Homology modelling of human CYP1A2 based on the CYP2C5 crystallographic template structure
article
1. The results of homology modelling of human cytochrome P4501A2 (CYP1A2) based on the CYP2C5 crystal structure are reported. It exhibits improved sequence homology relative to that of CYP102. 2. It was demonstrated that many selective substrates for CYP1A2 could fit within the putative active site of the enzyme, and in orientations which agree with documented evidence for CYP1A2-mediated metabolism. 3. Furthermore, a number of amino acid residues lining the haem pocket have been shown, via site-directed mutagenesis, to have an influence on substrate metabolism, and these experimental findings from the literature are consistent with the modelled interactions for selective substrates. 4. The binding affinities of several CYP1A2 substrates have also been calculated from the CYP1A2 active site interactions and they agree closely with experimental values. Chemicals/CAS: aflatoxin, 1402-68-2; caffeine, 30388-07-9, 58-08-2; estradiol, 50-28-2; furafylline, 80288-49-9; melatonin, 73-31-4; naproxen, 22204-53-1, 26159-34-2; phenacetin, 62-44-2; tacrine, 1684-40-8, 3198-41-2, 321-64-2; CYP2C5 protein, Oryctolagus cuniculus, EC 1.14.14.1; Cytochrome P-450 CYP1A2, EC 1.14.14.1; Cytochrome P-450 Enzyme System, 9035-51-2; Lipids; Steroid 21-Hydroxylase, EC 1.14.99.10
Topics
2 amino 1 ethyl 6 phenylimidazo[4,5 b]pyridine2 amino 3 methylimidazolo[4,5 f]quinoline4 methyl 2 amino 3 methylimidazolo[4,5 f]quinolineaflatoxincaffeinecytochrome P450 1A2cytochrome P450 2C5estradiolfurafyllinemelatoninmethoxyresorufinnaproxenphenacetinpyridine derivativequinoline derivativeresorufin derivativetacrineunclassified drugbinding affinitycrystal structuredrug metabolismenzyme active siteenzyme activityenzyme bindingenzyme structureenzyme substrateenzyme substrate complexmolecular modelsequence homologysite directed mutagenesisAmino Acid SequenceAnimalsChemistry, PhysicalCricetinaeCrystallography, X-RayCytochrome P-450 CYP1A2Cytochrome P-450 Enzyme SystemFishesHumansLipidsMiceModels, MolecularMolecular Sequence DataMutagenesis, Site-DirectedRabbitsSpecies SpecificitySteroid 21-HydroxylaseProkaryota
TNO Identifier
280276
ISSN
00498254
Source
Xenobiotica, 33(3), pp. 239-254.
Pages
239-254
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