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Lecture 14

BCH2011: Textbook summary - Lecture 14

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LECTURE 14 An Understanding of Protease Mechanisms Leads to New Treatments for HIV Infections: Retroviruses possess an RNA genome and an enzyme, reverse transcriptase, capable of using RNA to direct the synthesis of a complementary DNA. A retrovirus such as HIV has a relatively simple life cycle. Its RNA genome is converted to duplex DNA in several steps catalyzed by a reverse transcriptase. The duplex DNA is then inserted into a chromosome in the nucleus of the host cell by the enzyme integrase. The inserted copy of the viral genome can remain dormant indefinitely. Alternatively, it can be transcribed back into RNA, which can then be translated into proteins to construct new virus particles. Most of the viral genes are translated into large polypeptides, which are cut by the HIV protease into the individual proteins needed to make the virus. There are only three key enzymes in this cycle – the reverse transcriptase, the integrase, and the protease. The HIV protease is an aspartyl protease. Two active-step Asp residues facilitate a direct attack of water on the peptide bond to be cleaved. The initial product of the attack of water on the carbonyl group of the peptide bond is an unstable tetrahedral intermediate. This intermediate is close in structure and energy to the reaction transition state. The drugs that have been developed as HIV protease inhibitors form noncovalent complexes with the enzyme, but they bind to it so tightly that they can be considered irreversible inhibi
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