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)

Isonicotinic acid hydrazide (isoniazid) causes a large increase in the salt-solubility of collagen when injected into chick embryos; this change is accompanied by the inactivation of lysyl oxidase (EC 1.4.3.13), the enzyme responsible for initiating cross-link formation in collagen and elastin. In addition, isoniazid markedly decreases the liver content of pyridoxal phosphate. The depletion of pyridoxal phosphate takes approx. 6 h, whereas the inhibition of lysyl oxidase and the increase in collagen solubility occur more slowly. A reversal of these effects of isoniazid can be produced by the subsequent injection of a stoichiometric amount of pyridoxal, supporting the role of pyridoxal as a cofactor for lysyl oxidase. Treatment of chick embryos with beta-aminopropionitrile, an irreversible inhibitor of lysyl oxidase, causes an inhibition of the enzyme, which begins to recover within 24 h but which is not affected by the administration of pyridoxal; with isoniazid inhibition, however, lysyl oxidase activity does not show any sign of recovery by 48 h. It is proposed that isoniazid may cause the inhibition of lysyl oxidase by competing for its obligatory cofactor, pyridoxal phosphate. The potential clinical implications in the therapeutic control of fibrosis are briefly discussed.
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PMID:The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo. 614 76

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be comprised of two distinct components, a more abundant amorphous component and the microfibrillar component. The microfibrillar component is found in 10- to 12-nm fibrils which are located primarily around the periphery of the amorphous component but, to some extent, interspersed within it. The protein, elastin, makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom except for very primitive fish and possesses an unusual chemical composition consonant with its characteristic physical properties. Elastin is composed largely of glycine, proline, and other hydrophobic residues and contains multiple lysine-derived cross-links, such as the desmosines, which link the individual polypeptide chains into a rubber-like network. The intervening, hydrophobic regions of the polypeptide chains between the cross-links are highly mobile, and the elastic properties of the fibers can be described in terms of the theory of rubber elasticity. Recent application of recombinant DNA techniques has led to further understanding of the structure of elastin. Analyses of the bovine and human elastin genes have demonstrated that the hydrophobic and cross-linking domains are encoded in separate exons. These exons tend to be small, varying from 27 to 114 base pairs, and are separated by large intervening sequences. Furthermore, DNA sequence analysis has demonstrated that the elastin molecule contains two cysteine residues which were not previously identified near the carboxy terminus and which may be important in the interaction of elastin with other extracellular matrix proteins. Further DNA sequencing should determine the complete amino acid sequence of elastin. Biosynthetic studies and in vitro translation of elastin mRNA have demonstrated that a 72,000-dalton polypeptide, designated tropoelastin, is the initial translation product. Analysis of several developing systems has demonstrated that elastin synthesis is controlled by the level of elastin mRNA. After packaging into membrane-bound vesicles in the Golgi apparatus, tropoelastin is secreted by exocytosis into the extracellular space where it is cross-linked by a copper-requiring extracellular enzyme, lysyl oxidase. Elastin can be solubilized only by proteases that have consequently been designated elastases, although these are general, powerful proteases that can hydrolyze numerous proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Elastin: relation of protein and gene structure to disease. 615 Jan 37

Rheumatoid arthritis can be divided into two syndromes, one a potassium deficiency, the other an inappropriate copper requirement seriously affecting the elastin tissues through reduced lysyl oxidase cross linking. The malfunction in copper may arise from the steroids which regulate potassium, which reduces those steroids, and through that, increases the copper response to the needs of the immune system. It is a mechanism which may have evolved to help fight potassium wasting infections.
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PMID:Copper response to rheumatoid arthritis. 615 6

Elastic fibers are important for elasticity and extensibility of lung tissue. In the developing lung, elastic fibers appear in greatest numbers during the process or period of alveolarization . A variety of mesenchymal cells in lung appear responsible for elastin synthesis. Elastin is a novel protein both from the standpoint of its processing into elastic fibers and chemical properties. For example, elastin undergoes posttranslational modification before its assembly into fibers. These steps include limited proteolysis, hydroxylation of prolyl residues and the oxidative deamination of lysyl residues prior to their incorporation into the crosslinks that covalently bond together polypeptide chains of elastin. The crosslinking amino acids include lysinonorleucine , merodesmosine and desmosine isomers. A key enzyme that controls this process is lysyl oxidase. Lysyl oxidase is a copper metalloprotein whose activity is responsive to and modulated by environmental insults, nutrition deficiencies and the administration of various pharmacological agents. Regarding chemical properties, elastin is one of the most apolar proteins secreted by mammalian cells. Moreover, elastin is one of the most long-lived proteins secreted into the extracellular matrix. In relationship to its processing into elastic fibers and chemical properties, details related to major aspects of elastin metabolism as well as speculation on its potential as a factor in lung development and disease are discussed.
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PMID:Elastin metabolism and chemistry: potential roles in lung development and structure. 637 98

dl-Propranolol (propranolol) fed to immature and mature aneurysm-prone turkeys (Broad-Breasted White, BBW) for 6 weeks significantly raised the tensile strength of tissue rings from the abdominal aorta. The drug-mediated increase in tensile strength values was dose-related and independent of its heart rate- and arterial pressure-lowering effects. Propranolol acts, in part, by (a) stimulating lysyl oxidase to produce greater amounts of reactive aldehydes for intermolecular cross-links, (b) enhancing the progression of chemically unstable to stable forms of intermolecular elastin cross-links (lysinonorleucine and the desmosines), and (c) reducing the density of the age-related intermolecular cross-linking of collagen (pyridinoline). These propranolol effects on the lysyl cross-links were demonstrated in both the immature and mature animals and suggest a heretofore unrecognized potential for this widely used cardiovascular drug.
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PMID:Modulation by propranolol of the lysyl cross-links in aortic elastin and collagen of the aneurysm-prone turkey. 640 22

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

A spontaneously aneurysm-prone mouse has a mutation on the X chromosome, which results in an abnormality of copper metabolism. A deficiency of the copper metalloenzyme, lysyl oxidase, results in a deficiency of lysyl-derived cross-linkages in collagen and elastin. Homology of the X chromosome suggests that this model may be relevant to the human abdominal aortic aneurysm (AAA). The present studies on skin from eight AAA patients suggest that copper deficiency occurs in humans, by comparison to skin of paired control subjects with atherosclerotic occlusive disease of the aorta. The lysyl-derived cross-linkage pyridinoline (or some compound with similar ion exchange elution characteristics) is also deficient in patients with AAA; while there is an excess of one of the cross-linkage precursors, hydroxylysine. In addition, the fluorescent properties of hydrolysates of skin from the patients with AAA differ from those of the controls, suggesting that simple biochemical markers might be defined on the basis of these differences in the future. These experiments support the hypothesis that the mouse model is relevant to the disease as it occurs in humans.
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PMID:Deficiencies of copper and a compound with ion-exchange characteristics of pyridinoline in skin from patients with abdominal aortic aneurysms. 687 35

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

The spontaneously aneurysm-prone Blotchy mouse has a mutation on the X chromosome resulting in low hepatic copper levels; and copper is an essential cofactor for lysyl oxidase, which catalyzes reactions leading to the cross-linking of collagen and elastin. Population characteristics and family histories of patients with aneurysms suggest that aneurysmal disease may also be sex linked in man. Hepatic copper levels were determined in 13 patients who died with abdominal aortic aneurysms and in 13 control patients selected on the criterion of severe atherosclerotic occlusive disease of the abdominal aorta. Excluding two patients with severe liver disease, the tissue copper level in the patients with aneurysms was only 26% of the control level. The results suggest that additional studies of the biologic markers for aneurysm formation in the Blotchy mouse should be carried out prospectively in human subjects.
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PMID:Decreased hepatic copper levels. A possible chemical marker for the pathogenesis of aortic aneurysms in man. 720 50

Hair samples were collected from 74 patients with idiopathic adolescent scoliosis and from 25 control children and were analyzed for content of the following minerals: copper, sodium, iron, zinc, potassium, magnesium, cadmium, calcium, and manganese. The hair copper level of the scoliotic children was significantly higher than that of the controls. The scoliosis mean was 6.5 micrograms/dl and the control mean was 3.6 micrograms/dl, P less than 0.025. There was no correlation between the amount of hair copper and the severity of the scoliosis. The authors suggest that copper may be a factor in the development of scoliosis since it is part of the lysyl oxidase enzymes that are required for cross-linking of collagen and elastin. Another connection is that postpubertal girls have higher copper levels than boys and also have a greater severity of scoliosis.
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PMID:Elevated hair copper level in idiopathic scoliosis: preliminary observations. 739 62


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