PMID-sentid Pub_year Sent_text comp_official_name comp_offsetprotein_name organism prot_offset 30627802-9 2019 In the optimal docking pose, the N-oxide moiety of SNO was also found to interact directly with the heme moiety of CYP3A4. Heme 100-104 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 115-121 32712589-4 2020 It was shown that LA in the concentration range of 50-200 muM affects the stage of electron transfer (stage of cytochrome P450 3A4 heme reduction), decreasing the cathodic reduction current by an average of 20 +- 5%. Heme 131-135 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 111-130 32244772-8 2020 To predict the accessibility of substrate atoms to the heme iron, conventional protein-rigid docking methods failed due to the high flexibility of the CYP3A4 protein. Heme 55-59 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 151-157 31510073-1 2019 The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Heme 30-34 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 125-131 30676743-3 2019 Metyrapone and fluconazole are classic type II ligands that inhibit CYP3A4 with medium strength by ligating to the heme iron, whereas PMSF, lacking the heme-ligating moiety, acts as a weak type I ligand and inhibitor of CYP3A4. Heme 115-119 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 68-74 32664320-10 2020 Our docking calculations show that the bergamottin tendency towards pi-pi stacking is important and likely influences its interactions with the heme group of CYP3A4. Heme 144-148 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 158-164 28986474-8 2017 In CYP3A4, the most energetically favorable docking mode places testosterone in a position with the methyl groups directed toward the heme iron, which is more favorable for oxidation at C6beta, whereas for CYP3A7 the testosterone methyl groups are positioned away from the heme, which is more favorable for an oxidation event at C2alpha In conclusion, our data indicate an alternative binding mode for testosterone in CYP3A7 that favors the 2alpha-hydroxylation, suggesting significant structural differences in its active site compared with CYP3A4/5. Heme 273-277 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 3-9 30115511-3 2018 Then we used structure based design, first modifying the CYP3A4 crystal structure (pdb code: 4NY4) by adding an oxyferryl moiety to the heme, followed by validating the modified structure to obtain the 1" and 4 position oxidation products of midazolam and then recapitulating the metabolism patterns deciphered previously for 1 and analogs. Heme 136-140 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 57-63 28986474-8 2017 In CYP3A4, the most energetically favorable docking mode places testosterone in a position with the methyl groups directed toward the heme iron, which is more favorable for oxidation at C6beta, whereas for CYP3A7 the testosterone methyl groups are positioned away from the heme, which is more favorable for an oxidation event at C2alpha In conclusion, our data indicate an alternative binding mode for testosterone in CYP3A7 that favors the 2alpha-hydroxylation, suggesting significant structural differences in its active site compared with CYP3A4/5. Heme 134-138 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 3-9 31339834-3 2019 Docking simulations of these substrates to the heme moiety of reported crystal structures of CYP3A4 (Protein Data Bank code ITQN) and CYP3A5 (6MJM) were conducted. Heme 47-51 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 93-99 31339834-9 2019 Molecular docking simulations could partially explain the differences in the accessibility of substrates to the heme moiety of human CYP3A molecules, resulting in the enzymatic affinity of CYP3A4 and CYP3A5. Heme 112-116 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 133-138 31339834-9 2019 Molecular docking simulations could partially explain the differences in the accessibility of substrates to the heme moiety of human CYP3A molecules, resulting in the enzymatic affinity of CYP3A4 and CYP3A5. Heme 112-116 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 189-195 29991575-9 2018 Most bound to CYP3A4 via coordination to the heme iron, but several also demonstrated evidence of a distinct binding mode at low concentrations. Heme 45-49 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 14-20 29362093-7 2018 A molecular dynamics analysis of the Arg376 > Lys mutation based on the CYP3A4 (a human CYP450) protein structure found that it was responsible for the increase in axis length toward the heme (active site), which is critically important for biological activity and ligand binding. Heme 190-194 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 75-81 28986474-8 2017 In CYP3A4, the most energetically favorable docking mode places testosterone in a position with the methyl groups directed toward the heme iron, which is more favorable for oxidation at C6beta, whereas for CYP3A7 the testosterone methyl groups are positioned away from the heme, which is more favorable for an oxidation event at C2alpha In conclusion, our data indicate an alternative binding mode for testosterone in CYP3A7 that favors the 2alpha-hydroxylation, suggesting significant structural differences in its active site compared with CYP3A4/5. Heme 134-138 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 542-548 28986474-8 2017 In CYP3A4, the most energetically favorable docking mode places testosterone in a position with the methyl groups directed toward the heme iron, which is more favorable for oxidation at C6beta, whereas for CYP3A7 the testosterone methyl groups are positioned away from the heme, which is more favorable for an oxidation event at C2alpha In conclusion, our data indicate an alternative binding mode for testosterone in CYP3A7 that favors the 2alpha-hydroxylation, suggesting significant structural differences in its active site compared with CYP3A4/5. Heme 273-277 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 542-548 27469000-4 2016 Representative quasi-irreversible inhibitors form a metabolite-intermediate (MI) complex with the heme of CYP3A4 according to absorption analysis. Heme 98-102 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 106-112 28919040-5 2017 Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Heme 35-39 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 43-49 28919040-5 2017 Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Heme 35-39 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 90-96 28919040-6 2017 Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. Heme 105-109 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 98-104 28616684-10 2017 Our docking results projected that ethanol increases the average distance between DRV and CYP3A4 heme, and alter the orientation of DRV-CYP3A4 binding. Heme 97-101 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 90-96 27469000-8 2016 The docking study with CYP3A4 suggested that a methyl moiety introduced at the carbon atom at the root of the primary amine disrupts formation of the MI complex between the heme and the nitroso intermediate because of steric hindrance. Heme 173-177 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 23-29 26741368-4 2016 Methamphetamine-CYP3A4 docking showed that methamphetamine binds to the heme of CYP3A4 in two modes, both leading to N-demethylation. Heme 72-76 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 16-22 26939024-5 2016 To confirm that the emission is from the heme, we destroyed the heme by titration with cumene hydroperoxide and measured the changes in emission upon titration with compounds known to bind to the distal face of the heme in two human cytochrome P450 enzymes, known as CYP3A4 and CYP2C9. Heme 41-45 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 267-273 27530542-8 2016 The simulation demonstrated exclusion of all interactions between tri-acetoxy resveratrol and the heme due to distal binding, highlighting the complexity of the CYP3A4 binding site, which may allow simultaneous accommodation of two molecules. Heme 98-102 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 161-167 26741368-4 2016 Methamphetamine-CYP3A4 docking showed that methamphetamine binds to the heme of CYP3A4 in two modes, both leading to N-demethylation. Heme 72-76 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 80-86 26124807-5 2015 RESULTS: Gomisin G can be well docked into the activity site of CYP3A4, and distance between gomisin G the heme active site was 2.75 A. Heme 107-111 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 64-70 26211584-1 2015 CYP3A4, a "heme" containing isoform, abundantly found in the liver, gastro-intestinal tract, lungs and renal cells, also known as drug metabolising enzyme (DME) may be responsible for the disease progression in cancers such as lung cancer. Heme 11-15 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 0-6 25651456-5 2015 Similarly, according to the predicted binding orientation in the active site of the crystal structure of human CYP3A4 (PDB code: 4I4G ), the alkaloids were positioned in such a way that the C3 atom of lasiocarpine and retrorsine and the C26 of senkirkin were closest to the catalytic heme Fe. Heme 284-288 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 111-117 24805065-6 2014 This review summarizes our findings on the relative contribution of the heme-ligating moiety, side chains and the terminal group of ritonavir-like molecules to the ligand binding process, and highlights strategies for a structure-guided design of CYP3A4 inactivators. Heme 72-76 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 247-253 25499431-8 2015 The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Heme 116-120 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 131-137 22896728-8 2012 Molecular docking simulations showed that the 5" position of the pyrimidine moiety of PF-00734200 can access the heme iron-oxo of both CYP3A4 and CYP2D6 in an energetically favored orientation. Heme 113-117 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 135-141 24484539-5 2014 Among the substrates that are preferably metabolized by CYP3A4, including carebastine, itraconazole, haloperidol, and fluvastatin, the former three compounds were found to closely dock to the heme region of CYP3A4 but not to that of CYP3A5. Heme 192-196 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 56-62 24484539-5 2014 Among the substrates that are preferably metabolized by CYP3A4, including carebastine, itraconazole, haloperidol, and fluvastatin, the former three compounds were found to closely dock to the heme region of CYP3A4 but not to that of CYP3A5. Heme 192-196 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 207-213 24484539-9 2014 Molecular docking simulation could partly explain the differences of the affinities (km) of the substrates for CYP3A4 and CYP3A5 based on the accessibility of substrates to the heme moiety of CYP3A molecules. Heme 177-181 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 111-117 23404373-4 2013 We describe an approach combining heme iron oxidation with potassium ferricyanide and metabolite profiling to probe the mechanism of MI complex-based CYP3A4 inactivation by the secondary alkylamine drug lapatinib. Heme 34-38 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 150-156 24312617-4 2013 We investigated four CYP subfamilies (CYP1A, CYP2D, CYP2C, and CYP3A) that are involved in 90% of all metabolic drug transformations and identified four amino acid interaction networks associated with specific CYP functionalities, i.e., membrane binding, heme binding, catalytic activity, and dimerization. Heme 255-259 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 63-68 23886699-0 2013 The effect of ritonavir on human CYP2B6 catalytic activity: heme modification contributes to the mechanism-based inactivation of CYP2B6 and CYP3A4 by ritonavir. Heme 60-64 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 140-146 23886699-7 2013 Here, we provide evidence that RTV inactivation of CYP3A4 is due to heme destruction with the formation of a heme-protein adduct. Heme 68-72 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 51-57 23886699-7 2013 Here, we provide evidence that RTV inactivation of CYP3A4 is due to heme destruction with the formation of a heme-protein adduct. Heme 109-113 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 51-57 23586711-3 2013 We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Heme 105-109 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 33-39 23016756-1 2012 The reaction of peroxynitrite (PN) with purified human cytochrome P450 3A4 (CYP3A4) resulted in the loss of the reduced-CO difference spectrum, but the absolute absorption spectrum of the heme was not significantly altered. Heme 188-192 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 55-74 23016756-1 2012 The reaction of peroxynitrite (PN) with purified human cytochrome P450 3A4 (CYP3A4) resulted in the loss of the reduced-CO difference spectrum, but the absolute absorption spectrum of the heme was not significantly altered. Heme 188-192 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 76-82 22157006-3 2012 Here we present a 2.15 A crystal structure of the CYP3A4-BEC complex in which the drug, a type I heme ligand, is bound in a productive mode. Heme 97-101 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 50-56 22677141-6 2012 Conformational sampling of CYP3A4 with molecular dynamics simulations along multiple trajectories were used to generate representative structures for docking studies using recently published heme parameters. Heme 191-195 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 27-33 22677141-8 2012 RESULTS: Docking with MD-refined CYP3A4 structures incorporating hexa-coordinate heme parameters identifies a unique binding mode involving ARG212 and channel 4, unobserved in the starting PDB ID: 1TQN X-ray structure. Heme 81-85 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 33-39 22113809-1 2012 The binding free energies of the inhibitor-heme model complexes are calculated using the density functional methods and the implicit solvation models in water, where the 16 structurally diverse compounds with a spectrum of IC(50) values from 0.05 (clotrimazole) to 1000 (piroxicam) muM are chosen as inhibitors for Cytochrome P450 3A4 (CYP3A4). Heme 43-47 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 315-334 22113809-1 2012 The binding free energies of the inhibitor-heme model complexes are calculated using the density functional methods and the implicit solvation models in water, where the 16 structurally diverse compounds with a spectrum of IC(50) values from 0.05 (clotrimazole) to 1000 (piroxicam) muM are chosen as inhibitors for Cytochrome P450 3A4 (CYP3A4). Heme 43-47 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 336-342 22113809-8 2012 This indicates that the total binding free energies calculated for the inhibitor-heme model complexes can be a good descriptor in interpreting the inhibitor binding to CYP3A4 and the relative free energies in the gas phase are mainly responsible for the total binding free energies in water, although the desolvation can be a factor to affect the binding affinity of the inhibitors to CYP3A4. Heme 81-85 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 168-174 22113809-8 2012 This indicates that the total binding free energies calculated for the inhibitor-heme model complexes can be a good descriptor in interpreting the inhibitor binding to CYP3A4 and the relative free energies in the gas phase are mainly responsible for the total binding free energies in water, although the desolvation can be a factor to affect the binding affinity of the inhibitors to CYP3A4. Heme 81-85 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 385-391 22106171-1 2012 Itraconazole (ITZ) is a mixture of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. Heme 109-113 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 71-77 22106171-1 2012 Itraconazole (ITZ) is a mixture of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. Heme 109-113 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 102-108 22106171-8 2012 The catalytic rates of dioxolane ring scission were similar to the dissociation rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissociation of ITZ is necessary before catalysis. Heme 140-144 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 112-118 22513143-9 2012 From computational modeling studies atoms in the structure of sorafenib that undergo biotransformation were within ~5.4 A of the CYP3A4 heme. Heme 136-140 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 129-135 22187487-10 2012 The molecular docking study showed that the N-ethyl moiety of CP-945,598 can access to the heme iron-oxo of CYP3A4 in an energetically favored orientation. Heme 91-95 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 108-114 21997754-9 2012 Newly parameterized heme models are tested in implicit and explicitly solvated MD simulations in the absence and presence of enzyme structures, for CYP3A4, and appear to be stable on the nanosecond simulation timescale. Heme 20-24 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 148-154 18096676-2 2008 Sera of CBZ-hypersensitive patients often contain anti-CYP3A antibodies, including those to a CYP3A23 K-helix peptide that is also modified during peroxidative CYP3A4 heme-fragmentation. Heme 167-171 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 55-60 21212239-9 2011 Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. Heme 122-126 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 141-147 20624855-11 2010 In conclusion, we demonstrated for the first time that lapatinib is a mechanism-based inactivator of CYP3A4, most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety. Heme 265-269 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 101-107 19923256-9 2010 Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. Heme 174-178 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 93-99 19797609-6 2010 The metabolite identification revealed that CYP3A4 catalyzed the formation of a variety of metabolites as a result of presenting different parts of the substrates to the heme. Heme 170-174 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 44-50 19797609-9 2010 Levallorphan acted as a time-dependent inhibitor on CYP3A4, indicating a productive binding mode with this enzyme not observed with CYP2D6 that presumably resulted from close interactions of the N-allyl moiety oriented toward the heme. Heme 230-234 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 52-58 19364136-6 2009 On the basis of the coupling between the LSPR of the Ag nanoparticles and the electronic resonances of the heme chromophore in CYP3A4-Nanodiscs, LSPR spectroscopy is used to detect drug binding with high sensitivity. Heme 107-111 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 127-133 19414330-0 2009 Flexible structure of cytochrome P450: promiscuity of ligand binding in the CYP3A4 heme pocket. Heme 83-87 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 76-82 19414330-7 2009 CONCLUSION: The heme pocket of CYP3A4 is very flexible and is able to interact with various types of substrate. Heme 16-20 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 31-37 22197672-10 2012 The experimentally known epoxidized sites of CBZ by CYP3A4 were successfully predicted as the most accessible sites to the heme iron that was judged from a numerical analysis of calculated DeltaG(binding) and the frequency of appearance. Heme 123-127 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 52-58 21447734-0 2011 Mechanism-based inactivation of cytochrome P450 3A4 by mibefradil through heme destruction. Heme 74-78 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 32-51 21447734-10 2011 The decrease in CYP3A4 activity in the presence of mibefradil and NADPH was subsequently shown to have a good correlation with the time-dependent loss of CO binding, which, coupled with the lack of stable heme and/or apoprotein adducts, suggests heme destruction as the mechanism of inactivation of CYP3A4 by mibefradil. Heme 205-209 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 16-22 21447734-10 2011 The decrease in CYP3A4 activity in the presence of mibefradil and NADPH was subsequently shown to have a good correlation with the time-dependent loss of CO binding, which, coupled with the lack of stable heme and/or apoprotein adducts, suggests heme destruction as the mechanism of inactivation of CYP3A4 by mibefradil. Heme 246-250 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 16-22 21266595-10 2011 Docking studies with a CYP3A5 homology model based on the structure of CYP3A4 revealed that midazolam closely docked to the heme of CYP3A5 compared with sorafenib or sunitinib, suggesting that these anticancer drugs act as enhancers, not as substrates. Heme 124-128 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 71-77 18096676-2 2008 Sera of CBZ-hypersensitive patients often contain anti-CYP3A antibodies, including those to a CYP3A23 K-helix peptide that is also modified during peroxidative CYP3A4 heme-fragmentation. Heme 167-171 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 160-166 18201586-1 2007 BACKGROUND: Cytochrome P450 (CYP) 3A4 is an enzyme with activity dependent on the reduction of heme iron that is responsible for the metabolism of many drugs. Heme 95-99 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 12-37 18092806-7 2008 Mass spectrometry analysis indicates that Nile Red is metabolized sequentially by CYP3A4 to the N-monoethyl and N-desethyl products, confirming that the immediate vicinity of the heme iron is one binding site. Heme 179-183 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 82-88 16190729-5 2005 In the resting form of CYP3A4, a structural water molecule is bound to the sixth coordination position of the heme iron, stabilizing the octahedral coordination geometry. Heme 110-114 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 23-29 18043468-6 2007 Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. Heme 71-75 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 22-28 18043468-6 2007 Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. Heme 142-146 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 22-28 17573349-6 2007 Ligand binding to Nanodiscs was monitored by a combination of environment-sensitive ligand fluorescence and ligand-induced shifts in the fluorescence of tryptophan residues present in the scaffold proteins of Nanodiscs; binding to the CYP3A4 active site was monitored by ligand-induced shifts in the heme Soret band absorbance. Heme 300-304 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 235-241 17650504-6 2007 In contrast, the slow phase in the kinetics of cyanide binding to the ferric CYP3A4 correlated with a shift of the heme iron spin state, which is only caused by the association of a second molecule of testosterone. Heme 115-119 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 77-83 17555301-0 2007 Allosteric mechanisms in cytochrome P450 3A4 studied by high-pressure spectroscopy: pivotal role of substrate-induced changes in the accessibility and degree of hydration of the heme pocket. Heme 178-182 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 25-44 17555301-8 2007 These findings suggest that the mechanisms of interactions of CYP3A4 with 1-PB and testosterone involve an effector-induced transition that displaces a system of conformational equilibria in the enzyme toward the state(s) with decreased solvent accessibility of the active site so that the flux of water into the heme pocket is impeded and the high-spin state of the heme iron is stabilized. Heme 313-317 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 62-68 17555301-8 2007 These findings suggest that the mechanisms of interactions of CYP3A4 with 1-PB and testosterone involve an effector-induced transition that displaces a system of conformational equilibria in the enzyme toward the state(s) with decreased solvent accessibility of the active site so that the flux of water into the heme pocket is impeded and the high-spin state of the heme iron is stabilized. Heme 367-371 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 62-68 17357170-3 2007 On binding to CYP3A4, the fluorescence of the dansyl, deazaflavin, and pyrene probes is quenched by photophysical interaction of the fluorophore with the heme. Heme 154-158 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 14-20 16566594-1 2006 To explore the mechanism of homotropic cooperativity in human cytochrome P450 3A4 (CYP3A4) we studied the interactions of the enzyme with 1-pyrenebutanol (1-PB), 1-pyrenemethylamine (PMA), and bromocriptine by FRET from the substrate fluorophore to the heme, and by absorbance spectroscopy. Heme 253-257 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 62-81 16566594-1 2006 To explore the mechanism of homotropic cooperativity in human cytochrome P450 3A4 (CYP3A4) we studied the interactions of the enzyme with 1-pyrenebutanol (1-PB), 1-pyrenemethylamine (PMA), and bromocriptine by FRET from the substrate fluorophore to the heme, and by absorbance spectroscopy. Heme 253-257 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 83-89 17198380-7 2007 Investigation of the kinetics of fluorescence increase upon H2O2-dependent heme depletion suggests that labeled CYP3A4(C58,C64) is represented by two conformers, one of which has the fluorescence of the BADAN and CPM labels completely quenched, presumably by photoinduced electron transfer from the neighboring Trp-72 and/or Tyr-68 residues. Heme 75-79 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 112-118 17173379-0 2006 Inhibition of cytochrome P450 3A4 by a pyrimidineimidazole: Evidence for complex heme interactions. Heme 81-85 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 14-33 16700545-2 2006 The CYP3A4 isoform is inhibited by antifungal imidazoles or triazoles, which form low-spin heme iron complexes via formation of a nitrogen-ferric iron coordinate bond. Heme 91-95 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 4-10 16700545-7 2006 Preloading of CYP3A4 with the heme ligand imidazole abolishes this component of the antifungal azole binding trajectories, and it eliminates the conspicuously slow off-rate. Heme 30-34 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 14-20 16415110-6 2006 Despite these differences in metabolism, all four ITZ stereoisomers induced a type II binding spectrum with CYP3A4, characteristic of coordination of the triazole nitrogen to the heme iron (K(s) 2.2-10.6 nM). Heme 179-183 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 108-114 16229479-8 2005 These results suggest that in CYP3A4 oligomers in solution and in the membrane the enzyme is distributed between two persistent conformers with different accessibility of the heme for the reductant (SO*-(2) anion monomer). Heme 175-179 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 30-36 16190729-8 2005 The structural and dynamic features of the CYP3A4-progesterone complex indicate that the oxidative degradation of progesterone occurs through hydroxylation at the C16 position by the reactive oxygen coordinated to the heme iron. Heme 218-222 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 43-49 18360537-2 2005 Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. Heme 73-77 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 19-25 15870379-5 2005 Study of the influence of b(5) on the kinetics of H(2)O(2)-dependent destruction of the P450 heme moiety suggested two distinct conformers of CYP3A4 with different sensitivity to heme loss. Heme 93-97 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 142-148 18360537-2 2005 Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. Heme 144-148 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 19-25 15544435-4 2004 Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. Heme 95-99 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 32-38 15544435-4 2004 Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. Heme 166-170 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 32-38 14630029-8 2003 This fact suggests unusual stabilization of the high-spin state of CYP3A4, which is assumed to reflect decreased water accessibility of the heme moiety due to specific interactions of the hemoprotein with the protein partners (b(5) and CPR) and/or membrane lipids. Heme 140-144 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 67-73 11744058-2 2001 Among microsomal P450s, the most flexible active site has been found in the CYP3A4 enzyme as it is compressible and the heme vinyl side chains may adopt two different conformations. Heme 120-124 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 76-82 12781333-1 2003 We developed a biosensor based on the redox properties of human CYP3A4 to directly monitor electron transfer to the heme protein. Heme 116-120 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 64-70 12358527-8 2002 In lipid-free aqueous/glycerol solutions of CYP3A4, addition of pyrene affords a concentration-dependent low-spin to high-spin conversion of the CYP3A4 heme prosthetic group, indicating occupancy of the active site by pyrene. Heme 152-156 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 44-50 12358527-8 2002 In lipid-free aqueous/glycerol solutions of CYP3A4, addition of pyrene affords a concentration-dependent low-spin to high-spin conversion of the CYP3A4 heme prosthetic group, indicating occupancy of the active site by pyrene. Heme 152-156 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 145-151 11907170-0 2002 Mechanism-based inactivation of cytochrome P450 3A4 by 17 alpha-ethynylestradiol: evidence for heme destruction and covalent binding to protein. Heme 95-99 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 32-51 11744061-6 2001 Recently, we have shown that apo-high molecular weight cytochrome b5 (apo-HMWb5) is an efficient acceptor of heme when added to a preparation of purified recombinant CYP3A4. Heme 109-113 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 166-172 11744061-11 2001 An exception is CYP3A4 where a measurable amount of heme is transferred to apo-HMWb5 in the absence of denaturing agents. Heme 52-56 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 16-22 11019832-4 2000 Low monooxygenase activity of CYP3A4 was attributed to the insufficient reduction of heme iron of CYP3A4 by NADPH-P450 reductase. Heme 85-89 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 30-36 11516167-2 2001 We have previously shown that mechanism-based suicide inactivation of CYP3A4 and its rat liver ER orthologs, CYPs 3A, via heme-modification of their protein moieties, results in their ubiquitin (Ub)-dependent 26S proteasomal degradation (Korsmeyer et al. Heme 122-126 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 70-76 11124232-0 2001 Triazolam substrate inhibition: evidence of competition for heme-bound reactive oxygen within the CYP3A4 active site. Heme 60-64 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 98-104 11560479-0 2001 Phosphorylation of native and heme-modified CYP3A4 by protein kinase C: a mass spectrometric characterization of the phosphorylated peptides. Heme 30-34 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 44-50 11413149-0 2001 Stimulation of cytochrome P450 reactions by apo-cytochrome b5: evidence against transfer of heme from cytochrome P450 3A4 to apo-cytochrome b5 or heme oxygenase. Heme 92-96 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 102-121 11019832-4 2000 Low monooxygenase activity of CYP3A4 was attributed to the insufficient reduction of heme iron of CYP3A4 by NADPH-P450 reductase. Heme 85-89 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 98-104 10755318-18 2000 DPPE inhibits testosterone metabolism by interacting at two sites on CYP3A4, the first correlating with its K(S) value to bind the substrate site and the second, with its EC50 value to enhance HA binding to the heme iron. Heme 211-215 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 69-75 9918590-7 1999 High-performance liquid chromatography analysis of the incubation mixture showed that the peak containing the heme dissociated from the inactivated CYP3A4 was almost identical with that seen for the -NADPH control. Heme 110-114 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 148-154 9918590-10 1999 Therefore, the mechanism of inactivation of CYP-3A4 by mifepristone involves irreversible modification of the apoprotein at the enzyme active site instead of being the result of heme adduct formation or heme fragmentation. Heme 178-182 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 44-51 9918590-10 1999 Therefore, the mechanism of inactivation of CYP-3A4 by mifepristone involves irreversible modification of the apoprotein at the enzyme active site instead of being the result of heme adduct formation or heme fragmentation. Heme 203-207 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 44-51 9660842-15 1998 Collectively, these results suggest that the probable mechanism for CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the heme moiety of the P450. Heme 206-210 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 68-74 9860860-0 1998 Identification of the heme-modified peptides from cumene hydroperoxide-inactivated cytochrome P450 3A4. Heme 22-26 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 83-102 8033500-5 1994 Our results show that, in patients with porphyria and in healthy subjects, exogenous heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). Heme 85-89 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 187-193 34312304-0 2021 Icotinib induces mechanism-based inactivation of r hCYP3A4/5 possibly via heme destruction by ketene intermediate. Heme 74-78 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 51-60 34312304-12 2021 In conclusion, this study demonstrated that ICT was a mechanism-based inactivator of rhCYP3A4/5, and heme destruction by the ketene metabolite may be responsible for the observed CYP3A inactivation. Heme 101-105 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 179-184 35184709-5 2022 RESULTS: Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. Heme 111-115 cytochrome P450 family 3 subfamily A member 4 Homo sapiens 62-68