Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.4.3.13 (lysyl oxidase)
 1,248 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although D-Penicillamine (D-PeA) administration is getting popular in the treatment of rheumatoid arthritis (RA), the mechanism by which D-PeA produced therapeutic effect has not been fully elucidated. D-PeA had been shown to exert an antivitamine B6 effect. However, it has not been precisely confirmed if clinical dose of D-PeA induces vitamine B6 (VB6) deficiency. In order to clarify these questions, biochemical analyses of bone and skin collagens and determination of VB6 content in soft tissues have been performed in the rats administrated therapeutic dose of D-PeA. VB6 deficiency was not observed in the brain and skin from rats fed on normal diet containing D-PeA (13.0--33.5 mg/kg wt). There were no significant changes in the stability of collagen from bone and skin. On the other hand, significant VB6 deficiency and reduced stability of collagen were observed in rats fed on VB6 deficient diet containing the same amount of D-PeA. Aldehyde formation of collagen molecule and cross-link formation of collagen were also found to be suppressed. The same results were obtained from analyses in rats fed on VB6 deficient diet without D-PeA administration. These data indicate that D-PeA is not capable of producing VB6 deficiency in the dosage employed in patients. However, in the treatment for patients who are not taking enough nutrition, the possibility of VB6 deficiency can not be neglected. Once VB6 deficiency is induced by D-PeA administration, severe connective tissue disorder may be produced, since VB6 is required for enzymic activity of lysyl oxidase. It is unlikely that the therapeutic effects of D-PeA in the treatment of RA are produced the the disturbance of collagen cross-link formation as discussed before. Immunologic reactions of D-PeA may play more important role in the improvement of clinical symptoms of this disease.
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PMID:[Effect of D-penicillamine on vitamine B6 and collagen metabolism (author's transl)]. 52 98

A protective and curative effect of some flavonoids on collagen maturation in lathyrism has been previously demonstrated. This action appeared to involve cross linking of collagen. This paper deals with the effect in vitro of flavonoids and flavonoid-copper complexes on the oxidative deamination of lysine epsilon-amino groups in [4,5-3H]-lysine-labelled elastin. Flavonoids alone do not affect the reaction but it is evident that some flavonoid copper complexes are strongly effective: the aldehyde groups that are quickly formed then enable cross linking to occur. The lysine epsilon-amino groups of elastin are specifically concerned: in fact no effect was observed on free [4,5-3H]-lysine or on [4,5-3H]-lysine-labelled proteins obtained from mouse liver. The lysyl oxidase seems to interfere with the flavonoid-copper complees to regulate the oxidative deamination of lysine epsilon-amino groups.
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PMID:Influence of flavonoid-copper complexes on cross linking in elastin. 56 63

Procollagen synthesized by freshly excised chick enbryo leg tendons is efficiently processed by proteolytic removal of first the amino propeptides and then the carboxyl propeptides. The same processes proceed in confluent short term cell cultures derived from such tendon explants; in sparse cultures cleavage of the amino propeptides predominates. Separate amino and carboxyl procollagen peptidase activities were demonstrated by specific assays in enzymes obtained from cell culture media by ammonium sulfate precipitation, ion exchange chromatography, and velocity sedimentation. Both enzymes are inhibited by EDTA and 1:10 phenanthroline but not by inhibitors of serine proteases. Evidence is provided that the proteolytic scissions are specific and similar to the physiologically occurring processes. The collagen telopeptides left after cutting by the enzymes can participate in lysyl oxidase-induced cross-linking. The enzymes can remove propeptides from cross-linked procollagens without destroying these links which occur through telopeptides. The enzymes act on the separated amino and carboxyl portions of procollagen fragmented by vertebrate collagenase and can act on procollagens which have been associated as well as on molecules in solution.
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PMID:Separate amino and carboxyl procollagen peptidases in chick embryo tendon. 56 51

Nutritional copper deficiency effects marked changes in the crosslinking of collagen and elastin, presumably in relationship to copper's role as a cofactor for lysyl oxidase. Lysyl oxidase controls one of the initial steps in the crosslinking of elastin and collagen, i.e., the conversion of peptidyl lysine or hydroxylysine residues to peptidyl alpha-aminoadipic-delta-semialdehyde derivatives. Once lysine-derived aldehydic functions in collagen and elastin are formed, crosslinks occur via aldol and Schiff-base type condensations. A decrease in the degree of crosslinking results in changes in the biomechanical properties of both collagen- and elastin-rich tissues. Some of these changes are described with respect to chick bone and aorta. Likewise, penicillamine blocks crosslinking reactions. In this case, however, it is probably because of the formation of thiazolidine complexes between penicillamine aldehydic functions. The administration of penicillamine at different levels to young growing chicks allows the isolation of fibrous insoluble elastin varying in aldehyde content.
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PMID:Nutritional copper deficiency and penicillamine administration: some effects on bone collagen and arterial elastin crosslinking. 90 29

beta-Aminopropionitrile (BAPN) is an inhibitor of the lysyl oxidase required for cross-link formation in collagen maturation. The efficacy of BAPN, alone or in association with the anti-schistosomal drug, praziquantel (PZQ), was primarily assessed by measuring the reduction in liver and intestinal egg loads in murine schistosomiasis mansoni. Depending on the treatment group (PZQ, BAPN, BAPN + PZQ), organ-specific effects were observed using microscope image analysis. Most notable was the relatively small size of granulomas in the livers of BAPN-treated mice, which contrasted with the relatively large size and irregular shape of the granulomas in the intestinal tissues of these mice. Mice treated with the combination of BAPN and PZQ had decreased liver and spleen weights, and a significant reduction in the number of eggs trapped in both the liver (86%) and the intestine (99.1%), compared with untreated mice and those given PZQ alone. The lowest number of living eggs/g of tissue in both the liver and intestine was recorded in the combined BAPN + PZQ-treated group. These results suggest that the concurren treatment of infected mice with PZQ and BAPN enhances the release of eggs trapped in the intestine and also results in a significant reduction of liver egg load. The mechanism by which BAPN reduces the number of liver granulomas in PZQ-treated mice is currently being investigated.
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PMID:Experimental schistosomiasis mansoni: modulation of granulomas by inhibition of collagen cross-link formation. Preliminary report. 130 5

Various o- and p-quinones were assessed as oxidants of peptidyl lysine in elastin and collagen substrates in the presence and absence of divalent copper as paradigms of protein-lysine 6-oxidase (lysyl oxidase) which contains both quinone and copper cofactors. Pyrroloquinoline quinone was among the most active in the absence and the most active of the o- and p-quinones tested in the presence of copper. The optimal rate of elastin oxidation occurred at a 2:1 PQQ/Cu(II) ratio while Cu(II) itself oxidized elastin relatively slightly. Elastin oxidation by 2:1 PQQ/Cu(II) required aerobic conditions consistent with oxygen-dependent turnover of this catalytic pair. Dimethylsulfoxide and catalase individually or in combination inhibited elastin oxidation by PQQ/Cu(II) by approx. 50%, suggesting that oxygen free radical species participate in the reaction. Amino-acid analysis of elastin and collagen substrates oxidized by 2:1 PQQ/Cu and then reduced with borohydride revealed that alpha-aminoadipic-delta-semialdehyde and lesser amounts of covalent cross-linkages were generated by this oxidant. In contrast, lysine oxidase produced aldehydes and significantly greater quantities of cross-linkage products, consistent with the known specificity of the enzyme. These data, thus, indicate the potential for free quinones, such as PQQ, particularly when stimulated by appropriate metal ions, to act as adventitious oxidants of lysine side-chains in proteins.
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PMID:Oxidation of peptidyl lysine by copper complexes of pyrroloquinoline quinone and other quinones. A model for oxidative pathochemistry. 132 61

Knowledge regarding the steps and mechanisms related to the intra- and interchain cross-linking of collagen and elastin has evolved steadily during the past 30 years. Recently, effort has been directed at identifying the location and types of cross-links that are found in collagen and elastin. There are two major groups of cross-links: those initiated by the enzyme lysyl oxidase and those derived from nonenzymatically glycated lysine and hydroxylysine residues. The formation of enzymatic cross-links depends on specific enzymes, amino acid sequences, and quaternary structural arrangements. The cross-links that are derived nonenzymatically occur more adventitiously and are important to pathobiological processes. Considerable progress has been made in elucidating the pathways of synthesis for several of the enzymatically mediated cross-links, as well as possible mechanisms regulating the specificity of cross-linking. Although less is known about the chemistry of cross-links arising from nonenzymatically glycated residues, recent progress has also been made in understanding possible biosynthetic pathways and control mechanisms. This review focuses on such progress and hopes to underscore the biological importance of collagen and elastin cross-linking.
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PMID:Enzymatic and nonenzymatic cross-linking of collagen and elastin. 134 14

Lysyl oxidase (EC 1.4.3.13) is a copper-dependent enzyme acting principally on collagen and elastin catalyzing the formation of aldehyde cross-links. It is also believed to possess a tumor suppressor activity as the anti-oncogene of ras. While rat, human, and mouse lysyl oxidase cDNAs have been cloned, little is known about the structure of the gene, its organization, or regulation. This paper describes the cloning of an intronic segment of the human lysyl oxidase gene. Sequence analysis defined the location of an intron that separates the prepro-coding segments from the segment encoding the catalytic domain. Genomic restriction mapping and gene copy number data established that multiple lysyl oxidase mRNA transcripts originate from a single gene and thus are products of alternative splicing. Northern analysis of adult and fetal fibroblast RNA showed a dominant approximately 4.3-kilobase lysyl oxidase mRNA transcript that varied in abundance as a function of cell line. These data are consistent with a complex mechanism regulating the expression of the lysyl oxidase gene.
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PMID:Characterization of the human lysyl oxidase gene locus. 135 76

Lysyl oxidase catalyzes the oxidation of lysine residues to alpha-aminoadipic-delta-semialdehyde. This is the first step in the covalent cross-linking of collagen and tropoelastin and results in the formation of insoluble collagen and elastic fibers in the extracellular matrix. We have characterized the complete nucleotide sequence of human lysyl oxidase (EC 1.4.3.13) and compared the derived amino acid sequence (417-amino acids) to rat lysyl oxidase and the mouse ras recision gene (rrg). 88% of amino acids and 83% of nucleotides were conserved between human and rat lysyl oxidase. The mouse ras recision gene demonstrated 89% conservation of amino acids with human lysyl oxidase. The sequence conservation was not evenly distributed along the molecule. The carboxy terminus of the protein, which contains the putative copper binding sites and is likely to be the catalytically active domain, was more highly conserved than the amino terminus. The 89% amino acid sequence similarity between the murine ras recision gene and human lysyl oxidase suggests that they are the same gene product. Therefore, in addition to cross linking of extracellular matrix proteins, lysyl oxidase may have a direct role in tumor suppression. Northern blot analysis of poly A+RNA from cultured skin fibroblasts revealed at least three-distinct transcripts, sized 4.8 kb, 3.8 kb and 2.0 kb. In addition, using a panel of human mouse cell hybrids, the lysyl oxidase gene was assigned to human chromosome 5.
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PMID:The complete derived amino acid sequence of human lysyl oxidase and assignment of the gene to chromosome 5 (extensive sequence homology with the murine ras recision gene). 135 35

Lysyl oxidase, which cross-links collagen and elastin, was obtained from chick embryo bone and cartilage and its substrate, elastin, from aorta. The enzyme was studied using an improved assay which enabled the stability of the substrate to be monitored. The enzyme was fully inhibited in vivo by beta-aminopropionitrile, semicarbazide, thiosemicarbazide and isoniazid and in vitro by beta-aminopropionitrile and semicarbazide but only partially by thiosemicarbazide and isoniazid. Penicillamine, which solubilizes collagen by labilizing Schiff base cross-links in vivo and which prevents stable cross-link formation in vitro indirectly by binding to aldehyde groups on collagen, was shown to have no direct inhibitory effect on lysyl oxidase in vivo or in vitro. Homocysteine, which also solubilizes collagen by a mechanism similar to penicillamine does not inhibit lysyl oxidase either in vivo or in vitro. Pyridoxal reversed the inhibition of lysyl oxidase by semicarbazide and isoniazid in vivo but was unable to reverse that produced by either beta-aminopropionitrile or thiosemicarbazide. These results can be explained by the presence of a sulphydryl group near the active site of lysyl oxidase, which can form a complex with the nitrile group on beta-aminopropionitrile or with the thiol group on thiosemicarbazide leading to irreversible inhibition.
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PMID:Inhibition of chick embryo lysyl oxidase by various lathyrogens and the antagonistic effect of pyridoxal. 135 70


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