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

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

Experimental lathyrism was induced by feeding newborn chicks a diet containing 0.2 and 0.4% DL-Penicillamine, with or without CuSO4 (10 mg/Kg diet) and Vitamin B6 (100 mg/Kg diet), or 0.015 and 0.1% beta-aminopropionitrile fumarate (beta-APN). After 7, 15, 25 and 55 days of treatment the animals were killed, the aortas removed and processed for electron microscopy in the presence of markers for proteoglycans, and the elastic fibers were carefully examined. Penicillamine, which prevents the formation of desmosine crosslinks by binding to precursors, induced the production of numerous new elastin fibers which appeared normal from the ultrastructural point of view. It seems, therefore, that at least in chick aortas, desmosine crosslinks are not necessary for the aggregation of tropoelastin molecules into structurally normal fibers. On the contrary, beta-APN, a classical inhibitor of lysyl oxidase, induced the tropoelastin molecules to aggregate into abnormal protuberances on the old fibers. Moreover, the elastin deposited during beta-APN treatment was always permeated by cytochemically revealed proteoglycans, which were never observed after penicillamine treatment. It is speculated that, at least in the system under study, the epsilon-amino groups of tropoelastin molecules may offer the binding sites for matrix proteoglycans until they are removed by lysyl oxidase, and that matrix proteoglycans might play a role in elastin fibrogenesis by preventing spontaneous tropoelastin aggregation in areas far from growing elastin fibers.
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PMID:Alterations of elastin fibrogenesis by inhibition of the formation of desmosine crosslinks. Comparison between the effect of beta-aminopropionitrile (beta-APN) and penicillamine. 293 20