discovery Potential trypanocidaldrug target Unique metabolic pathways found in the parasites from Alan Fairlamb, related with Trypanothionemetabolism In conjunction with Mammals use Glutathione -short ipeptide Main enzymes Glu-Cys-Gly Glutathione reductase Glutathione peroxidase Regulate intracellular thiollevels, thiolhomeostasesand redoxmetabolism DDeeffeenncese agagaaiinnsstt ffrreeee rraadidiccaalsls AntioAxidanntioxt idandefetn decefense Defense against oxidative stress Trypanosomatidparasites In conjunction with distinct exploit the properties of enzymes Trypanothione Trypanothyonereductase contributing defense Tryparedoxin against oxidative stress Tryparedoxinperoxidase Trypanothione (Mr= 721.86 g/mol) is unusualformofglutathionecontaining twomoleculesofglutathionejoinedbyapolyamine spermidine, which play role of a linker Itisfoundinparasiticprotozoa suchasleishmaniaandtrypanosomes. The differences between host (humans and animals) and parasite present opportunities to target trypanothionemetabolism for drug discovery. Trypanothyonereductase Potential drug targets: Tryparedoxin Tryparedoxinperoxidase Now we focus on the enzyme responsible for the synthesis and degradation of Trypanothione–trypanothionesynthase Inenzymology, a trypanothionesynthase (EC 6.3.1.9.) isanenzyme thatcatalyzes the folowingchemical reaction: glutathione+ glutathionylspermidine+ ATP N1,N8-bis(glutathionyl)spermidine+ ADP + phosphate However, it was established that this enzyme is actually a Glutationylspermidinesynthetase–an hetrodimer and was identified in the model trypanosomatid Crithidiafasciculata. In the human pathogens Trypanosomabrucei, Trypanosomacruzi, Leishmania major and Leishmaniadonovani, a monomericprotein is responsible for the synthesis of thrypanoioneand the name of this enzyme is trypanothione synthetase-amidase(TSA). Balance between spermidineand TSA catalyzes 4 reactions by acting as: trypanothionemaintenance redox • Glutationylspermidine metabolism and the level of cell synthetase proliferation and cell diffenetiation. • Trypanothionesynthetase • Trypanothioneamidase Spermidine, polyamine related with cell proliferation and cell • Glutationylspermidineamidase diffenetiation. So TSA is our target. The target is: •Protein •Enzyme, which catalyzes 4 reactions and respectively have at least 3 substrates –spermidine, glutathione, and glutathionylspermidine. •The eventual drugs or ligandscould be enzyme inhibitors and eventually analogues of the substrates. Which kind of questions could be post in order to continue with bioinformaticstudies ??? • Is there data for 3D structure of TSA ??? • Which kind of data for 3 D, obtained from biophysical techniquesuch as x-ray crystallography or NMR spectroscopy, are more relevenatfor our target? • Which kind of search algorithms have to be used to suggest the biggest pockets? • Since, we have 3 substrates, how many pockets have to be expected ? The strength of the non-covalent interaction or binding affinity as a parameter of ligand-target interaction, is predicted by so-called scoring functions. Is it possible to reach these levels of investigations and to initiatedrug discovery by virtual screening, lead optimization etc. • Which kind of popular docking approaches, such as shape complementarity, simulation etc. are better and who will master them ??? Two examples from the Fyfe P.K., OzaS.L., FairlambA.H., Hunter W.N. LeishmaniaTrypanothioneSynthetase-AmidaseStructure Reveals a Basis for Regulation of Conflicting Synthetic and Hydrolytic Activities THE JOURNAL OF BIOLOGICAL CHEMISTRY 2008, 283 (25), 17672- 17680. Example 1 Secondary, tertiary, anddomainstructureof LmTSA N-terminal domain –responsible for the amidaseactivity (protease) red star C-terminal domain –responsible for the synthetaseactivity –black star Selected elements of the secondary structure (a or b-barrel) are caloured On right –subdomainstrucutreof ATP-grasp synthetasedomain, which binds nucleotide. Example 2 The synthetaseactive site a –Model of substrates (ATP, GSH and spermidine) at the onset of Istreaction. The protein surface is depicted as a semi-transparent van derWaalssurface b –Model for the onset of the second reaction. Findings of Noel Dognin AbouttrypanothionereductaseandsynthetasestructuresintheProtein DataBank: The reductasecavbe found in both –bound and unbound state, and thanks to theboundedstructures, wehavethedefinitionofthedomainesandtheir SCOP classification. Thestructurescomefrombrucei, cruzyandleishmania. Thesynthetasecanonlybefoundinunboundstate, andstructuresonly comefromleishmania. Thank you ! Dockingglossary •Receptor or host –The"receiving" molecule, mostcommonlya protein orother biopolymer. • Ligand or guest –Thecomplementarypartnermoleculewhich binds tothe receptor. Ligandsaremostoften smallmolecules butcouldalsobeanother biopolymer. • Docking –Computationalsimulationofa candidateligandbindingtoa receptor. • Bindingmode –Theorientationoftheligandrelativetothereceptoraswellas the conformation oftheligandandreceptorwhenboundtoeachother. • Pose –A candidatebindingmode. • Scoring –Theprocessofevaluatinga particularposebycountingthenumber offavorable intermolecularinteractions suchas hydrogenbonds and hydrophobic contacts. • Ranking –Theprocessofclassifyingwhichligandsaremostlikelytointeract favorablytoa particularreceptorbasedonthepredicted free-energy ofbinding. Trypanosomes area groupof kinetoplastid protozoadistinguishedbyhaving onlya single flagellum. Allmembersareexclusively parasitic, foundprimarilyin insects.[1] A fewgenerahavelife-cyclesinvolvinga secondaryhost, whichmay bea vertebrate ora plant. Theseincludeseveralspeciesthatcausemajor diseasesinhumans.[2] Themostimportanttrypanosomaldiseasesare trypanosomiasis (African SleepingSickness andSouthAmerican ChagasDisease); thesearecausedby speciesof Trypanosoma. The Leishmaniases area setoftrypanosomal diseasescausedbyvariousspeciesof Leishmania. Leishmania isa genus of trypanosome protozoa, andisthe parasite responsibleforthedisease leishmaniasis.[1][2] Itisspreadthrough sandflies of thegenus Phlebotomus inthe OldWorld, andofthegenus Lutzomyia inthe NewWorld. Theirprimaryhostsare vertebrates; Leishmania commonlyinfects hyraxes, canids, rodents, and humans. Leishmania currentlyaffects12 million peoplein88 countries. Theparasitewasnamedin1903 afterthe Scottish pathologist WilliamBoog Leishman. Docking ChemicalCompounddockedtoProteinstructure (acetyltransferase) Trypanothione (Mr= 721.86 g/mol) isanunusualformof glutathione containing twomoleculesofglutathionejoinedbya spermidine (polyamine) linker. Itisfoundin parasiticprotozoasuchas leishmania and trypanosomes.[1] Theseprotozoal parasitesarethecauseof leishmaniasis, sleepingsickness and Chagas'disease. Trypanothionewasdiscoveredby AlanFairlamb. Itsstructurewasprovenby chemicalsynthesis.[2] Itisuniquetothe Kinetoplastida andnotfoundinother parasiticprotozoasuchas Entamoebahistolytica.[3] Sincethisthiolisabsentfrom humansandisessentialforthesurvivaloftheparasites, the enzymes thatmake andusethismoleculearetargetsforthedevelopmentofnewdrugstotreatthese diseases.[4] Trypanothione-dependentenzymesinclude reductases, peroxidases, glyoxalases and transferases. Trypanothione-disulfidereductase (TryR) wasthefirst trypanothione-dependentenzymetobediscovered(EC 1.8.1.12). ItisanNADPH- dependentflavoenzymethatreducestrypanothionedisulfide. TryRisessentialfor survivaloftheseparasitesboth invitro andinthehumanhost.[5][6] A majorfunctionoftrypanothioneisinthedefenceagainst oxidativestress.[7] Here, trypanothione-dependentenzymessuchastryparedoxinperoxidase(TryP) reduce peroxides usingelectronsdonatedeitherdirectlyfromtrypanothione, orviathe redoxintermediatetryparedoxin(TryX). Trypanothione-dependent hydrogen peroxide metabolismisparticularlyimportantintheseorganismsbecausetheylack catalase. Sincethetrypanosomatidsalsolackanequivalentof thioredoxin reductase, trypanothionereductaseisthesolepaththatelectronscantakefrom NADPH totheseantioxidantenzymes .
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