Search results for: Dan A. Rock

Items from 1 to 14 out of 14 results

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Immunoaffinity capture coupled with capillary electrophoresis - mass spectrometry to study therapeutic protein stability in vivo

Mei Han, Josh T. Pearson, Yunan Wang, Dwight Winters, more

Analytical Biochemistry > 2017 > 539 > C > 118-126

Protein engineering is at an all-time high in biopharmaceutics. As a result, absorption, distribution, metabolism and excretion (ADME) of proteins has become more important to understand in the context of engineering strategies to optimize therapeutic properties of potential lead constructs. Immunoaffinity capture coupled with a newly developed capillary electrophoresis – mass spectrometry (CE-MS)...

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Intact mass analysis of monoclonal antibodies by capillary electrophoresis—Mass spectrometry

Mei Han, Brooke M. Rock, Josh T. Pearson, Dan A. Rock

Journal of Chromatography B > 2016 > 1011 > C > 24-32

Characterization of monoclonal antibody (mAb) therapeutics by intact mass analysis provides important information on sequence integrity and post-translational modifications. In order to obtain domain specific information, monoclonal antibodies are reduced to heavy and light chain components or enzymatically digested into smaller portions or peptides. Liquid chromatography (LC) is widely used for separation...

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Formation of raloxifene homo-dimer in CYP3A4, evidence for multi-substrate binding in a single catalytically competent P450 active site

John A. Davis, Robert J. Greene, Sean Han, Dan A. Rock, more

Archives of Biochemistry and Biophysics > 2011 > 513 > 2 > 110-118

Raloxifene is a polyaromatic compound which has been reported to form radicals when incubated with horseradish peroxidase resulting in formation of a homo-dimer product. Polyaromatic phenols have also been reported to undergo oxidation by P450 enzymes to form reactive intermediates, presumably through the formation of phenoxy radical species. Recently, we observed that a raloxifene homo-dimer was...

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The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4

Chi-Chi Peng, Josh T. Pearson, Dan A. Rock, Carolyn A. Joswig-Jones, more

Archives of Biochemistry and Biophysics > 2010 > 497 > 1-2 > 68-81

One goal in drug design is to decrease clearance due to metabolism. It has been suggested that a compound’s metabolic stability can be increased by incorporation of a sp ² nitrogen into an aromatic ring. Nitrogen incorporation is hypothesized to increase metabolic stability by coordination of nitrogen to the heme-iron (termed type II binding). However, questions regarding binding affinity,...

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In Vitro Modulation of Cytochrome P450 Reductase Supported Indoleamine 2,3-Dioxygenase Activity by Allosteric Effectors Cytochrome b ₅ and Methylene Blue

Josh T. Pearson, Sophia Siu, David P. Meininger, Larry C. Wienkers, more

Biochemistry > 2010 > 49 > 12 > 2647 - 2656

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Assessment of the Metabolism and Intrinsic Reactivity of a Novel Catechol Metabolite

J. Matthew Hutzler, Roger J. Melton, Jeanne M. Rumsey, David C. Thompson, more

Chemical Research in Toxicology > 2008 > 21 > 5 > 1125 - 1133

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Differential Time-Dependent Inactivation of P450 3A4 and P450 3A5 by Raloxifene: A Key Role for C239 in Quenching Reactive Intermediates

Josh T. Pearson, Jan L. Wahlstrom, Leslie J. Dickmann, Santosh Kumar, more

Chemical Research in Toxicology > 2007 > 20 > 12 > 1778 - 1786

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Time-Dependent Inactivation of P450 3A4 by Raloxifene: Identification of Cys239 as the Site of Apoprotein Alkylation ¹

Brian R. Baer, Larry C. Wienkers, Dan A. Rock

Chemical Research in Toxicology > 2007 > 20 > 6 > 954 - 964

article

Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors

Hisashi Suzuki, M. Byron Kneller, Dan A. Rock, Jeffrey P. Jones, more

Archives of Biochemistry and Biophysics > 2004 > 429 > 1 > 1-15

Three series of N-3 alkyl substituted phenytoin, nirvanol, and barbiturate derivatives were synthesized and their inhibitor potencies were tested against recombinant CYP2C19 and CYP2C9 to probe the interaction of these ligands with the active sites of these enzymes. All compounds were found to be competitive inhibitors of both enzymes, although the degree of inhibitory potency was generally much greater...

article

Kinetic Isotope Effects Implicate the Iron−Oxene as the Sole Oxidant in P450-Catalyzed N-Dealkylation

Tamara S. Dowers, Dan A. Rock, Denise A. Rock, Jeffrey P. Jones

Journal of the American Chemical Society > 2004 > 126 > 29 > 8868 - 8869

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A method for determining two substrates binding in the same active site of cytochrome P450 _B _M ₃ : an explanation of high energy ω product formation

Dan A. Rock, Brandon N.S. Perkins, Jan Wahlstrom, Jeffrey P. Jones

Archives of Biochemistry and Biophysics > 2003 > 416 > 1 > 9-16

A number of enzymes from the cytochrome P450 family show atypical (non-Michaelis-Menten) kinetic behavior resulting from substrate activation, inhibition, partial inhibition, biphasic saturation, or autoactivation. Herein, we provide a technique that can identify multiple substrate occupancy in the same active site of a P450 as a result of an altered kinetic profile. Using an isotope effect on product...

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Use of Kinetic Isotope Effects to Delineate the Role of Phenylalanine 87 in P450BM-3

Dan A Rock, Anthony E Boitano, Jan L Wahlstrom, Denise A Rock, more

Bioorganic Chemistry > 2002 > 30 > 2 > 107-118

The substrate oxidation rates of P450 _BM-3 are unparalleled in the cytochrome P450 (CYP) superfamily of enzymes. Furthermore, the bacterial enzyme, originating from Bacillus megaterium, has been used repeatedly as a model to study the metabolism of mammalian P450s. A specific example is presented where studying P450 _BM-3 substrate dynamics can define important enzyme-substrate characteristics,...

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Active Site Mutations of Cytochrome P450cam Alter the Binding, Coupling, and Oxidation of the Foreign Substrates (R)- and (S)-2-Ethylhexanol

Kevin J. French, Dan A. Rock, Denise A. Rock, John I. Manchester, more

Archives of Biochemistry and Biophysics > 2002 > 398 > 2 > 188-197

Three factors are of primary importance with respect to designing efficient P450 biocatalysts. (1) The substrate must be oxidized at a significant rate. (2) The regioselectivity must heavily favor the desired product. (3) The enzyme must use the majority of the reducing equivalents from NADH or NADPH to produce product. The reaction we chose to study was oxidation of 2-ethylhexanol to 2-ethylhexanoic...

article

Benign Synthesis of 2-Ethylhexanoic Acid by Cytochrome P450cam: Enzymatic, Crystallographic, and Theoretical Studies ^†

Kevin J. French, Michael D. Strickler, Dan A. Rock, Denise A. Rock, more

Biochemistry > 2001 > 40 > 32 > 9532 - 9538

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