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Phosphonium compounds as new and specific inhibitors of bovine serum amine oxidase

BIOCHEMICAL JOURNAL 2004年第PT 3期384卷 551-558页

作者： Di Paolo, ML Lunelli, M Scarpa, M Rigo, A Univ Padua Dipartimento Chim Biol I-35121 Padua Italy Univ Trent Dipartimento Fis I-38050 Trento Italy Univ Trent INFM I-38050 Trento Italy

TPP+ (tetraphenylphosphonium ion) and its analogues were found to act as powerful competitive inhibitors of BSAO (bovine serum amine oxidase). The binding of this new class of inhibitors, to BSAO was characterized by kinetic measurements. TPP+ can bind to the BSAO active site by hydrophobic and by coulombian interactions. The binding probably occurs in the region of the 'cation-binding site' [Di Paolo, Scarpa, Corazza, Stevanato and Rigo (2002) Biophys. J. 83, 2231-2239]. Under physiological conditions, the association constant of TPP+ for this site is higher than 10(6) M-1, the change of enthalpy being the main free-energy term controlling binding. Analysis of the relationships between substrate structure and extent of inhibition by TPP+ reveals some new molecular features of the BSAO active site.

关键词： amine oxidases competitive inhibitors phosphoniurn compounds structure-function relationships

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DNA hydrolysis promoted by di- and multi-nuclear metal complexes

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COORDINATION CHEMISTRY REVIEWS 2004年第1-2期248卷 147-168页

作者： Liu, CL Wang, M Zhang, TL Sun, HZ Huazhong Univ Sci & Technol Dept Chem Wuhan 430074 Peoples R China Cent China Normal Univ Dept Chem Wuhan 430079 Peoples R China Univ Hong Kong Dept Chem Hong Kong Hong Kong Peoples R China

DNA hydrolysis mediated by di- and multi-nuclear metal complexes is of increasing importance in biotechnology and medicine. Many systems for enzyme-mediated nucleic acid hydrolysis, including type 11 restriction endonucleases and phosphatases, contain di- and multi-nuclear metal active sites. Recent progress in the design of di- and multi-nuclear metal artificial nucleases has included Fe3+, Zn2+, Cu2+, Co3+ and Ln(3+/4+)-azamacrocyclic, aminocarboxylic and pyridyl- or benzimidazolyl-based organic ligands complexes and their conjugates to biomacromolecules. The focus in this article is on di- and multi-nuclear metal complexes that promote DNA cleavage via hydrolytic rather than oxidative pathway. Our purpose is to highlight the relationships between the structures of di- and multi-nuclear metal complexes and their functions, the cooperativities between metal and ligands and between metal sites in the course of DNA hydrolysis and the problems that are faced toward the development of di- and multi-nuclear metal-based artificial restriction enzymes by applying the principles of coordination chemistry and enzymatic chemistry. In order to be able to conveniently compare kinetic data that have been reported for many di- and multi-nuclear metal complexes, we propose two parameters alpha and beta that are associated with the kinetic studies on DNA hydrolysis. The former alpha is defined as the ratio of the hydrolytic rate constant mediated by a di- or multi-nuclear metal complex to that by the analogous mononuclear complex under identical or similar conditions, indicating the degree of cooperativity between metal sites. The latter beta is recognized as a rate enhancement over unhydrolyzed double-stranded DNA. (C) 2003 Published by Elsevier B.V.

关键词： DNA hydrolysis phosphate diester bond Di- and multi-nuclear metal complexes catalytic cooperativity structure-function relationships type II restriction endonucleases artificial nucleases

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The effect of reciprocal active site mutations in human cytochromes P450 1A1 and 1A2 on alkoxyresorufin metabolism

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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2004年第1期424卷 33-43页

作者： Liu, JG Ericksen, SS Sivaneri, M Besspiata, D Fisher, CW Szklarz, GD W Virginia Univ Sch Pharm Dept Basic Pharmaceut Sci Morgantown WV 26506 USA Texas Tech Hlth Sci Ctr Dept Pharmaceut Sci Sch Pharm Amarillo TX 79106 USA

Five reciprocal active site mutants of P450 1A1 and 1A2 and an additional mutant, Val/Leu-382 --> Ala, were constructed, expressed in Escherichia coli, and purified by Ni-NTA affinity chromatography. In nearly every case, the residue replacement led to loss of 7-methoxy- and 7-ethoxyresorufin O-dealkylase activity compared to the wild-type enzymes, except for the P450 1A1 S122T mutation which increased both activities. Mutations at position 382 in both P450 1A1 and 1A2 shifted substrate specificity from one enzyme to another, confirming the importance of this residue. Changes in activity of P450 1A enzymes upon amino acid replacement were, in general, consistent with molecular dynamics analyses of substrate motion in the active site of homology models. (C) 2004 Elsevier Inc. All rights reserved.

关键词： cytochrome P450 site-directed mutagenesis structure-function relationships substrate specificity alkoxyresorufin 0-dealkylation molecular modeling molecular dynamics

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Biological activity and conformational analysis of C20 and C14 epimers of CD-ring modified trans-decalin 1α,25-dihydroxyvitamin D analogs

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JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 2004年第1-5期89-90卷 61-66页

作者： De Clercq, PJ Murad, I Gao, LJ Chen, YJ Van Haver, D Vandewalle, M Verstuyf, A Verlinden, L Verboven, C Bouillon, R State Univ Ghent Dept Organ Chem Organ Synth Lab B-9000 Ghent Belgium Catholic Univ Louvain Lab Expt Med & Endocrinol B-3000 Louvain Belgium

In the context of our ongoing study of vitamin D structure-function relationships and in an attempt to obtain a better dissociation of their prodifferentiating (HL-60) and/or anti proliferative (MCF-7) activities and their calcemic activity, further 20-epi and 14-epi modifications were made to three trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D(3), the hormonally active metabolite of vitamin D(3), possessing a natural 20R side chain and featuring additional structural modifications in the seco-B-ring and in the A-ring. Following a previously observed trend and in agreement with the conformational analysis results, all three 20-epi derivatives show substantially lower biological activities, opposite to what is usually observed for analogs having the natural CD-ring. The 14-epi modification (cis-decalins) has little effect on the biological activity of the ynediene type and the saturated derivative, but results in an approximate 10-fold reduction in activity of the previtamin derivative. No better dissociation of the prodifferentiating and/or antiproliferative activities and the calcemic activity was achieved. (C) 2004 Elsevier Ltd. All rights reserved.

关键词： structure-function relationships vitamin D synthesis conformational analysis

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The structural dynamics of myoglobin

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JOURNAL OF STRUCTURAL BIOLOGY 2004年第3期147卷 223-234页

作者： Brunori, M Bourgeois, D Vallone, B Univ Roma La Sapienza Dipartimento Sci Biochim I-00185 Rome Italy Univ Roma La Sapienza Inst Pasteur Fdn Cenci Bolognetti I-00185 Rome Italy European Synchrotron Radiat Facil Grenoble France Univ Grenoble 1 CEA IBS UMR 9015LCCP F-38027 Grenoble France

Conformational fluctuations in proteins were initially invoked to explain the observation that diffusion of small ligands through the matrix is a global phenomenon. Small globular proteins contain internal cavities that play a role not only in matrix dynamics but also in controlling function, tracing a pathway for the diffusion of the ligand to and from the active site. This is the main point addressed in this Review, which presents pertinent information obtained on myoglobin (Mb). Mb, a simple globular heme protein which binds reversibly oxygen and other ligands. The bond between the heme Fe(II) and gaseous ligands can be photodissociated by a laser pulse, generating a non-equilibrium population of protein structures that relaxes on a picosecond to millisecond time range. This process is associated with migration of the ligand to internal cavities of the protein, which are known to bind xenon. Some of the results obtained by laser photolysis, molecular dynamics simulations, and X-ray diffraction of intermediate states of wild-type and mutant myoglobins are summarized. The extended relaxation of the globin moiety directly observed by Laue crystallography reflects re-equilibration among conformational substates known to play an essential role in controlling protein function. (C) 2004 Elsevier Inc. All rights reserved.

关键词： protein crystallography Laue crystallography photolyis intermediate states structure-function relationships myoglobin cavities

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structure-function Relationship in DNA sequence Recognition by Transcription Factors 04

Structure-Function Relationship in DNA sequence Recognition ...

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Asia-Pacific Bioinformatics Conference

作者： Akinori Sarai Samuel Selvaraj Michael M. Gromiha Hidetoshi Kono Dept. Biochemical Engineering and Science Kyushu Institute of Technology lizuka Japan

ISBN: (纸本)1920682112

Transcription factors play essential role in the gene regulation in higher organisms, binding to multiple target sequences and regulating multiple genes in a complex manner. In order to understand the molecular mechanism of target recognition, and topredict target genes for transcription factors at the genome level, it is important to analyze the relationship between the structure and function (specificity) of transcription factors. We have used a knowledge-based approach, utilizing rapidly increasing structural data of protein-DNA complexes, to derive empirical potential functions for the specific interactions between bases and amino acids as well as for DNA conformation, from the statistical analyses on the structural data. Then these statisticalpotentials are used to quantify the specificity of protein-DNA recognition. The quantification of specificity has enabled us to establish the structure-function analysis of transcription factors, such as the effects of binding cooperativity on target recognition. The method is also applied to real genome sequences, predicting potential target sites. We are also using computer simulations of protein-DNA interactions in order to complement the empirical method. Combining the two approaches together, we can better understand the mechanism of protein-DNA recognition and improve the target prediction of transcription factors.

关键词： protein-DNA recognition structure-function relation transcription factors target prediction Transcription Factors Gene regulation Target recognition structure activity relation HSP40 Heat-Shock Proteins Specificity DNA Conformation structure-function relationships

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On the role of general system theory for functional neuroimaging

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JOURNAL OF ANATOMY 2004年第6期205卷 443-470页

作者： Stephan, KE UCL Inst Neurol Wellcome Dept Imaging Neurosci London WC1N 3BG England Newcastle Univ Sch Biol Dept Psychol Newcastle Upon Tyne NE1 7RU Tyne & Wear England

One of the most important goals of neuroscience is to establish precise structure-function relationships in the brain. Since the 19th century, a major scientific endeavour has been to associate structurally distinct cortical regions with specific cognitive functions. This was traditionally accomplished by correlating microstructurally defined areas with lesion sites found in patients with specific neuropsychological symptoms. Modern neuroimaging techniques with high spatial resolution have promised an alternative approach, enabling non-invasive measurements of regionally specific changes of brain activity that are correlated with certain components of a cognitive process. Reviewing classic approaches towards brain structure-function relationships that are based on correlational approaches, this article argues that these approaches are not sufficient to provide an understanding of the operational principles of a dynamic system such as the brain but must be complemented by models based on general system theory. These models reflect the connectional structure of the system under investigation and emphasize context-dependent couplings between the system elements in terms of effective connectivity. The usefulness of system models whose parameters are fitted to measured functional imaging data for testing hypotheses about structure-function relationships in the brain and their potential for clinical applications is demonstrated by several empirical examples.

关键词： connectivity fMRI structure-function relationships systems theory

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Mapping of movement in the isometrically contracting human soleus muscle reveals details of its structural and functional complexity

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JOURNAL OF APPLIED PHYSIOLOGY 2003年第5期95卷 2128-2133页

作者： Finni, T Hodgson, JA Lai, AM Edgerton, VR Sinha, S Univ Calif Los Angeles Dept Physiol Sci Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Radiol Los Angeles CA 90095 USA Univ Calif Los Angeles Brain Res Inst Los Angeles CA 90095 USA

It is becoming increasingly apparent that precise knowledge of the anatomic features of muscle, aponeurosis, and tendons is necessary for understanding how a muscle-tendon complex generates force and accomplishes length changes. This report presents both anatomic and functional data from the human soleus muscle acquired by using magnetic resonance imaging. The results show a strong relationship between the complex three-dimensional structure of the muscle-tendon system and the intramuscular distribution of tissue velocities during in vivo isometric contractions. The proximal region of the muscle is unipennate, whereas the midregion has a radially bipennate hemicylindrical structure, and the distal region is quadripennate. Tissue velocity mapping shows that the highest velocity regions overlay the aponeuroses connected to the Achilles tendon. These are located on the anterior and posterior surfaces of the muscle. The lowest velocities overlay the aponeuroses connected to the origin of the muscle and are generally located intramuscularly.

关键词： structure-function relationships modeling compartmentalization biomechanics

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All progestins are not created equal

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STEROIDS 2003年第1-13期68卷 879-890页

作者： Stanczyk, FZ Univ So Calif Womens & Childrens Hosp Keck Sch Med Dept Obstet & Gynecol Los Angeles CA 90033 USA Univ So Calif Womens & Childrens Hosp Keck Sch Med Dept Prevent Med Los Angeles CA 90033 USA

A variety of progestins are available for therapeutic use. It is convenient to classify them into those related in chemical structure to progesterone or testosterone. Progestins related to progesterone can be subdivided into pregnanes and 19-norpregnanes, whereas those related to testosterone can be subdivided into those with and without a 17-ethinyl group. 17-Ethinylated progestins consist of the families of norethindrone (estranes) and levonorgestrel (13-ethylgonanes). Progestins administered orally undergo extensive hepatic first pass metabolism primarily by reduction and conjugation, and in most instances, relatively high progestin doses are required for therapeutic use. There are limited reliable data on the pharmacokinetics of most progestins. Some progestins are prodrugs, requiring transformation prior to exhibiting progestational activity. Qualitative and quantitative tests utilizing either human or animal species have been used to establish progestin potency. However, profound differences in progestational activity are often observed between human and animal tissues. Also, there is a misconception about androgenicity of progestins due largely to extrapolation of data from rat studies to the human. Progestins differ widely in their chemical structures, structure-function relationships, metabolism, pharmacokinetics, and potencies;they are not created equal. (C) 2003 Published by Elsevier Inc.

关键词： progestin structure-function relationships biologic activity metabolism pharmacokinetics potency

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Insulin 3: From chemical synthesis to biological function

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LETTERS IN PEPTIDE SCIENCE 2003年第5-6期10卷 387-391页

作者： Fu, P Bathgate, RAD Tregear, GW Wade, JD Univ Melbourne Howard Florey Inst Melbourne Vic 3010 Australia

Insulin-like peptide 3 (INSL3) is one of ten members of the human insulin superfamily and consists of two peptide chains that contain the characteristic insulin fold and disulfide bond pairings. It is primarily produced in the Leydig cells of the testes, and gene knockout experiments have identified a key biological role as initiating testes descent during foetal development. Its receptor has recently been shown to be a member of the leucine-rich repeat-containing G-protein-coupled receptor family (LGR) and is known as LGR8. Considerable work has recently been undertaken with the aim of studying the mechanism of INSL3 downstream action on responsive cells and, towards this goal, the use of synthetic peptides has proved particularly beneficial. This mini-review outlines how these together with basic structure-function studies are beginning to reveal not only its molecular actions but also its potential new biological actions.

关键词： G-protein-coupled receptor insulin-like peptides INSL3 LGR7 LGR8 solid-phase peptide synthesis structure-function relationships

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