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)

Aromatic amine dehydrogenase (AADH) is the second enzyme known to possess the tryptophan tryptophylquinone (TTQ) prosthetic group. Its ability to catalyze the oxidative deamination of a wide range of aromatic and aliphatic amines has been investigated. Steady-state and transient kinetic studies of the reaction of AADH with a series of p-substituted phenylethylamines were performed to determine structure-reactivity correlations. The Km values correlated strongly with hydrophobic effects. The microscopic rate constant associated with TTQ reduction, k3, correlated with electronic substituent effects, particularly field/inductive effects, in a manner consistent with the formation of a carbanionic reaction intermediate in the reductive half-reaction. Transient kinetic studies were also performed with a series of p-substituted benzylamines, which were not substrates in the steady-state assay, but which did stoichiometrically reduce TTQ. The k3 for the reaction with benzylamines also correlated well with electronic effects. The rate constant associated with the release of the aldehyde product was also determined for the phenylethylamines and appears to be the most rate-limiting step in the overall oxidation-reduction reaction. This rate constant correlated with hydrophobic amines. This substrate specificity for aliphatic amines is opposite of that of methylamine dehydrogenase (MADH), the other known TTQ enzyme. On the basis of these studies, a reaction mechanism is proposed for AADH. These data are discussed in relation to the results of structure-reactivity correlation studies of the reactions catalyzed by MADH and two eukaryotic quinoproteins with different quinone prosthetic groups, plasma amine oxidase and lysyl oxidase.
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PMID:Mechanistic studies of aromatic amine dehydrogenase, a tryptophan tryptophylquinone enzyme. 782 40

Research spurred by the discovery of pyrroloquinoline quinone (PPQ) in 1979 led to the discovery of four additional oxidation-reduction (redox) cofactors, all of which result from transmogrification of amino acyl side chains in respective enzymes. These cofactors are (a) topa quinone in copper-containing amine oxidases, enzymes found in nearly all forms of life, including human; (b) lysyl topa quinone of the copper protein lysyl oxidase, an enzyme required for proper cross-linking of collagen and elastin; (c) tryptophan tryptophylquinone of alkylamine dehydrogenases from gram-negative soil bacteria; and (d) the copper-complexed cysteinyltyrosyl radical of fungal galactose oxidase. Originally, PQQ was thought to be a covalently bound cofactor in numerous enzymes from eukaryotes and prokaryotes. Today, PQQ is only found as a noncovalent cofactor in bacterial enzymes. The ubiquity of PQQ in the environment and its steady accessibility in the human diet has raised questions concerning its role as a vitamin, or an essential or helpful nutrient. The relevance to nutrition, medicine, and pharmacology of PQQ, topa quinone, lysyl topa quinone, tryptophan trytophylquinone, the galactose oxidase cofactor, and the enzymes harboring these cofactors are discussed in this review.
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PMID:Newly discovered redox cofactors: possible nutritional, medical, and pharmacological relevance to higher animals. 970 22

O-quinone cofactors derived from tyrosine and tryptophan are involved in novel biological reactions that range from oxidative deaminations to free-radical redox reactions. The formation of each of these cofactors appears to involve post-translational modifications of either tyrosine or tryptophan residues. The modifications result in cofactors, such as topaquinone (TPQ), tryptophan tryptophylquinone (TTQ), lysine tyrosylquinone (LTQ) or the copper-complexed cysteinyl-tyrosyl radical from metal-catalyzed reactions. Pyrroloquinoline quinone (PQQ) appears to be formed from the annulation of peptidyl glutamic acid and tyrosine residues stemming from their modification as components of a precursor peptide substrate. PQQ, a primary focus of this review, has invoked considerable interest because of its presence in foods, antioxidant properties and role as a growth-promoting factor. Although no enzymes in animals have been identified that exclusively utilize PQQ, oral supplementation of PQQ in nanomolar amounts increases the responsiveness of B- and T-cells to mitogens and improves neurologic function and reproductive outcome in rodents. Regarding TPQ and LTQ, a case may be made that the formation of TPQ and LTQ is also influenced by nutritional status, specifically dietary copper. For at least one of the amine oxidases, lysyl oxidase, enzymatic activity correlates directly with copper intake. TPQ and LTQ are generated following the incorporation of copper by a process that involves the two-step oxidation of a specified tyrosyl residue to first peptidyl dopa and then peptidyl topaquinone to generate active enzymes, generally classed as "quinoenzymes." Limited attention is also paid to TTQ and the copper-complexed cysteinyl-tyrosyl radical, cofactors important to fungal and bacterial redox processes.
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PMID:Physiological importance of quinoenzymes and the O-quinone family of cofactors. 1073 20

The predicted amino acid sequence derived from a mouse expressed sequence tag (EST) contig contained two domains that are highly conserved among members of the lysyl oxidase gene family: a copper binding-site with four histidines and a catalytic domain that includes a tryptophan residue. This new cDNA sequence showed the highest level of sequence homology with the human loxl2 cDNA and suggested that it encoded the mouse equivalent of hLOXL2. The mLOXL2 gene was mapped to chromosome 14 by radiation hybrid analysis. The mLOXL2 locus was tightly linked with a LOD score over 9 to the marker D14Mit32. The mLOXL2 gene is expressed as a 4-kb mRNA in almost all tissues analyzed, with highest levels of mRNA in skin, lung and thymus.
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PMID:The mouse lysyl oxidase-like 2 gene (mLOXL2) maps to chromosome 14 and is highly expressed in skin, lung and thymus. 1084 2

Prior to 1990, redox cofactors were widely believed to be small molecule, dissociable compounds. In the past 10 years, however, four novel redox cofactors have been discovered, each of which is derived from posttranslational modification of specific amino acids within their cognate enzymes. These include topa quinone, found in copper amine oxidases, lysine tyrosyl quinone, found in lysyl oxidase, tryptophan tryptophylquinone, found in methylamine dehydrogenase, and the cysteine-cross-linked tyrosine found in galactose oxidase. The processes by which these cofactors are formed, called biogenesis, is currently a major focus of mechanistic work in this field. In this review, the latest progress toward elucidating the various biogenesis mechanisms is discussed, along with possible linkages between the chemistries involved in catalysis and biogenesis.
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PMID:Mechanisms of biosynthesis of protein-derived redox cofactors. 1115 67

Cofactors made from constitutive amino acids in proteins are now known to be relatively common. A number of these involve the generation of quinone cofactors, such as topaquinone in the copper-containing amine oxidases, and lysine tyrosylquinone in lysyl oxidase. The biogenesis of the quinone cofactor tryptophan tryptophylquinone (TTQ) in methylamine dehydrogenase (MADH) involves the post-translational modification of two constitutive Trp residues (Trp(beta)(57) and Trp(beta)(108) in Paracoccus denitrificans MADH). The modifications for generating TTQ are the addition of two oxygens to the indole ring of Trp(beta)(57) and the formation of a covalent cross-link between Cepsilon3 of Trp(beta)(57) and Cdelta1 of Trp(beta)(108). The order in which these events occur is unknown. To investigate the role Trp(beta)(108) may play in this process, this residue was mutated to both a His (betaW108H) and a Cys (betaW108C) residue. For each mutant, the majority of the protein that was isolated was inactive and exhibited weaker subunit-subunit interactions than native MADH. Analysis by mass spectrometry suggested that the inactive protein was a biosynthetic intermediate with only one oxygen atom incorporated into Trp(beta)(57) and no cross-link with residue beta108. However, in each mutant preparation, a small percentage of the mutant enzyme was active and appears to possess a functional tryptophylquinone cofactor. In the case of betaW108C, this cofactor may be identical to cysteine tryptophylquinone, recently described in the bacterial quinohemoprotein amine dehydrogenase. In betaW108H, the active cofactor is presumably a histidine tryptophylquinone, which has not been previously described, and represents the synthesis of a novel quinone protein cofactor.
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PMID:Understanding quinone cofactor biogenesis in methylamine dehydrogenase through novel cofactor generation. 1264 53