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Nucleic Acids Research Advance Access originally published online on December 20, 2007
Nucleic Acids Research 2008 36(3):1009-1016; doi:10.1093/nar/gkm1087
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Nucleic Acids Research, 2008, Vol. 36, No. 3 1009-1016
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

AZT resistance of simian foamy virus reverse transcriptase is based on the excision of AZTMP in the presence of ATP

Maximilian J. Hartl1, Benedikt Kretzschmar2, Anne Frohn1, Ali Nowrouzi2, Axel Rethwilm2 and Birgitta M. Wöhrl1,*

1Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere & Research Center for Biomacromolecules, 95440 Bayreuth and 2Universität Würzburg, Institut für Virologie und Immunbiologie, Würzburg, Germany

*To whom correspondence should be addressed. Tel: +49 921 55 3542; Fax: +49 921 55 3544; Email: birgitta.woehrl{at}uni-bayreuth.de

Received September 25, 2007. Revised November 17, 2007. Accepted November 19, 2007.

Azidothymidine (AZT, zidovudine) is one of the few nucleoside inhibitors known to inhibit foamy virus replication. We have shown previously that up to four mutations in the reverse transcriptase gene of simian foamy virus from macaque (SFVmac) are necessary to confer high resistance against AZT. To characterize the mechanism of AZT resistance we expressed two recombinant reverse transcriptases of highly AZT-resistant SFVmac in Escherichia coli harboring three (K211I, S345T, E350K) or four mutations (K211I, I224T, S345T, E350K) in the reverse transcriptase gene. Our analyses show that the polymerization activity of these mutants is impaired. In contrast to the AZT-resistant reverse transcriptase of HIV-1, the AZT resistant enzymes of SFVmac reveal differences in their kinetic properties. The SFVmac enzymes exhibit lower specific activities on poly(rA)/oligo(dT) and higher KM-values for polymerization but no change in KD-values for DNA/DNA or RNA/DNA substrates. The AZT resistance of the mutant enzymes is based on the excision of the incorporated inhibitor in the presence of ATP. The additional amino acid change of the quadruple mutant appears to be important for regaining polymerization efficiency.

Present address: Anne Frohn, Max Planck Institut für Biochemie, Martinsried, Germany


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