Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphonoformate (foscarnet) is a pyrophosphate (PP(i)) analogue and a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), acting through the PP(i) binding site on the enzyme. HIV-1 RT can unblock a chain-terminated DNA primer by phosphorolytic transfer of the terminal residue to an acceptor substrate (PP(i) or a nucleotide such as ATP) which also interacts with the PP(i) binding site. Primer-unblocking activity is increased in mutants of HIV-1 that are resistant to the chain-terminating nucleoside inhibitor 3'-azido-3'-deoxythymidine (AZT). We have compared the primer-unblocking activity for HIV-1 RT containing various foscarnet resistance mutations (K65R, W88G, W88S, E89K, S117T, Q161L, M164I, and the double mutant Q161L/H208Y) alone or in combination with AZT resistance mutations. The level of primer-unblocking activity varied over a 150-fold range for these enzymes and was inversely correlated with foscarnet resistance and directly correlated with AZT resistance. Based on published crystal structures of HIV-1 RT, many of the foscarnet resistance mutations affect residues that do not make direct contact with the catalytic residues of RT, the incoming deoxynucleoside triphosphate (dNTP), or the primer-template. These mutations may confer foscarnet resistance and reduce primer unblocking by indirectly decreasing the binding and retention of foscarnet, PP(i), and ATP. Alternatively, the binding position or orientation of PP(i), ATP, or the primer-template may be changed in the mutant enzyme complex so that molecular interactions required for the unblocking reaction are impaired while dNTP binding and incorporation are not.
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PMID:Relationship between 3'-azido-3'-deoxythymidine resistance and primer unblocking activity in foscarnet-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase. 1274 70

Extracts from twenty two medicinal plants popularly used in preparing traditional remedies in Kenya were screened for activity against the HIV-1 reverse transcriptase. The screening procedure involved the use of tritium labeled thymidine triphosphate as the enzyme substrate and polyadenylic acid.oligodeoxythymidylic acid [poly(rA).p(dT)12-18] as the template primer dimer. Foscarnet was used as a positive control in these experiments. At a concentration of 100 microg/ml, extracts from eight of these plants showed at least 50 per cent reverse transcriptase inhibition. This activity was arbitrarily considered as significant. This indicates that there is the probability that some antiretroviral compounds could be identified and isolated from materials from these plants.
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PMID:Evaluation of the HIV-1 reverse transcriptase inhibitory properties of extracts from some medicinal plants in Kenya. 1729 48


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