Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.4.3.13 (lysyl oxidase)
1,248 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oxidation of an elastin substrate by highly purified bovine aortic lysyl oxidase (LO) is markedly influenced by amphiphilic molecules known to bind to elastin. Negatively charged elastin ligands, including fatty acids, bile salts or sodium dodecyl sulfate can completely inhibit the oxidation of lysine in elastin, the cationic amphiphilic ligands stimulate the enzymatic reaction five-fold, while small hydrophilic molecules of either charge or neutral detergents have no effect. In addition, evidence has been obtained that changes in the conformation of a synthetic polypeptide substrate markedly alter its susceptibility to LO. The coacervated state of the substrate is most readily oxidized and crosslinked by the enzyme. These results point to the importance of small ligands, electrostatic charge, and conformation as substrate-directed influences which can control the expression of LO activity.
...
PMID:Substrate-directed modulation of elastin oxidation by lysyl oxidase. 611 10

Elastin is synthesized by fibroblasts and chondroblasts in cell culture shortly before the cells become confluent. Fibroblasts secrete elastin into the medium as soluble tropoelastin molecules, which form desmosine crosslinks and become constituents of the cell layer only after three weeks in culture. Even then only a small fraction of the available tropoelastin molecules from crosslinks. Conversely, the chondrocytes secrete an elastin which never reaches the media as soluble elastin in significant quantities. Crosslinking occurs immediately in the chondroblast cell layer forming stable, insoluble elastic fibers. Both cells in culture produce lysyl oxidase at approximately the same levels. The reason for the marked differences between these cells in the mode of conversion of soluble elastin to insoluble elastin is not known. The suggestion of Mecham that the extracellular matrix may play a major role in the development of elastogenesis may provide an answer.
...
PMID:Desmosine radioimmunoassay as a means of studying elastogenesis in cell culture. 611 11

A mild form of emphysema was produced in pigs raised on a copper-deficient, zinc-supplemented diet. The copper-requiring enzyme, lysyl oxidase, catalyzes the cross-linking of tropoelastin into mature elastin. Zinc further inhibits the activity of lysyl oxidase. Lungs from animals raised on copper-deficient, zinc-supplemented diets of demonstrate perforations in alveolar walls and diminished amounts of elastin bronchi and pulmonary arteries. Mean linear intercepts are greater and alveolar internal surface areas are less than those in control animals, fulfilling the generally accepted definition of emphysema. Physiologic confirmation is provided by a leftward shift of the saline volume-pressure curves when compared with those in control animals. Ultrastructurally, the alveolar walls are effaced and pores of Kohn are enlarged. There are areas in which elastin is absent leaving remnant microfibrils, and there are other changes consistent with active elastin synthesis. Biochemical data demonstrate no difference in elastin content as micrograms/ml of fat-free dry weight but do demonstrate increased collagen content in experimental animal lungs compared with that in control lungs. Ultrastructural similarities to enzyme-induced models of emphysema suggest the presence of elastin degradation in our model. We speculate that although the copper-deficient, zinc-supplemented state may stimulate protein synthesis in general, elastin is being degraded by endogenous means, but collagen is not.
...
PMID:A copper-deficient, zinc-supplemented diet produces emphysema in pigs. 612 18

D-penicillamine, added to a low copper diet fed through pregnancy or given by gavage to pregnant rts which were on a copper-deficient or a normal diet produced fetal resorptions and malformations. Doses of 300 to 400 mg per day for 6 days (days 9-14 or gestation) with a diet normal for copper prevented maternal weight gain and at 350 or 400 mg/day caused fetal death on day 16 or 17. Forty percent of offspring had tracheobronchomegaly and 42% had cystic lungs. Associated abnormalities included pleural hemorrhages, dilated esophagi, and anaerated lungs. The lungs had large, poorly formed, thick-walled acini without partitioning and a thick rim of connective tissue around vessels and bronchi. At the higher doses, all members of one of 12 litters had angulation of the spine and half the members of another litter had cleft palates. A postulated mechanism for these alterations in pulmonary connective tissue productive of malformations which model human tracheobronchomegaly and cystic lungs, is interference with lysyl oxidase, a copper-requiring enzyme, which cross-links elastin.
...
PMID:Neonatal deaths and pulmonary dysplasia due to D-penicillamine in the rat. 612 15

The synthesis of collagen (measured as the formation of non-dialyzable hydroxyproline) and other proteins, and the activity of lysyl oxidase, the enzyme responsible for the formation of cross-links in elastin and collagen, were measured in cultured human aortic smooth muscle cells in the presence of various cortisol concentrations. In addition, the effect of cortisol on the proliferation of the cells was also studied. At concentrations of 10(-6) M and greater, cortisol retarded cell growth markedly, as judged by decreased incorporation of 3H-thymidine by the cells and decreased DNA content of the cultures. At the same concentrations, cortisol increased the synthesis of collagen and other proteins. The magnitude of the increase was similar for collagen and other proteins. The activity of lysyl oxidase was also increased in the presence of 10(-6) and 10(-5) M cortisol, but to a lesser extent than the synthesis of collagen. Other studies using cultured cells have shown that cortisol decreases the synthesis of hyaluronic acid but not of sulphated glycosaminoglycans by smooth muscle cells and does not injure endothelial cells. Considering these findings in the light of the present results, it is suggested that cortisol induces changes in the metabolism of connective tissue macromolecules of smooth muscle cells that can be regarded as atherogenic. However, some other important biological changes associated with atherogenesis (smooth muscle cell proliferation and endothelial injury) do not occur in vascular cells exposed to cortisol.
...
PMID:Effect of cortisol on the proliferation and protein synthesis of human aortic smooth muscle cells in culture. 612 4

Lysyl oxidase purified from bovine aorta can oxidize simple alkyl mono- and diamine substrates yielding the respective aldehyde, H2O2, and ammonia as products. The oxidation of such substrates is limited to approximately 100 catalytic turnovers per enzyme molecule since lysyl oxidase is syncatalytically and irreversibly inactivated in the course of oxidation of these amines. The present study reveals that addition of oxidant scavengers protects significantly against inactivation of lysyl oxidase and that the ammonia product is a reversible competitive inhibitor of amine oxidation. Further, the enzyme becomes covalently labeled by the amine substrate or its enzyme-processed derivative during catalysis. Thus, lysyl oxidase appears subject to multiple modes of catalysis-dependent inhibition or inactivation. Syncatalytic inactivation of lysyl oxidase might represent a means of restricting the activity of this enzyme toward its elastin and collagen substrates in vivo.
...
PMID:Multiple modes of catalysis-dependent inhibition and inactivation of aortic lysyl oxidase. 613 46

beta-Aminopropionitrile (BAPN) is a potent irreversible inhibitor of lysyl oxidase, the enzyme which initiates cross-linkage formation in elastin and collagen. The initial interaction of BAPN with aortic lysyl oxidase is competitive with elastin or alkyl amine substrates. Irreversible inhibition develops in a time- and temperature-dependent fashion upon incubation of enzyme with BAPN in the absence of substrate with a limiting inactivation rate constant of 0.16 min-1 and a KI of 6 microM at 37 degrees C. The labeled carbons of [1,2-14C]BAPN and [3-14C]BAPN covalently bind to the enzyme to equivalent extents and in parallel with the development of inactivation, negating the possibility that the nitrile moiety is eliminated from BAPN by enzymatic action. The copper content of the enzyme is not significantly altered upon interaction with BAPN. The extent of labeling by [14C]BAPN is reduced by prior treatment of the enzyme with carbonyl-modifying reagents, suggesting the possibility of enzyme-inhibitor Schiff base formation. However, BAPN is not processed to a free aldehyde product upon incubation with lysyl oxidase. A mechanism of inhibition is postulated which involves the formation of a covalent bond between an enzyme nucleophile and a ketenimine formed from BAPN by enzyme-assisted beta-proton abstraction.
...
PMID:Reaction of aortic lysyl oxidase with beta-aminopropionitrile. 613 92

In the presence of ascorbate, there is an increase in collagen synthesis with a concomitant decrease in insoluble elastin and lysyl oxidase activity in cultured rabbit aortic smooth muscle cells. While the addition of 0.5 micrograms ascorbate per ml of medium enhances collagen synthesis and accumulation, detectable insoluble elastin and lysyl oxidase activity remain essentially unchanged. However, at 2 micrograms ascorbate per ml, the integrity of the insoluble elastin is lost and lysyl oxidase activity is decreased. These studies suggest that by modifying the levels of ascorbate in the culture medium one can alter the nature of the extracellular matrix produced by the smooth muscle cells.
...
PMID:Effect of varying amounts of ascorbate on collagen, elastin and lysyl oxidase synthesis in aortic smooth muscle cell cultures. 614 Sep 57

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.
...
PMID:Beta-substituted ethylamine derivatives as suicide inhibitors of lysyl oxidase. 614 Nov 64

Lysyl oxidase initiates the covalent cross-linking of elastin and collagen by oxidizing lysine residues in these proteins to alpha-aminoadipic-delta-semialdehyde. Sequences surrounding susceptible lysines in elastin are considerably different from those in collagen and yet the same enzyme can oxidize both substrates. Possible bases of the specificity have been explored assaying for H2O2 release accompanying the oxidation of synthetic peptide and protein substrates. Rates of oxidation of random co-polymers were maximal with (Ala,Lys)n and decreased in the order (Val,Lys)n greater than (Leu,Lys)n greater than (Lys)n greater than (Phe,Lys)n greater than (Tyr,Lys)n. The ordered polymer (Ala-Lys-Glu)n was oxidized at only 3% of the rate of (Ala,Lys)n, implying inhibition by peptidyl glutamate. Consistent with this conclusion, kinetic analyses using ordered oligopeptides revealed that, relative to Ala-Ala-Lys-Ala-Ala, Km is increased 9.3-fold for lysine in Ala-Ala-Lys-Glu-Ala-Ala, 2.5-fold in Ala-Ala-Lys-Arg-Ala-Ala, and 1.8-fold in Ala-Ala-Glu-Lys-Ala-Ala. Tyrosine C-terminal to lysine in such peptides also increases Km 5-fold. In addition, lysyl oxidase oxidized lysine in various proteins with basic isoelectric points and was much less or not active against various acidic proteins. Lysyl oxidase was inactive against native bovine serum albumin but effectively oxidized albumin if albumin carboxyl functions were first amidated by chemical modification. These results suggest that peptides bind to lysyl oxidase in a preferred directional sense and indicate-that net anionic character as well as the specific position of anionic residues in substrates can selectively effect substrate potential. Implications of these results for the oxidation of elastin and collagen are discussed.
...
PMID:Influence of sequence and charge on the specificity of lysyl oxidase toward protein and synthetic peptide substrates. 614 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---