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

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

Water-soluble components of the gas phase of filtered cigarette smoke inhibit formation of covalent desmosine cross-links during conversion of tropoelastin to elastin in vitro. These same smoke components also suppress lysyl-oxidase-catalyzed oxidation of lysine epsilon-amino groups in tropoelastin (the chemical step preceding formation of all elastin cross-links, including desmosine) in a dose-dependent fashion. However, gas phase smoke does not block the oxidation of diaminopentane by lysyl oxidase. Thus, gas phase cigarette smoke may possess substrate-directed (rather than enzyme-directed) inhibitory components capable of interfering with elastin cross-linking in vitro. Similar effects occurring in smokers' lungs could impede elastin repair and contribute to the development of pulmonary emphysema.
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PMID:Cigarette smoke blocks cross-linking of elastin in vitro. 683 36

Elastin contains a number of cross-linking amino acid residues such as desmosine and isodesmosine which are primarily hydrophobic in character, but have a positively charged pyridinium ring. These cross-linking residues are formed by the action of lysyl oxidase upon Lys residues in tropoelastin, a precursor of elastin. A series of tetrapeptide 4-nitroanilides which contain Lys and a series of modified lysine residues were synthesized. The modified lysine residues [epsilon-carbobenzyloxy (Z), epsilon-benzoyl (Bz), epsilon-benzimidoyl (Bim), and epsilon-2-picolinoyl (Pic)] have various characteristics of desmosine and isodesmosine residues, such as a positive charge, a hydrophobic aromatic ring, or a pyridine ring. The reactivity of the tetrapeptide 4-nitroanilides containing the model desmosine residues at P4, P3, or P2 with human leukocyte (HL) and porcine pancreatic (PP) elastase was measured at pH 7.5 and 25 degrees C. HL elastase exhibited high reactivity toward the substrates with P4 or P3 hydrophobic groups (Z, Bz, or Pic), and MeO-Suc-Lys(Pic)-Ala-Pro-Val-NA is 7 times more reactive than the previous best HL elastase substrate, MeO-Suc-Ala-Ala-Pro-Val-NA. The major change occurred in KM values. The substrates containing Lys residues were either nonreactive or poor. Except for two substrates with P2 hydrophobic residues (Bz and Pic), PP elastase was less reactive toward the substrates containing model desmosine residues than toward MeO-Suc-Ala-Ala-Pro-Val-NA. The data support the hypothesis that HL elastase cleaves elastin selectively ner cross-linking residues. The results also indicate that HL elastase binds tightly to these regions and would be poorly effective toward regions of elastin or tropoelastin which contain Lys residues.
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PMID:Reactivity of human leukocyte elastase and porcine pancreatic elastase toward peptide 4-nitroanilides containing model desmosine residues. Evidence that human leukocyte elastase is selective for cross-linked regions of elastin. 691 69

Enzymic hydrolysis, followed by amino acid analysis, provided no evidence for the presence of epsilon-(gamma-glutamyl) lysine or other isopeptide crosslinks in connectin. Gel elecrrophoresis in the presence of sodium dodecyl sulphate did not reveal any difference in connectin between normal and lathyritic muscle, indicating that lysyl oxidase does not initiate cross-link formation in connectin. Although connectin may be covalently crosslinked by some unknown mechanism, the available evidence suggests that the subunit of MW approximately to 900 000 is synthesised as a single polypeptide chain. In developing fetal muscle, myosin heavy chains are apparent some weeks earlier than connectin. This, together with the known susceptibility of connectin to hydrolysis, suggests that connectin exists in an exposed environment rather than as a core to the thick filament.
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PMID:Studies on the structure of connectin in muscle. 717 2

The alignment of elastin molecules in the mature elastic fiber was investigated by purifying and sequencing cross-link-containing peptides generated by proteolytic digestion incompletely cross-linked insoluble elastin. Peptides of interest were purified by reverse phase and size exclusion high performance liquid chromatography and characterized by amino acid analysis and protein sequencing. One peptide, consisting of the cross-linking domain encoded by exon 10, contained a modified lysine residue that had not condensed to form a polyfunctional cross-link. Although this domain contains the characteristic paired lysine residues found in other cross-linking domains of elastin, protein sequence analysis indicated that the first but not the second lysine had been oxidized by lysyl oxidase. This finding suggests that lysine residues in an individual cross-linking domain may not have equal susceptibility to oxidation by lysyl oxidase. In a second peptide, we found that a major cross-linking site in elastin is formed through the association of sequences encoded by exons 10, 19, and 25 and that the three chains are joined together by one desmosine and two lysinonorleucine cross-links. Past structural studies and computer modeling predict that domains 19 and 25 are linked by a desmosine cross-link, while domain 10 bridges domains 19 and 25 through lysinonorleucine cross-links. These findings, together with the high degree of sequence conservation for these three domains, suggest an important function for these regions of the molecule, possibly nucleating the aggregation and polymerization of tropoelastin monomers in the developing elastic fiber.
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PMID:Identification of an elastin cross-linking domain that joins three peptide chains. Possible role in nucleated assembly. 762 78

Lysyl oxidase (EC 1.4.3.13), an extracellular copper amino oxidase, initiates the cross-linking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues. We developed here a polymerase chain reaction (PCR) method for the quantification of lysyl oxidase mRNA in which a synthetic RNA is used as an internal standard for coamplification with the targeted mRNA. The amount of lysyl oxidase mRNA when studied by Northern blot analysis and the number of lysyl oxidase mRNA molecules when determined by the quantitative PCR method were found to be markedly low in various malignantly transformed cell lines relative to control cell lines, quantitative PCR indicating values of about 2-10% of those in the controls. No difference was found in the number of beta-actin mRNA molecules between the transformed cells and the controls. Nuclear runoff experiments indicated that most if not all of the decrease in the number of lysyl oxidase mRNA molecules can be explained by diminished transcription of the respective gene.
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PMID:Quantitative polymerase chain reaction of lysyl oxidase mRNA in malignantly transformed human cell lines demonstrates that their low lysyl oxidase activity is due to low quantities of its mRNA and low levels of transcription of the respective gene. 766 72

Lysyl oxidase oxidizes peptidyl lysine in collagen and elastin substrates to residues of alpha-aminoadipic-delta-semialdehyde. The peptidyl aldehydes can then undergo spontaneous condensations with unreacted epsilon-amino groups and with neighboring aldehyde functions, thus forming the covalent crosslinkages which convert elastin and collagen into insoluble fibers. The unique role of lysyl oxidase in the post-translational modification of these proteins qualifies this enzymatic reaction as a potentially pivotal site of biological and/or chemotherapeutic control of collagen fiber deposition. Recent advances in the study of the catalytic mechanism, in the development of active site inhibitors, and in the biosynthesis and regulation of this unusual catalyst are reviewed as are studies on the response of lysyl oxidase in fibrotic liver.
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PMID:Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis. 789 40

Lysyl oxidase (EC 1.4.3.13), an extracellular copper enzyme, initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues. We report here that the human lysyl oxidase gene is about 15 kb in size and consists of seven exons. Transcription is initiated at one major site and four minor sites, and the first exon consists of 273 bp of untranslated sequences (calculated to the major site) and 631 bp of translated sequences, which accounts for about half of all the translated sequences of the gene. The seventh exon, on the other hand, codes for only the last codon of amino acid 416 and for amino acid 417, which are followed by the translation termination codon and the 3' untranslated sequences. Exons 2-6 vary in size from 96 to 157 bp, and the introns from 331 bp to about 3.5 kb. The 5' flanking region contains a TATA-like sequence at -30 relative to the major transcription initiation site and a CCAAT motif at -109. The 5' flanking region and the downstream sequences present in the first exon and first intron contain altogether five possible binding sequences for Sp1, six for AP-2, one for AP-1, three for PEA3, three for MEP-1, and three CCCTCCC motifs, all of which may be involved in the regulation of the expression of the gene.
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PMID:Structure of the human lysyl oxidase gene. 790 22

The substrate specificity of lysyl oxidase has been explored with synthetic oligopeptides. kcat/Km increased with increasing peptide length in Ac-(Gly)n-Lys-(Gly)n-CONH2 (n = 1-5). Using 11-mers as the standard peptide length, Glu immediately N-terminal to Lys increased kcat/Km 8.8-fold over that for the -Lys-Glu- sequence and 4.9-fold over the glutamate-free control. Kinetic constants were significantly less perturbed when Glu was 2 or more residues distant from Lys. Replacement of Glu in -Glu-Lys- with Gln significantly increased Km and lowered kcat/Km. Asp rather than Glu N-terminal to Lys decreased Km similar to that of the -Glu-Lys- 11-mer, although the kcat decreased considerably, indicating that lysyl oxidase responds to the side chain length of vicinal Asp or Glu at this position. -Asp-Glu-Lys- within an 11-mer was not oxidized, although this sequence is oxidized within the N-terminal telopeptide of the alpha 1(I) chain in type I collagen fibrils. Thus, lysyl oxidase exhibits distinct preferences for sequences vicinal to lysine. These results are discussed with respect to a model requiring collagen fibril formation prior to oxidation of lysine in collagen by lysyl oxidase.
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PMID:Modulation of lysyl oxidase activity toward peptidyl lysine by vicinal dicarboxylic amino acid residues. Implications for collagen cross-linking. 791 81

The use of recombinant human tropoelastin (rTE) and selected variants thereof as substrates for the assay of lysyl oxidase activity in vitro was explored. The possibility was also assessed that an insoluble elastin-like product could be generated from this elastin precursor in the absence of other macromolecules found associated with elastin in vivo. rTE was more efficiently oxidized by lysyl oxidase than the insoluble chick aorta elastin substrate conventionally used. Anionic amphiphilic elastin ligands strongly inhibited rTE oxidation consistent with the importance of electrostatic enzyme-substrate interactions previously noted with the insoluble elastin substrate. An rTE variant, rTE delta 26A, lacking the hydrophilic sequence coded by exon 26A, was a less effective substrate than rTE, largely due to an increase in Km, while the kinetic parameters for the oxidation of rTE delta 36, lacking the C-terminal polybasic sequence coded by exon 36, were quite similar to those for rTE. Incubation of rTE delta 26A with lysyl oxidase not only resulted in the generation of peptidyl alpha-aminoadipic-delta-semialdehyde and lysine-derived cross-linkages, but also yielded a product insoluble in hot 0.1 N NaOH, consistent with the properties of insoluble elastin. Thus, oxidation, cross-linking and insolubilization of elastin substrates by lysyl oxidase can occur in the absence of other macromolecules implicated as being involved in this process in vivo, although such macromolecules may be essential to obtain the proper alignment between tropoelastin units for specifically placed cross-linkages and optimally functional elastic fibers.
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PMID:Oxidation, cross-linking, and insolubilization of recombinant tropoelastin by purified lysyl oxidase. 809 38

trans-2-Phenylcyclopropylamine hydrochloride (tranylcypromine; TCP) was found to be both an inhibitor and a substrate of lysyl oxidase, the enzyme which oxidizes peptidyl lysine in elastin and collagen to initiate cross-linking in these proteins. The reaction of TCP with this enzyme was further characterized in view of the potential interference that chronic administration of this antidepressant compound may exert on the development and repair of connective tissues. In contrast to the irreversible and/or competitive inhibitors of lysyl oxidase previously described, TCP noncompetitively and reversibly inhibited the oxidation of both alkylamine and elastin substrates with Ki values of 386 and 375 microM, respectively. The noncompetitive mode of interaction affected the accessibility of the active site to productive amine substrates since the reductive trapping of n-hexylamine to lysyl oxidase was largely prevented by the presence of TCP. It was of additional interest that lysyl oxidase catalyzed a limited degree of conversion of TCP to cinnamaldehyde accompanied by the production of hydrogen peroxide. The lack of significant incorporation of protein-bound tritium accompanying reduction of the enzyme-TCP complex with [3H]NaBH4 argued against the formation of a Schiff base between the enzyme and the cinnamaldehyde product as the basis of the inhibitory effect. Spectral evidence was also obtained for an additional interaction between TCP and lysyl oxidase that was independent of the inhibitory effect of TCP. Cyclopropylamine, lacking the benzene moiety of TCP, inhibited lysyl oxidase irreversibly and competitively, and was not a substrate, pointing toward a defining role for the benzene moiety in the interaction of TCP with lysyl oxidase.
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PMID:Reaction of lysyl oxidase with trans-2-phenylcyclopropylamine. 809 55


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