The atomic enzyme DNA topoisomerase II is a major mark for anticancer agents. A voir To clearly understand why, a closer expression at the map and the mechanism of the enzyme is of import. Toposisomerases are molecules which are able to weave and weave the molecule of DNA. Two major types of topoisomerases exist: type I and type II. Parler des autres. They both involve different mechanisms. During DNA written text and reproduction, DNA spiral demands to be unwond to let larger enzyme such as RNA and DNA polymerases to run on its strand in order for Deoxyribonucleic acid to command the synthesis of proteins and to ease DNA reproduction. Reference a trouver, sur toposisomerase de ta daronne.
Topoisomerases II inhibitors are of two sorts. Each of them interferes with one of the measure of the catalytic rhythm of the enzyme. A differentiation is made between topoisomerase II catalytic inhibitors and topoisomerase II toxicants. Topoisomerase II catalytic inhibitors are compounds that will interrupt catalytic turnover, whereas topoisomerase II toxicants will interact with the composite formed of DNA and topoisomerase II, stabilising it.
Topoisomerase II toxicants are the most often used category of topoisomerase inhibitors in clinical usage ; they are used for their antitumor activity whereas catalytic inhibitors are used for several grounds. Depending on the compound, catalytic inhibitors can hold anticancer activity, cardioprotectors or modulators in order to increase the efficaciousness of other agents. Avoir Si of import
Poisons are called this manner because by stabilising the covalent DNA complex topoisomerase composite, lasting lesions to the Deoxyribonucleic acid will be observed. Having for finalit & A ; eacute ; , the devastation of the whole molecule of DNA, therefore the devastation of the cell.
Catalytic inihibitors putting to deaths cells by extinguishing the indispensable activity of the topoisomerase activity.
Topoisomerase II is an of import enzyme which is involved in many molecular procedures such as reproduction and written text. Toposisomerase has the ability to uncoil DNA ‘s molecule by opening the two-base hit spiral which is the first indispensable measure that leads to both written text and reproduction. Accessing familial informations, represent a tough topological challenge because the familial stuff is anchored to the chromosome scaffold, and the two strands of the dual spiral are coiled. It helps to modulate DNA under and overwinding in order to take knots and tangles. It is besides involved in the atomization of the genome when it is necessary for cell endurance.
The enzyme is a homodimer that creates double stranded interruptions in DNA, passes another unbroken Deoxyribonucleic acid spiral through it, and so reanneals the cut strand.
Unlike lower eucaryotes, craniate species possess two isoforms of the enzyme, called topoisomerase II? and topoisomerase II? . Their constructions are truly similar and lone differ in two ways. Their protomer molecular weight is somewhat different ( 170 kDa for topoisomerase II? and 180 kDa for the 2nd 1 ) are encoded by separate cistrons and most of import they have separate cellular maps. Topoisomerase II? degree has been observed high during period of cell growing in the work of mention, it is believed that it is indispensable for the endurance of proliferating cells. Indeed this isoform plays a function in both reproduction and chromosome segregation processes. Action of topoisomerase II? from what is known seems to be independent of proliferative position and cell rhythm although its map II? has yet to be defined clearly.
All type of topoisomerase has the ability to split and ligate Deoxyribonucleic acid by using its active site tyrosyl residues. Each protomer fractional monetary unit of both topoisomerase II? and ? contain one ( Tyr 805 and Tyr 821 severally ) . Deoxyribonucleic acid cleavage is initiated by the nucleophilic onslaught of the enzyme ‘s active site tyrosin on the phosphate of the nucleic acid anchor. It generates a phosphotyrosyl bond that links together enzyme and DNA. Therefore a interruption in sequence is created and 5′-terminus and 3’-hydroxyl medieties are generated on each side of it. Topoisomerase is linked to the freshly generated 5’terminus side of both strand of the DNA go forthing each strand separated in two.
Phosphotyrosyl bond dramas two of import functions in the mechanism in the manner that it maintains the unity of the sequence and conserves the bond energy of the sugar-phosphate DNA anchor. The intermediate making during this reaction is called cleavage composite and is the cardinal characteristic for the pharmaceutical activities of the enzyme.
The enzyme cleaves at preferred sites. It is impossible to foretell at the minute where will the enzyme perform its undertaking, the consensus sequence for it being weak. Contrary what one might believe, topoisomerase II do non straight acknowledge the bases that comprise the sequence and its specificity to adhere DNA is believed to depend on the local construction, flexibleness or plasticity of the molecule. mention
The enzyme can be potentially unsafe ; it creates interruptions in DNA ‘s molecule and can trip the atomization of the molecule. The cardinal factor is the complex cleavage degree and depending on it, different state of affairss might be encountered. When degree beads below threshold concentrations, girl chromosome will non be able to segregate decently during mitosis as they will stay embroiled after reproduction. Cell will accordingly decease. When degrees of cleavage composite are excessively high, lasting DNA interruptions will look in high Numberss. Recognition/repair system of DNA will be overwhelmed and wo n’t be able to make full in DNA ‘s interruptions if they are excessively legion and cell will originate decease tract. Enzymes from DNA tracking system by their action will meet cleavage composites on DNA ‘s molecule if their concentration is high. Collisions will happen ( helicase will meet cleavage composites on DNA strands ) and will interrupt cleavage composites arousing lasting dual strand interruptions. ( Parler de & A ; ccedil ; a plus tard ) As a consequence recombination/repair tracts will be initiated and DNA aberrances might be generated, taking to possible mutants that might arouse malignant neoplastic disease. Cell might even acquire overwhelmed if excessively many strand interruptions are happening and programmed cell death will be triggered. Having a high concentration of cleavage composite can arouse terrible injuries to the molecule of DNA, therefore several anticancer drugs work on this footing.
Molecules which modify activity of topoisomerase II are divided in two categories. A differentiation is made between chemicals diminishing the overall activity of the enzyme and those increasing degrees of topoisomerase II-DNA cleavage composites. The first category of merchandises is known as catalytic inhibitors whereas the 2nd category of compound are called topoisomerase II toxicants.
Nowadays, of all type of antineoplastic drug, topisomerase II toxicants are the most widely prescribed in clinical usage. Six toposiomerase II targeted anticancer agents are approved in the United State and extra drugs are prescribed elsewhere in the universe. mention
Many topoisomerase II toxicants have shown to hold anticancer activity. Toposiomerase II toxicants convert the enzyme into a deadly agent that will arouse programmed cell death ( more information will be provided farther ) . They act on the concentration of cleavage composites doing it raise until a certain point that will trip decease tract. Poisons are believed to adhere to DNA, the topoisomerase, or either molecule at or near the part of the enzyme involved in the formation of the DNA-protein covalent linkage. Anthracyclines and DNA Intercalators/Epipodophyllotoxins/DNA Topoisomerases
Eric H Rubin, MD and William N Hait, MD, PhD
Two different tracts can take to high concentration of cleavage composite. Some chemicals act without suppressing overall catalytic activity, they work chiefly by heightening the forward rate of scission ( clarifier ) while other compounds perform their work by suppressing the ability of the enzyme to ligate cleaved DNA molecules.
Most presently used topoisomerase targeted agents move this manner, barricading the catalytic rhythm between the cleavage and the re-ligation stairss. Anthracyclines and epipodophyllotoxins ( etoposide ) are one of these compounds. Generation of high degree of topoisomerase II-DNA cleavage composites is the chief consequence that these compound cause but they besides prevent enzyme turnover and are considered as strong inhibitors of catalytic activity. Voir si ce n’est pas La meme chose que je viens de dire dans la dreniere phrase.
They can be moreover divided into intercalating and non-intercalating agents. Intercalating agents are compound that presents assorted and different structural characteristics. Their ability to intercalate DNA is the lone feature that compounds like anthracyclines, mitoxanthrone or mAMSA are sharing ( compounds that are already in clinical usage ) . The geometry required for re-ligation is disrupted when an intercalating topoisomerase II toxicants interact with DNA. Some experiments performed with the usage of little intercalating agents such as ethidium bromide where unsuccessful, taking to the undermentioned decision: intercalating agents have to be voluminous plenty for topoisomerase II to be trapped as a covalent composite on Deoxyribonucleic acid. mention
Anthracycline like certain other intercalating agents moving on topoisomerase II present a scope of effects on cell that are independent of their action on topoisomerase II. Doxorubicin is known to bring forth free groups, do protein-DNA crosslinks and membrane harm. By doing protein-DNA crosslinks, these molecules prevent the fond regard of the enzyme to DNA.Voir Si plus tot j’ai vitamin D & A ; eacute ; J & A ; agrave ; introduit cette famille de compose sinon lupus erythematosus faire et dire que doxorubicin ne fait partie.
Non-intercalating agents moving on topoisomerase II do non interact strongly with DNA, and it is believed that their mechanism of action is linked to protein-drug interactions. Nevertheless effect for the enzyme is the same, it will be trapped on Deoxyribonucleic acid and cascade of events will be triggered which might take to apoptosis. Etoposide is one of the most used non-intercalating topoidomerase II toxicant.
Double strand cleavage is non necessary for the toxicant to be effectual. Single strand cleavage by topoisomerase II can besides ensue in cytotoxicity. Therefore topoisomerase II toxicants can merely interact with one of the dimer of the enzyme.
Beyond Topoisomerase II toxicants ( exclusion of DNA lesions ) act by two different mechanisms. One the mechanism requires redox activity to ease their actions against topoisomerase II whereas the other is redox-independent. Their actions against the enzyme are non affected by cut downing agents such as dithithreitol. Unlike the other mechanism, which require redox chemical science for activation which will be abrogated by cut downing agents.
Catalytic inhibitors are a heterogeneous group of compounds that might interfere with the binding between DNA and toposiomerase ( aclarubicin and suramin ) , stabilize noncovalent DNA topoisomerase II composites ( merbarone, ICRF-187 and structurally realted bisdioxopiperazine derived functions ) ot inhibit ATP binding ( Novobiocin ) .
One of the large challenges in happening or planing inhibitors of topisomerase II is their specificity. Most of them are non specific. An exclusion is bisdioxopiperazines but it generates DNA harm responses merely after a long clip exposure. Catalytic inhibitors of toposiomerase II antagonize the toxicity of topoisomerase II toxicants. These are decisions made after executing experiments in vitro. Topoisomerase II inhibitors that are non toxicants still need to be studied to reply the inquiry of whether or non they can be active anticancer agents. Voir si topographic point dans la decision ou pas.
Inhibitors that act on topoisomerase II can move at different minute in its reaction rhythm. Each of these actions will hold accordingly different effects and effects on the cell. Toposisomerase II operates by a strand transition mechanism in which one section of DNA is passed through a transeunt interruption in another. The Deoxyribonucleic acid strand transition reaction of topoisomerase II is coupled to the hydrolysis of ATP. CouplingATPhydrolysistoDNAstrandpassageintypeIIADNAtopoisomerasesA.Maxwell*1, L.Costenaro* , S.Mitelheiser*andA.D.Bates†*DepartmentofBiologicalChemistry, JohnInnesCentre, Colney, NorwichNR47UH, U.K. , and†SchoolofBiologicalSciences, UniversityofLiverpool, CrownStreet, LiverpoolL697ZB, U. Competitive inhibitors of ATP adhering prevent strand transition and do non bring forth enzyme-mediated DNA harm.
Novobiocin and coumerycin are able to suppress both procaryotic and eucaryotic type II topoisomerase enzyme but coumermycin is ill taken up by mammalian cells and novobiocin is less powerful and non particular.
Aclarubicin Acts of the Apostless by forestalling the fond regard of the enzyme to DNA. Merbarone is an agent that prevents DNA cleavage by the enzyme and so acts as a catalytic inhibitor. Most presently used topoisomerase targeted agents barricade the catalytic rhythm between the cleavage and the re-ligation stairss. Anthracyclines and epipodophyllotoxins ( etoposide ) are one of these compounds. Generation of high degree of topoisomerase II-DNA cleavage composites is the chief consequence that these compound cause but they besides prevent enzyme turnover and are considered as strong inhibitors of catalytic activity. Voir si ce n’est pas La meme chose que je viens de dire dans la dreniere phrase. A relier avec lupus erythematosus paragraphe plus haut
The enzyme can be inhibited after strand transition but before ATP hydrolysis and dissociation and dissociation of amino-terminal dimerization. Dexrazoxane is able to suppress ATP hydrolysis and keep the enzyme construction as a closed clinch. Like anthracyclines and epipodophyllotoxin, bisdioxopiperazines ( dexrazoxane ) inhibit the enzyme catalytic activity chiefly by barricading enzyme turnover. These agents leave toposiomerase II stuck on Deoxyribonucleic acid and this might take to interventions with DNA metamorphosis. Even though based on this specialness they might arouse the same effects than topoisomerase II toxicants, they are classified as catalytic inhibitors. As they are specific to topoisomerase II, they are the most normally used catalytic inhibitors of topoisomease II in mammalian cells.
Calatyic inhibitors such as bisdioxopiperazines have modest tumor activity and they are chiefly used for cut downing the cardiotoxicity of anthracyclines. However being the most specific type of catalytic inhibitors they are good tools for analyzing the consequence of topoisomerase II suppression. Parler des different ICRF et MST
The first topoisomerase II targeted agent to be discovered was Etoposide which is derived from podophyllotoxin. Podophyllotoxin presented a high toxicity but etoposide and teniposide discovered later on based on the pharmacophore of the natural merchandise shown increased anticancer activity and reduced toxicity. mitoxantrone in anticancer regimens, it is used as a intervention for autoimmune diseases, such as multiple induration
Topoisomerase II mark drugs constitute indispensable compounds that will be used to handle a malignant neoplastic disease curable by chemotherapy. They will be prescribed to each patient necessitating chemotherapy.
Mitoxanthrone is used to handle chest malignant neoplastic disease, while Etopoxide, doxorubicin and other drugs are the first therapy envisaged toward solid tumours and malignant neoplastic disease such as leukaemia, lymphomas, lung and chest malignant neoplastic disease.
Amsacrine along mitoxanthrone are used at the same clip to handle acute myeloid leukaemia.
MOTS SUR LES DIFFERENTES TOPOISOMERASES ALPHA ET BETA
Topoisomerase II toxicants are besides found in the nutriment, and many nutrient merchandises. Bioflavonoids are the most of import category of natural merchandise doing this consequence. Bioflavonoids are the constituent of many fruits, veggies and foliages ( donner lesquelles ) . They have a wide scope of effects on the human organic structure ( mammalian? ) but certain of them are powerful topoisomerase II toxicants. Geinistein is one of them.
Genistein ‘s ring construction presents tonss of similarities compared to the quinolone. They both increase the degree of toposisomerase II-DNA cleavage composites as
Metabolites from some drugs and chemical used in the industry are topoisomerase II toxicant. In all instances know until now, they all present the same feature, The one of possessing a quinone ring ( aromatic ring having a ketone group ) . ( Mettre petite image de construction )
Acetaminophen is an frequently used analgetic. N-acetyl p-benzoquinone imine ( NAPQI ) , its metabolite is a powerful topoisomerase II toxicant.
Benzene nowadays every bit good metabolite which act as toposiomerase II toxicant: 1,4-benzoquinone. This dissolver is believed to do human leukaemia.
Polychlorinated biphenyls ( PCBs ) to complete with this portion, have quinone metabolites which binds the enzyme covalently. They present a high activity against human type II topoisomerase.