Tip II topoizomeraza

Tip II topoizomeraze presecaju ova lanca DNK heliksa simultano radi upravljanja zamršenjem DNK i supernamotavanjima.^[1]^[2] One koriste hidrolizu ATP-a, za razliku od tip I topoizomeraza. U tom procesu, ovi enzimi menjanju koeficijent povezivanja cirkularne DNK za +/-2.

Struktura 42 KDa fragmenta N-terminalne ATPaze DNK giraze koja je homologna sa svim drugim tipovima IIA topoizomeraza.

Funkcija

Nakon presecanja, krajevi DNK se razdvajaju, i drugi DNK dupleks se propušta kroz presek. Nakon prolaza, presečena DNK se ponovo ligira. Ova rekcija omogućava tip II topoizomerazama da povećaju ili smanje koeficijent povezivanje DNK petlje za 2 jedinice, i promoviše hromozomsko razmršavanje.^[3]

Inhibicija

Mali molekuli čija biološka meta je tip II topoizomeraza se dele u dve klase: inhibitore i otrove.

Inhibitori tipa II topoizomeraze su između ostalih HU-331, ICRF-187, ICRF-193, i mitindomid. Ti molekuli inhibiraju dejstvo ATPaze putem nekompetitivne inhibicije ATP-a. To je pokazano putem strukturnih (Classen et al. Proceedings of the National Academy of Science, 2005) u biohemijskih studija.

Otrovi tip II topoizomeraza su etopozid, novobiocin, hinolon (uključujući ciprofloksacin), i tenipozid. Biološka meta ovih malih molekula je DNA-proteinski kompleks. Neki od tih molekula dovode do povećanog presecanja, dok drugi puput etopozida, inhibiraju religaciju.

Eksperimentalni antitumorski lek m-AMSA (4'-(9'-akridinilamino)metanesulfon-m-anizidid) takođe inhibira tip 2 topoizomerazu.^[4]

Reference

↑ Champoux JJ (2001). „DNA topoisomerases: structure, function, and mechanism”. Annu. Rev. Biochem. 70: 369–413. DOI:10.1146/annurev.biochem.70.1.369. PMID 11395412.
↑ „National Academy of Sciences: NAS Award in Molecular Biology”. National Academy of Science. Pristupljeno 07. 01. 2009.
↑ Wang, J.C. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40.
↑ Willmore E, de Caux S, Sunter NJ, et al. (2004). „A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia”. Blood 103 (12): 4659–65. DOI:10.1182/blood-2003-07-2527. PMID 15010369.

Literatura

Nicholas C. Price, Lewis Stevens (1999). Fundamentals of Enzymology: The Cell and Molecular Biology of Catalytic Proteins (Third izd.). USA: Oxford University Press. ISBN 019850229X.
Eric J. Toone (2006). Advances in Enzymology and Related Areas of Molecular Biology, Protein Evolution (Volume 75 izd.). Wiley-Interscience. ISBN 0471205036.
Branden C, Tooze J.. Introduction to Protein Structure. New York, NY: Garland Publishing. ISBN: 0-8153-2305-0.
Irwin H. Segel. Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems (Book 44 izd.). Wiley Classics Library. ISBN 0471303097.
Robert A. Copeland (2013). Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (2nd izd.). Wiley-Interscience. ISBN 111848813X.
Gerhard Michal, Dietmar Schomburg (2012). Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology (2nd izd.). Wiley. ISBN 0470146842.

[pmid11395412-1] Champoux JJ (2001). „DNA topoisomerases: structure, function, and mechanism”. Annu. Rev. Biochem. 70: 369–413. DOI:10.1146/annurev.biochem.70.1.369. PMID 11395412.

[urlNational_Academy_of_Sciences:_NAS_Award_in_Molecular_Biology-2] „National Academy of Sciences: NAS Award in Molecular Biology”. National Academy of Science. Pristupljeno 07. 01. 2009.

[3] Wang, J.C. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40.

[pmid15010369-4] Willmore E, de Caux S, Sunter NJ, et al. (2004). „A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia”. Blood 103 (12): 4659–65. DOI:10.1182/blood-2003-07-2527. PMID 15010369.

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