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Pre-Steady-State Kinetic Characterization of Wild Type and 3‘-Azido-3‘-deoxythymidine (AZT) Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase:  Implication of RNA Directed DNA Polymerization in the Mechanism of AZT Resistance

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Department of Pharmacology, 333 Cedar Street, Yale University School of Medicine, New Haven, Connecticut 06520-8066
Cite this: Biochemistry 1997, 36, 46, 14064–14070
Publication Date (Web):November 18, 1997
https://doi.org/10.1021/bi9713862
Copyright © 1997 American Chemical Society

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    Abstract

    There is lack of a correlation between biochemical studies and the observed clinical resistance of AIDS patients on long term AZT therapy. Mutant HIV-1 reverse transcriptase in the viral isolates from these patients shows a 100-fold decrease in sensitivity whereas little or no difference is observed in kinetic parameters in vitro using steady-state kinetic analysis. A detailed pre-steady-state kinetic analysis of wild type and the clinically important AZT resistant mutant (D67N, K70R, T215Y, K219Q) HIV-1 reverse transcriptase was conducted to understand the mechanistic basis of drug resistance. In contrast to steady-state techniques, a pre-steady-state kinetic analysis allows for the direct observation of catalytic events occurring at the active site of the enzyme, including subtle conformational changes enabling a greater degree of mechanistic detail. In this investigation the rate of incorporation of dTMP and AZTMP by wild type and mutant HIV-1 RT was determined using an RNA and the corresponding DNA template. The present study has shown a 1.5-fold decrease in the rate constant for polymerization (kpol) and a 2.5-fold decrease in the equilibrium dissociation constant (Kd) for AZTTP for the mutant reverse transcriptase as compared to the wild type, for RNA dependent DNA replication. These values translate into a 4-fold decrease in selectivity (kpol/Kd) for AZTMP incorporation by mutant reverse transcriptase as compared to wild type for RNA dependent DNA replication. No such decrease in selectivity was detected for DNA dependent replication. These results suggest that the basis of AZT resistance is related to RNA dependent replication rather than DNA dependent replication.

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     This work was supported by NIH Grant GM49551 to K.S.A.

     Present address:  Massachusetts College of Pharmacy & Allied Health Sciences, 179 Longwood Ave., Boston, MA 02115.

    *

     Author to whom correspondence should be addressed. Telephone:  (203)-785-4526. Fax:  (203)-785-7670. email:  karen.anderson@ yale.edu.

     Abstract published in Advance ACS Abstracts, November 1, 1997.

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    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect