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Yasuhiro Tateishi - One of the best experts on this subject based on the ideXlab platform.
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stepwise binding of inhibitors to human cytochrome p450 17a1 and rapid kinetics of inhibition of androgen biosynthesis
Journal of Biological Chemistry, 2021Co-Authors: Peter F Guengerich, Kevin D Mccarty, Jesse G Chapman, Yasuhiro TateishiAbstract:Cytochrome P450 (P450) 17A1 catalyzes the 17α-hydroxylation of progesterone and pregnenolone as well as the subsequent lyase cleavage of both Products to generate androgens. However, the selective inhibition of the lyase reactions, particularly with 17α-hydroxy pregnenolone, remains a challenge for the treatment of prostate cancer. Here, we considered the mechanisms of inhibition of drugs that have been developed to inhibit P450 17A1, including ketoconazole, seviteronel, orteronel, and abiraterone, the only approved inhibitor used for prostate cancer therapy, as well as clotrimazole, known to inhibit P450 17A1. All five compounds bound to P450 17A1 in a multistep process, as observed spectrally, over a period of 10 to 30 s. However, no lags were observed for the onset of inhibition in rapid-quench experiments with any of these five compounds. Furthermore, the addition of substrate to inhibitor–P450 17A1 complexes led to an immediate Formation of Product, without a lag that could be attributed to conFormational changes. Although abiraterone has been previously described as showing slow-onset inhibition (t1/2 = 30 min), we observed rapid and strong inhibition. These results are in contrast to inhibitors of P450 3A4, an enzyme with a larger active site in which complete inhibition is not observed with ketoconazole and clotrimazole until the changes are completed. Overall, our results indicate that both P450 17A1 reactions—17α-hydroxylation and lyase activity—are inhibited by the initial binding of any of these inhibitors, even though subsequent conFormational changes occur.
M L Budni - One of the best experts on this subject based on the ideXlab platform.
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interaction of 2 3 dichloro 1 4 naphthoquinone with n butylamine in halocarbon solvents
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2005Co-Authors: Gururaj M Neelgund, M L BudniAbstract:The rapid interaction between 2,3-dichloro-1,4-naphthoquinone (DCINQ)and n-butylamine results in the Formation of 2N(n-butylamino)-3-chloro-1,4-naphthoquinone as the final Product, The reaction is found to proceed through the initial Formation of charge-transfer (CT) complex as an intermediate. The final Product of the reaction has been isolated and characterized using FTIR, H-1 and C-13 NMR spectroscopy, mass spectrometry, and elemental analysis. The rate of Formation of Product has been measured as a function of time in different halocarbon solvents, viz., chloroform, dichloromethane and 1: 1 (v/v) mixture of two solvents. The pseudo first order and second order rate constants at various temperatures for the transFormation process were evaluated from the absorbance time data. The activation parameters (E,, AS', Delta H-#and Delta G(#)) were obtained from temperature dependence of rate constants. The influence of dielectric constant on the properties of reaction was discussed and the probable course of reaction ispresented.
Scott A Mcluckey - One of the best experts on this subject based on the ideXlab platform.
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charge state dependent sequence analysis of protonated ubiquitin ions via ion trap tandem mass spectrometry
Analytical Chemistry, 2001Co-Authors: Gavin E Reid, Paul A Chrisman, And Mitchell J Wells, Scott A McluckeyAbstract:One of the major factors governing the “top-down” sequence analysis of intact multiply protonated proteins by tandem mass spectrometry is the effect of the precursor ion charge state on the Formation of Product ions. To more fully understand this effect, electrospray ionization coupled to a quadrupole ion trap mass spectrometer, collision-induced dissociation, and gas-phase ion/ion reactions have been employed to examine the fragmentation of the [M + 12H]12+ to [M + H]+ ions of bovine ubiquitin. At low charge states (+1 to +6), loss of NH3 or H2O from the protonated precursor and directed cleavage at aspartic acid residues was observed. At intermediate charge states, (+7, +8, and +9), extensive nonspecific fragmentation of the protein backbone was observed, with 50% sequence coverage obtained from the [M + 8H]8+ ion alone. At high charge states, (+10, +11, +12), the single dominant channel that was observed was the preferential fragmentation of a single proline residue. These data can be readily explained...
Chung Ling Yang - One of the best experts on this subject based on the ideXlab platform.
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tuning the regio and stereoselectivity of c h activation in n octanes by cytochrome p450 bm 3 with fluorine substituents evidence for interactions between a c f bond and aromatic π systems
Chemistry: A European Journal, 2011Co-Authors: Chung Ling Yang, Chih Hsiang Chiang, Chunwei Chang, Hohsuan Chou, Huei Ying Hung, Sunney I ChanAbstract:We employed the water- soluble cytochrome P450 BM-3 to study the activity and regiospecificity of oxidation of fluorinated n-octanes. Three mutations, A74G, F87V, and L188Q, were introduced into P450 BM-3 to allow the system to undergo n-octane oxidation. In addition, the alanine at residue 328 was replaced with a phenylalanine to introduce an aromatic residue into the hydrophobic pocket to examine whether or not van der Waals interactions between a CF substituent in the substrate and the polarizable π system of the phenylalanine may be used to steer the positioning of the substrate within the active-site pocket of the enzyme and control the regioselectivity and stereoselectivity of hydroxylation. Interestingly, not only was the regioselectivity controlled when the fluorine substituent was judiciously positioned in the substrate, but the electron input into the iron–heme group became tightly coupled to the Formation of Product, essentially without abortive side reactions. Remarkable enhancement of the coupling efficiency between electron input and Product Formation was observed for a range of fluorinated octanes in the enzyme even without the A328F mutation, presumably because of interactions of the CF substituent with the π system of the porphyrin macrocycle within the active-site pocket. Evidently, tightening the protein domain containing the heme pocket tunes the distribution of accessible enzyme conFormations and the associated protein dynamics that activate the iron porphyrin for substrate hydroxylation to allow the reactions mediated by the high-valent FeIVO to become kinetically more commensurate with electron transfer from the flavin adenine dinucleotide (FAD)/flavin mononucleotide (FMN) reductase. These observations lend compelling evidence to support significant van der Waals interactions between the CF2 group and aromatic π systems within the heme pocket when the fluorinated octane substrate is bound.
Vipan Kumar - One of the best experts on this subject based on the ideXlab platform.
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triflic acid promoted fries rearrangement of c 3 vinyl isopropenyl azetidin 2 ones single pot synthesis of c 3 functionalized 2 aryl 2 3 dihydro quinoline 4 1h ones
RSC Advances, 2014Co-Authors: Vishu Mehra, Parvesh Singh, Krishna Bisetty, Vipan KumarAbstract:The β-lactam-synthon-interceded synthesis of C-3 functionalized 2-aryl-2,3-dihydro-quinoline-4(1H)-ones has been described via the Fries rearrangement of C-3 vinyl/isopropenyl substituted β-lactams. The reaction at 0 °C resulted in the isolation of a tautomeric mixture, and the preferential Formation of the conjugated Product was observed at higher temperatures. Density functional theory (DFT) calculations and molecular dynamics (MD) simulations were additionally performed to explain the preferential Formation of Product 2 over 3. The proposed mechanism was further validated via the base-induced isomerisation of the mixture of 2a and 3a.