Year-end Sale % OFF 
Abstract
Lysyl oxidase initiates the covalent cross-linking of elastin and collagen, converting lysyl residues in these proteins to peptidyl aldehyde residues. The present study explored structural and electron withdrawing features required to generate mechanism-based inhibitors of this enzyme with antifibrotic potential. It was found that the electron withdrawing nitrile moiety of beta-aminopropionitrile (BAPN), a naturally occurring syncatalytic inhibitor of lysyl oxidase, can be replaced by chlorine, bromine, or the nitro function to yield 2-haloamines or nitroethylamine compounds which also act as mechanism-based irreversible inhibitors of this enzyme. BAPN and 2-bromo- and 2-chloroethylamine exhibit similar KI values of 6-10 microM. However, the enzyme becomes irreversibly inactivated significantly faster by either of the 2-haloamines than by BAPN. 2-Nitroethylamine has by far the poorest affinity for the enzyme and inactivates much more slowly than the other amines of this series, consistent with interference with optimal enzyme-inhibitor interactions by the anionic nitro group. Unlike BAPN, 2-bromoethylamine is processed to a detectable aldehyde product upon incubation with enzyme, showing a partition ratio of 1.2 mol of acetaldehyde formed per mol of 2-bromo-ethylamine which becomes covalently incorporated in the enzyme. The results are consistent with the processing of 2-bromo-ethylamine to an enzyme-ethyleneamine Schiff base subject to hydrolysis to acetaldehyde or to covalent attack at carbon 2 by an enzyme nucleophile. Thus, beta-haloamines represent a new series of suicide inhibitors of lysyl oxidase which can inactivate the enzyme faster than BAPN and hence may have antifibrotic potential.
Highlights
Lysyl oxidase initiates the covalent cross-linkingof eides, hydrazides, and hydrazines, have been reported tohave elastin andcollagen, converting lysyl residuesin these lathyrogenic activity [4].Among these, 0-aminopropionitrile proteins to peptidyl aldehyde residues
BAPN and 2-bromo- and 2-chloroethylamine exhibit similar K I values of 6-10 p ~ H. owever, the enzyme becomes irreversibly inactivated significantly nitrile moiety is essential to the covalent derivatizazion and theirreversible inactivation of lysyl oxidase by this lathyrogen [5].This studyalso revealed that the rate constant for inactivation of lysyl oxidase by BAPN is relatively slow [5]
Materials-Lysyl oxidase was isolated from bovine aorta by a is processed to a detectablealdehydeproduct upon method which yields a mixture of the four species of this enzyme incubation with enzyme, showing a partition ratio of apparently free of other proteins, asjudged by sodium dodecyl sulfate
Summary
Comparisons were made of the effects of various substituted alkylamines on the oxidatioonf the elastin substrateby lysyl oxidase. Substitution at the 0-carbon of the ethylamine structure by nitrile, bromo,chloro, or nitro moieties generates inhibitors of the activity of lysyl oxidase with 160 values of 10-6-10-5 M. 3 3-Br-Propylamine 7 Ethanolamlns a 4-Br-Bulyronltrlle s 2.2.Z-Tritluoroethylamlne turnovers ( 5 ) .3-bromopropylamine and ethanolamine each are effective substrates for lysyl oxidase (Table I). Decrease as the carbon chain length of primary amines increases from 2to 4 to 5, while the V,,, values increase slightly to an apparentmaximum for this series of 4.3 nmol of H20,/. The P-hydroxy group of ethanolamine increases the V,,, and decreases the K , relative to ethylamine, making this acatalyticallymoreefficient substrate than ethylamine. It is of interest that 1,2-diaminoethane is not a substrate while 1,5-diaminopentane is the mosteffective substrate of thosetested in this series of amines
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
