Search results for "Active site"

Amino Acid derivatives as new zinc binding groups for the design of selective matrix metalloproteinase inhibitors.

2012

A number of matrix metalloproteinases (MMPs) are important medicinal targets for conditions ranging from rheumatoid arthritis to cardiomyopathy, periodontal disease, liver cirrhosis, multiple sclerosis, and cancer invasion and metastasis, where they showed to have a dual role, inhibiting or promoting important processes involved in the pathology. MMPs contain a zinc (II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In an effort to devise new approaches to selective inhibitors, in this paper, we describe the synthesis and preliminary biological evaluation of amino acid derivatives as new zinc b…

Kinetics of alkaline phosphatase from pig kidney. Influence of complexing agents on stability and activity

1976

Metal ion-complexing agents, like KCN, EDTA etc., inactivate alkaline phosphatase of pig kidney. This inactivation is reversible at low concentrations of the complexing agents and irreversible at high concentrations. The reversible inhibition is probably due to removal of Zn2+ ions from the active site, where they are necessary for catalytic action, whereas the irreversible inhibition results from the removal of Zn2+ ions necessary for preservation of the structure. The inactivation is pseudo-first order. It depends on the concentration, size and charge of the complexing agents. β-Glycerophosphate and Mg2+ ions protect the enzyme from inactivation by complexing agents. Quantitative examinat…

Nitrate Reductase Activity of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) as a Redox Sensor for Cardiovascular Oxidative Stress

2009

In 2002, mitochondrial aldehyde dehydrogenase (ALDH-2) was identified as an organic nitrate bioactivating enzyme. This so-called nitrate reductase activity denitrates nitroglycerin (glycerol trinitrate) to its 1,2-glycerol dinitrate metabolite and nitrite. This reaction relies on reduced thiols at the active site of the enzyme and on the presence of reduced dithiols as the electron source. During bioconversion of nitroglycerin, and also in the presence of reactive oxygen and nitrogen species, the active site thiols of ALDH-2 are oxidized and the enzyme looses its activity. We, therefore, speculated that ALDH-2 activity could be a useful marker for cardiovascular oxidative stress. Indeed, th…

Acetylcholine esterase: the structure.

1991

Structural and functional models for the dinuclear copper active site in catechol oxidases

2003

Two new mu-methoxo-bridged dinuclear copper(II) complexes with a N-substituted sulfonamide, [Cu(mu-OMe)(L)(NH(3))](2) (1) and [Cu(mu-OMe)(L)(DMSO)](2) (2) [HL, N-2-(4-methylbenzothiazole)benzenesulfonamide], have been prepared and characterized by single-crystal X-ray difraction analyses. Compound 1 crystallizes in the monoclinic space group C(2)/c with a=22.0678(18), b=7.9134(7), c=21.1186(18)A, beta=113.788(4) degrees and Z=8. Compound 2 crystallizes in the monoclinic space group C(2)/c with a=18.0900(10), b=9.5720(10), c=24.2620(10) A, beta=98.7120(10) degrees and Z=8. In both complexes the copper atoms have square-planar environments bridged by two oxygen atoms from methoxide groups. Ma…

A three-dimensional model of mammalian tyrosinase active site accounting for loss of function mutations

2007

Tyrosinases are the first and rate-limiting enzymes in the synthesis of melanin pigments responsible for colouring hair, skin and eyes. Mutation of tyrosinases often decreases melanin production resulting in albinism, but the effects are not always understood at the molecular level. Homology modelling of mouse tyrosinase based on recently published crystal structures of non-mammalian tyrosinases provides an active site model accounting for loss-of-function mutations. According to the model, the copper-binding histidines are located in a helix bundle comprising four densely packed helices. A loop containing residues M374, S375 and V377 connects the CuA and CuB centres, with the peptide oxyge…

Bleomycin, an Antibiotic That Removes Thymine from Double-Stranded DNA

1977

Publisher Summary This chapter reviews that bleomycins are members of a new class of DNA-modifying agents, the quasi-enzymes. In in vitro systems, bleomycin first removes thymines from native DNA by hydrolysis of the N-glycosidic bonds without modifying the deoxyribose moiety. In a second step, single-strand scissions occur at the sites of the nonglycosidic deoxyribose moieties, resulting in the formation of 3'-OH and 5'-P termini. It is suggested that bleomycin is bound to DNA by interaction of the positively charged terminal amine moiety with the negatively charged phosphate group in DNA; intercalation seems to be involved in binding. Bleomycin is inactivated by copper and zinc ions, prob…

Substrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes: In Vitro Enzyme Kinetics and In Silico Modeling

2021

Of the three enzymes in the human cytochrome P450 family 1, CYP1A2 is an important enzyme mediating metabolism of xenobiotics including drugs in the liver, while CYP1A1 and CYP1B1 are expressed in extrahepatic tissues. Currently used CYP substrates, such as 7-ethoxycoumarin and 7-ethoxyresorufin, are oxidized by all individual CYP1 forms. The main aim of this study was to find profluorescent coumarin substrates that are more selective for the individual CYP1 forms. Eleven 3-phenylcoumarin derivatives were synthetized, their enzyme kinetic parameters were determined, and their interactions in the active sites of CYP1 enzymes were analyzed by docking and molecular dynamic simulations. All cou…

Candida antarctica Lipase A-Based Enantiorecognition of a Highly Strained 4-Dibenzocyclooctynol (DIBO) Used for PET Imaging

2020

The enantiomers of aromatic 4-dibenzocyclooctynol (DIBO), used for radiolabeling and subsequent conjugation of biomolecules to form radioligands for positron emission tomography (PET), were separated by kinetic resolution using lipase A from Candida antarctica (CAL-A). In optimized conditions, (R)-DIBO [(R)-1, ee 95%] and its acetylated (S)-ester [(S)-2, ee 96%] were isolated. In silico docking results explained the ability of CAL-A to differentiate the enantiomers of DIBO and to accommodate various acyl donors. Anhydrous MgCl2 was used for binding water from the reaction medium and, thus, for obtaining higher conversion by preventing hydrolysis of the product (S)-2 into the starting materi…

The reduction of molecular oxygen by iron porphyrins

2002

Abstract Molecular assemblies have been synthesised to reproduce the structure of the cytochrome c oxidase (C c O) active site and to explore the roles played by its different features. It was discovered that a single iron porphyrin, adsorbed at the surface of a graphite electrode, is a selective catalyst for the four-electron reduction of dioxygen to water, at pH 7. To cite this article: D. Ricard et al., C. R. Chimie 5 (2002) 33–36