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)

The collagens are the major structural glycoproteins of connective tissues. A unique primary structure and a multiplicity of post-translational modification reactions are required for normal fibrillogenesis. The post-translational modifications include hydroxylation of prolyl and lysyl residues, glycosylation, folding of the molecule into triple-helical conformation, proteolytic conversion of precursor procollagen to collagen, and oxidative deamination of certain lysyl and hydroxylysyl residues. Any defect in the normal mechanisms responsible for the synthesis and secretion of collagen molecules or the deposition of these molecules into extracellular fibers could result in abnormal fibrillogenesis; such defects could result in a connective tissue disease. Recently, defects in the regulation of the types of collagen synthesized and in the enzymes involved in the post-translational modifications have been found in heritable diseases of connective tissue. Thus far, the primary heritable disorders of collagen metabolism in man include lysyl hydroxylase deficiency in Ehlers-Danlos syndrome type VI, p-collagen peptidase deficency in Ehlers-Danlos syndrome type VII, decreased synthesis of type III collagen in Ehlers-Danlos syndrome type IV, lysyl oxidase deficency in S-linked cutis laxa and Ehlers-Danlos syndrome type V, and decreased synthesis of type I collagen in osteogenesis imperfecta.
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PMID:Defects in the biochemistry of collagen in diseases of connective tissue. 0 48

Lysyl oxidase catalyzes the crosslinking of collagen and elastin. Lysyl oxidase activity was measured and localized in rat liver during the evolution of hepatic fibrosis induced by CCl4. Enzyme activity measured with DL-[6-3H]-lysine-labeled collagen substrates in liver and plasma increased sharply after approximately 3 wk of injection, reached a maximum at 6 wk, and then decreased. The increase in activity correlated histologically with early connective tissue septa formation, and the magnitude of increase was significantly greater than that found for the intracellular collagen biosynthetic enzymes protocollagen prolyl hydroxylase and lysyl hydroxylase. Indirect immunofluorescence studies showed that lysyl oxidase was present in association with collagen in the extracellular space. However, it was not possible to correlate the distribution pattern with a particular liver cell type. These observations suggest that serial measurements of lysyl oxidase activity in liver or plasma may be useful for correlating changes in connective tissue formation with histologic connective tissue deposition.
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PMID:Biochemical and immunochemical study of lysyl oxidase in experimental hepatic fibrosis in the rat. 2 18

Prolyl hydroxylase [EC 1.14.11.2] was shown to be inhibited by an ultrafiltrate (less than 30,000 molecular weight) fraction isolated from skin and blood of neonatal and adult rabbits. This fraction also inhibited two other alpha-ketoglutarate requiring mixed function oxidases, lysyl hydroxylase [EC 1.14.11.4] and alpha-butyrobetaine hydroxylase [EC 1.14.11.1] but not the amine oxidase, lysyl oxidase. Purification of the skin ultrafiltrate on Sephadex G-25 demonstrated a peak of prolyl hydroxylase inhibitory activity which chromatographed at a molecular weight corresponding to approximately 3,000. Chromatography of a blood ultrafiltrate separated a similar peak of material which was inhibitory for prolyl hydroxylase.
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PMID:Evidence for the presence of an endogenous inhibition of prolyl hydroxylase. 625 23

Several abnormalities in collagen biosynthesis have been described in patients with Ehlers-Danlos syndrome. Examples of collagen structural mutations as well as post-translational enzymatic defects have been detected. Patients with hydroxylysine-deficient collagen disease (Ehlers-Danlos type VI) have diminished lysyl hydroxylase activity. One mutant enzyme has been characterized which is thermally labile and had an altered affinity for ascorbate. Another mutant enzyme had a normal requirement for cofactors but activity was diminished. Type VII Ehlers-Danlos syndrome is associated with altered processing of procollagen to collagen. Most often the disorder is associated with deficient procollagen aminoprotease activity. One patient appears to represent a structural mutation of pro alpha 2 (I) resulting in incomplete cleavage of the amino terminal propeptide. One family with x-linked Ehlers-Danlos syndrome (type V) has been described with altered lysyl oxidase activity. Other patients with this disorder have had normal lysyl oxidase activity. The ecchymotic form of Ehlers-Danlos syndrome (type IV) has defective type III collagen-synthesis. Patients have been described with absent synthesis, diminished synthesis and diminished secretion.
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PMID:Molecular defects in the Ehlers-Danlos syndrome. 708 95

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders characterized clinically by skin fragility, skin hyperextensibility, joint hypermobility, and excessive bruising. At least 10 different subtypes of EDS have been classified based on genetic, biochemical, and clinical characteristics. Recent advances in the molecular analysis of EDS have identified defects responsible for EDS IV (mutations in the type III collagen gene), EDS VI (homozygous and compound heterozygous mutations in the lysyl hydroxylase gene), EDS VIIA and VIIB (mutations in the type I collagen genes), EDS VIIC (deficiency of procollagen N-proteinase), and EDS IX (decreased lysyl oxidase activity). Very little is known about the genetic or biochemical defects responsible for the other EDS subtypes, but with the application of the tools of molecular biology, analysis of these defects is now within reach.
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PMID:The Ehlers-Danlos syndromes. 821 61

The developmental changes in skin collagen biosynthesis pathway in male and female chickens were evaluated. Concentration of collagen, levels of mRNA for collagen type I subunits and for lysyl hydroxylase, and the level of three lysyl oxidase-derived cross-links: dehydro-dihydroxylysinonorleucine (DHLNL), dehydro-hydroxylysinonorleucine (HLNL), and dehydro-histidinohydroxymerodesmosine (HHMD) were determined during 4 wk posthatching. Skin collagen content increased with age and was higher in males than in females. In both sexes, the expression of the genes coding for alpha 1 and alpha 2 of collagen type I decreased with age: alpha 1(I) gene expression decreased from Day 3 onwards, whereas the reduction in alpha 2(I) gene expression started 1 wk later. At all ages examined, the expression of both genes was higher in male than in female skin. Males and females lysyl hydroxylase gene expression remained low until Day 16, after which an increase in the enzyme gene expression was observed. An increase in skin HLNL content was observed from Day 3 in both sexes reaching a peak in males at Day 9 and in females 1 wk later. The DHLNL content, which was higher in males than in females at all ages tested, dramatically decreased in both male and female skin from 3 d of age, reaching its lowest level at Day 16, and remained at that low level thereafter. The skin content of HHMD in males and females followed an oscillatory behavior with higher peaks in the male skin. The results suggest that the higher tensile strength of male skin than female skin may be due to the elevated skin collagen content that resulted from increased expression in collagen type I genes on the one hand, and from the higher amounts of various collagen cross-links on the other.
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PMID:Developmental changes in skin collagen biosynthesis pathway in posthatch male and female chickens. 878 37

Collagen biosynthesis was analyzed in C57BL/6J mice homozygous for the high-growth locus. Plasma levels of insulin-like growth factor-1 (IGF-1) were significantly elevated in high-growth mice at all ages studied (3 wk-6 mo); IGF-binding proteins were also elevated. Skin biopsies were obtained from mice aged 3, 6, and 9 wk under halothane anesthesia. Mice were killed at 6 mo of age. Collagen, expressed per weight of tissue, was significantly increased in all tissues from high-growth mice, as was collagen cross-linking, expressed as moles of cross-link per mole of collagen. Expression of types I and III collagen, lysyl oxidase, and lysyl hydroxylase was increased in all tissues analyzed. There was a preferential increase in type III expression relative to type I expression. Rate and extent of accumulation of collagen in granulation tissue were measured in polyvinyl alcohol sponges implanted subcutaneously; collagen accumulation was significantly greater in the high-growth mice. These results suggest that 1) elevated circulating IGF-1 may increase collagen deposition both in normal tissue as well as in granulation tissue by increasing collagen gene expression, 2) IGF-1 may increase collagen cross-linking by stimulating expression of lysyl oxidase, and 3) the preferential increase in dihydroxylated cross-links observed in high-growth mice may be due to the stimulation of lysyl hydroxylase expression by IGF-1. In summary, elevated levels of IGF-1 appear to affect collagen both quantitatively and qualitatively, primarily through their effects on gene expression of collagen and of those enzymes responsible for posttranslational modifications of collagen.
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PMID:Effects of elevated circulating IGF-1 on the extracellular matrix in "high-growth" C57BL/6J mice. 885 93

Coenzyme A, a cofactor in enzymatic acetyl transfer reactions, stimulates collagen production in cultured fibroblasts. The mechanisms involved in this collagen stimulation were investigated. Enzymatic studies using radiolabeled procollagen as substrate revealed that coenzyme A enhanced prolyl hydroxylase activity. Prolyl hydroxylase is a key enzyme in collagen synthesis acting by hydroxylation of proline residues in procollagen peptide, which is necessary for stabilizing collagen. Northern blot analysis demonstrated that coenzyme A also enhanced mRNA levels of both the alpha subunit of prolyl hydroxylase and the alpha1 chain of type I collagen. The levels of protein production of prolyl hydroxylase and type I collagen were also increased in cultured fibroblasts by coenzyme A, which correlated well with observations from Northern blotting. On the other hand, coenzyme A did not stimulate the activity nor the gene expression of two other processing enzymes: lysyl hydroxylase, which provides the sites for glycosylation and crosslinking between collagen peptides, and lysyl oxidase, a fundamental enzyme in intermolecular crosslinking. These results indicate that coenzyme A stimulates collagen production by at least two separate mechanisms: by enhancing prolyl hydroxylase activity as well as stimulating gene expression of the alpha subunit of this enzyme, and by stimulating gene expression of alpha1 chain of type I collagen.
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PMID:Coenzyme A stimulates collagen production in cultured fibroblasts; possible mechanisms in enzymatic and gene expression. 1182 Jul 29

Different intensities of pulsed ultrasound have distinct biological effects on bone mineralization in the process of bone fracture repair, even across a narrow range (e.g., 30-120 mW/cm(2)). The aim of our study was to elucidate the effect of low-intensity (30 mW/cm(2)) and high-intensity (120 mW/cm(2)) pulsed ultrasound on collagen metabolism by using MC3T3-E1 osteoblasts. Of special interest was the relationship between posttranslational collagen quality and prostaglandin E(2) activity. Cells with or without a cyclooxygenase-2 inhibitor, NS398, were exposed every day for four consecutive days to high-level or low-level intensities of pulsed ultrasound. We examined the, expression patterns of cyclooxygenase-2, lysyl oxidase, telopeptidyl lysyl hydroxylase (TLH), and helical lysyl hydroxylase by real-time polymerase chain reaction analysis. Quantitative analyses of reducible immature and nonreducible mature cross-links were also performed. Ultrasound at 30 mW/cm(2) upregulated TLH messenger RNA (mRNA) expression and enzyme activity compared to the control and resulted in increased relative concentrations of telopeptidyl hydroxylysine-derived cross-links. In addition to upregulated lysyl oxidase mRNA expression, increased total reducible and nonreducible cross-links were observed by 30 mW/cm(2) exposure compared to the control. In contrast, ultrasound at 120 mW/cm(2) had no obvious effect on collagen metabolism owing to high levels of endogenous prostaglandin E(2) induced by ultrasound. Our results showed that (1) low-intensity, but not high-intensity, ultrasound may accelerate the formation of the unique molecular packing of collagen fibers conducive to bone mineralization and that (2) the high dose of endogenous prostaglandin E(2) induced by pulsed ultrasound may be detrimental to calcifiable cross-link formation.
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PMID:Effect of low- and high-intensity pulsed ultrasound on collagen post-translational modifications in MC3T3-E1 osteoblasts. 1559 95

The hallmark of fibrosis is the excessive accumulation of collagen. The deposited collagen contains increased pyridinoline cross-link levels due to an overhydroxylation of lysine residues within the collagen telopeptides. Lysyl hydroxylase 2b (LH2b) is the only lysyl hydroxylase consistently up-regulated in several forms of fibrosis, suggesting that an enhanced LH2b level is responsible for the overhydroxylation of collagen telopeptides. The present paper reports the effect of profibrotic cytokines on the expression of collagen, lysyl hydroxylases and lysyl oxidase in normal human skin fibroblasts, as well as the effect on pyridinoline formation in the deposited matrix. All three isoforms of TGF-beta induce a substantial increase in LH2b mRNA levels, also when expressed relatively to the mRNA levels of collagen type I alpha2 (COL1A2). The TGF-beta isoforms also clearly influence the collagen cross-linking pathway, since higher levels of pyridinoline cross-links were measured. Similar stimulatory effects on LH2b/COL1A2 mRNA expression and pyridinoline formation were observed for IL-4, activin A, and TNF-alpha. An exception was BMP-2, which has no effect on LH2b/COL1A2 mRNA levels nor on pyridinoline formation. Our data show for the first time that two processes, i.e., up-regulation of LH2b mRNA levels and increased formation of pyridinoline cross-links, previously recognized to be inherent to fibrotic processes, are induced by various profibrotic cytokines.
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PMID:Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced lysyl hydroxylase 2b levels. 1595 52


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