Investigation of Surface Interactions Between Cytochrome B5 and Major Cytochrome P450 Isoforms PDF Download
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Author: Chunsheng Zhao
Publisher:
ISBN:
Category :
Languages : en
Pages : 206
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Book Description
Cytochrome b5 (cyt b5 or holo b5) is known as one of the key components in the microsomal cytochrome P450 (CYP) monooxygenase system that metabolizes structurally diverse endogenous and exogenous compounds. It has been reported to modulate many CYPs activity and the effect is both CYP isoform and substrate dependent. However, to date no consensus has been made on the underlying mechanism. In the present study, the surface interactions between cyt b5 and major hepatic CYP isoforms 3A4, 2C9, 2A6 and 2D6 were investigated. Chemical cross-linking coupled with mass spectrometric analysis was used to identify the potential electrostatic interactions on protein surfaces of cyt b5 and CYPs. Subsequently, the interaction models of cyt b5-CYPs were built using these identified cross-linking sites as constraints. For the first time, holo b5 and apo b5 (cyt b5 devoid of heme) surface interactions with CYPs were compared. The models suggest both of them bind to the same the groove on CYPs with very small difference in their orientations. The closest distances between the heme groups of cyt b5 and each CYP isoform are beyond direct electron transfer distance, indicating that cyt b5 likely modulates these CYP isoforms activity through allosteric effect in addition to the potential electron transfer role. In order to confirm that the residues involved in cross-linking are functionally important for cyt b5-CYP interaction, site-directed mutagenesis of CYP3A4 were carried out with the identified Lys residues on CYP3A4 being substituted with neutral residue Ala. In addition, the importance of Arg446 on CYP3A4 at the interface of the cyt b5-CYP3A4 complex model was also accessed by single-point mutation. Mutation of these residues reduced or abolished cyt b5 binding affinity, suggesting that electrostatic interactions on the interface of the two protein are functionally important and the chemical cross-linking coupled with mass spectrometric analysis serves as a useful tool to study protein-protein interaction.
Author: Chunsheng Zhao
Publisher:
ISBN:
Category :
Languages : en
Pages : 206
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Book Description
Cytochrome b5 (cyt b5 or holo b5) is known as one of the key components in the microsomal cytochrome P450 (CYP) monooxygenase system that metabolizes structurally diverse endogenous and exogenous compounds. It has been reported to modulate many CYPs activity and the effect is both CYP isoform and substrate dependent. However, to date no consensus has been made on the underlying mechanism. In the present study, the surface interactions between cyt b5 and major hepatic CYP isoforms 3A4, 2C9, 2A6 and 2D6 were investigated. Chemical cross-linking coupled with mass spectrometric analysis was used to identify the potential electrostatic interactions on protein surfaces of cyt b5 and CYPs. Subsequently, the interaction models of cyt b5-CYPs were built using these identified cross-linking sites as constraints. For the first time, holo b5 and apo b5 (cyt b5 devoid of heme) surface interactions with CYPs were compared. The models suggest both of them bind to the same the groove on CYPs with very small difference in their orientations. The closest distances between the heme groups of cyt b5 and each CYP isoform are beyond direct electron transfer distance, indicating that cyt b5 likely modulates these CYP isoforms activity through allosteric effect in addition to the potential electron transfer role. In order to confirm that the residues involved in cross-linking are functionally important for cyt b5-CYP interaction, site-directed mutagenesis of CYP3A4 were carried out with the identified Lys residues on CYP3A4 being substituted with neutral residue Ala. In addition, the importance of Arg446 on CYP3A4 at the interface of the cyt b5-CYP3A4 complex model was also accessed by single-point mutation. Mutation of these residues reduced or abolished cyt b5 binding affinity, suggesting that electrostatic interactions on the interface of the two protein are functionally important and the chemical cross-linking coupled with mass spectrometric analysis serves as a useful tool to study protein-protein interaction.
Author: Qiuxia Gao
Publisher:
ISBN:
Category :
Languages : en
Pages : 410
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Book Description
Author: Paul R. Ortiz de Montellano
Publisher: Springer Science & Business Media
ISBN: 0387274472
Category : Medical
Languages : en
Pages : 702
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Book Description
Cytochrome P450: Structure, Mechanism, and Biochemistry, third edition is a revision of a review that summarizes the current state of research in the field of drug metabolism. The emphasis is on structure, mechanism, biochemistry, and regulation. Coverage is interdisciplinary, ranging from bioinorganic chemistry of cytochrome P450 to its relevance in human medicine. Each chapter provides an in-depth review of a given topic, but concentrates on advances of the last 10 years.
Author: Aparajita Dey
Publisher: Springer Science & Business Media
ISBN: 9400758812
Category : Medical
Languages : en
Pages : 269
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Book Description
The book deals with various clinical aspects of cytochrome P450 2E1 (CYP2E1) which is a potent source for oxidative stress. Oxidative stress is critical for pathogenesis of diseases and CYP2E1 is a major contributor for oxidative stress. Several clinical disorders are associated with changes in regulation of CYP2E1 and the consequent abnormalities which include alcoholic liver disease, alcoholic pancreatitis, carcinogenesis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, obesity, hepatitis C virus infection, reproductive organ toxicity, hepatocellular and cholestatic liver cirrhosis, inhibition of bone repair, cross-tolerance in smokers and people treated with nicotine, disorders of central nervous system, changes in metabolism of protoxicants in the circulatory system and susceptibility to human papillomavirus infection. Hence, CYP2E1 emerges as a new and potent player in aggravating injury and furthering disease complications.
Author: Paul Ortiz De Monetllano
Publisher: Springer Science & Business Media
ISBN: 9780306421471
Category : Science
Languages : en
Pages : 572
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Book Description
Major advances have been made in recent years in clarifying the molecular properties of the cytochrome P-450 system. These advances stem, in practical terms, from the generally recognized importance of cytochrome P-450 in the metabolism of drugs and in the bioactivation of xenobiotics to toxic products. The fascinating multiplicity and differential regulation of cytochrome P-450 isozymes, and their ability to catalyze extraordinarily difficult chemical transformations, have independently drawn many chemists and biochemists into the P-450 circle. Progress in the field, from a technical point of view, has been propelled by the de velopment of reliable procedures for the purification of membrane-bound enzymes, by the growing repertoire of molecular biological techniques, and by the development of chemical models that mimic the catalytic action of P-450. As a result, our understanding of the P-450 system is moving from the descriptive, pharmacological level into the tangible realm of atomic detail. The rapid progress and multidisciplinary character of the cytochrome P-450 field, which cuts across the lines that traditionally divide disciplines as diverse as inorganic chemistry and genetics, have created a need for an up-to-date evaluation of the advances that have been made. It is hoped that this book, with its molecular focus on the cytochrome P-450 system, will alleviate this need. The authors of the individual chapters have strived to emphasize recent results without sacrificing the background required to make their chapters comprehensible to informed nonspecialists.
Author: Eugene G. Hrycay
Publisher: Springer
ISBN: 3319160095
Category : Medical
Languages : en
Pages : 376
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Book Description
This book describes in 13 chapters mechanisms of P450 used to monooxygenate substrates via the NAD(P)H/O2 pathway using its peroxidase and peroxygenase functions. P450 also utilizes peroxides, peracids, periodate and iodosobenzene to oxygenate substrates via the shunt pathway. Also described are mechanisms used in the oxidation of pharmaceuticals by CYP3A4; acyl- carbon cleavage by CYP17A1, CYP19A1 and CYP51A1; metabolism of tetrabromodiphenyl ethers and bile acids by CYP2B6 and CYP3A4; metabolism of ω-6 and ω-3 polyunsaturated fatty acids; H2O2-mediated peroxygenation of substrates using substrate misrecognition; P450 oxidative reactions using electrochemical methods; electron transfer to P450 by redox proteins; hydroxylation of 1,8-cineole by P450cin; and peroxygenation by unspecific peroxygenases using H2O2. The topics covered are relevant to P450 researchers, professors and students from a variety of disciplines ranging from pharmacology, toxicology and microbiology to chemistry.
Author: Pavel Anzenbacher
Publisher: John Wiley & Sons
ISBN: 352732903X
Category : Medical
Languages : en
Pages : 755
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Book Description
A practice-oriented desktop reference for medical professionals, toxicologists and pharmaceutical researchers, this handbook provides systematic coverage of the metabolic pathways of all major classes of xenobiotics in the human body. The first part comprehensively reviews the main enzyme systems involved in biotransformation and how they are orchestrated in the body, while parts two to four cover the three main classes of xenobiotics: drugs, natural products, environmental pollutants. The part on drugs includes more than 300 substances from five major therapeutic groups (central nervous system, cardiovascular system, cancer, infection, and pain) as well as most drugs of abuse including nicotine, alcohol and "designer" drugs. Selected, well-documented case studies from the most important xenobiotics classes illustrate general principles of metabolism, making this equally useful for teaching courses on pharmacology, drug metabolism or molecular toxicology. Of particular interest, and unique to this volume is the inclusion of a wide range of additional xenobiotic compounds, including food supplements, herbal preparations, and agrochemicals.
Author: Alok Dhawan
Publisher: Humana Press
ISBN: 9781627035286
Category : Medical
Languages : en
Pages : 0
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Book Description
Genetic toxicology is recognized by geneticists and researchers concerned with the genetic impact of man-made chemicals. In Genotoxicity Assessment: Methods and Protocols, expert researchers in the field provide comprehensive genetic toxicology protocols. These include in vitro and in vivo protocols on mutation assays, cytogenetic techniques, and primary DNA damage, assays in alternate to animal models, and updated ICH guidelines. Written in the highly successful Methods in Molecular Biology series format, the chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step and readily reproducible laboratory protocols, as well as key tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Genotoxicity Assessment: Methods and Protocols seeks to aid research students and scientists working in regulatory toxicology as well as biomedical, biochemical and pharmaceutical sciences.
Author: Erich Grotewold
Publisher: Springer Science & Business Media
ISBN: 9780387745503
Category : Science
Languages : en
Pages : 300
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Book Description
This is the only book of its kind to provide an overview of the science of flavonoids in plants.
Author: Mino R. Caira
Publisher: Springer Science & Business Media
ISBN: 140204142X
Category : Medical
Languages : en
Pages : 431
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Book Description
Drug Metabolism: Current Concepts provides a comprehensive understanding of the processes that take place following ingestion of a medicinal agent or xenobiotic, with an emphasis on the crucial role of metabolism (biotransformation). How a sound knowledge of these phenomena is incorporated into the design of effective new drug candidates is also explained. The user-friendly text focuses on concepts rather than extraneous details and is supported by many illustrated examples of biotransformations as well as frequent references to current critical reviews and articles highlighting the nature of research objectives in this vibrant area of medicinal development. The final topic on strategies for drug design relies on the background provided by the rest of the book. This book is ideally suited as an advanced text for courses in drug metabolism for students of medicine, pharmacy, pharmacology, biochemistry; and for courses in drug design and drug delivery for students of medicinal chemistry. It is also appropriate for professional seminars or courses that relate to the fate of a drug in the body, drug interactions, adverse reactions and drug design.
