lysine-tyrosylquinone and 6-hydroxydopa-quinone

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.

Topics: Amino Acid Oxidoreductases; Amino Acids; Coenzymes; Dihydroxyphenylalanine; Galactose Oxidase; Indolequinones; Lysine; Oxidation-Reduction; Quinones; Tryptophan

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.

Topics: Animals; Coenzymes; Dihydroxyphenylalanine; Enzymes; Humans; Indolequinones; Lysine; PQQ Cofactor; Quinolones; Quinones; Tryptophan

The structure of a new biological redox cofactor-topaquinone (TPQ), the quinone of 2,4,5-trihydroxyphenylalanine-was elucidated in 1990. TPQ is the cofactor in most copper-containing amine oxidases. It is produced by post-translational modification of a strictly conserved active-site tyrosine residue. Recent work has established that TPQ biogenesis proceeds via a novel self-processing pathway requiring only the protein, copper, and molecular oxygen. The oxidation of tyrosine to TPQ by dioxygen is a six-electron process, which has intriguing mechanistic implications because copper is a one-electron redox agent, and dioxygen can function as either a two-electron or four-electron oxidant. This review adopts an historical perspective in discussing the structure and reactivity of TPQ in amine oxidases, and then assesses what is currently understood about the mechanism of the oxidation of tyrosine to produce TPQ. Aspects of the structures and chemistry of related cofactors, such as the Tyr-Cys radical in galactose oxidase and the lysine tyrosylquinone of lysyl oxidase, are also discussed.

Topics: Amine Oxidase (Copper-Containing); Binding Sites; Copper; Dihydroxyphenylalanine; Galactose Oxidase; Lysine; Mechanics; Models, Molecular; Oxidation-Reduction; Quinones; Tyrosine

Topics: Amino Acids; Animals; Catalysis; Coenzymes; Dihydroxyphenylalanine; Indolequinones; Lysine; Protein Processing, Post-Translational; Quinones; Tryptophan

Topics: Amine Oxidase (Copper-Containing); Amino Acid Sequence; Animals; Binding Sites; Chemotactic Factors; Dihydroxyphenylalanine; Gram-Negative Bacteria; Lysine; Oxidoreductases Acting on CH-NH Group Donors; PQQ Cofactor; Quinolones; Quinones

This review is concerned with the structure and function of the quinoprotein enzymes, sometimes called quinoenzymes. These have prosthetic groups containing quinones, the name thus being analogous to the flavoproteins containing flavin prosthetic groups. Pyrrolo-quinoline quinone (PQQ) is non-covalently attached, whereas tryptophan tryptophylquinone (TTQ), topaquinone (TPQ) and lysine tyrosylquinone (LTQ) are derived from amino acid residues in the backbone of the enzymes. The mechanisms of the quinoproteins are reviewed and related to their recently determined three-dimensional structures. As expected, the quinone structures in the prosthetic groups play important roles in the mechanisms. A second common feature is the presence of a catalytic base (aspartate) at the active site which initiates the reactions by abstracting a proton from the substrate, and it is likely to be involved in multiple reactions in the mechanism. A third common feature of these enzymes is that the first part of the reaction produces a reduced prosthetic group; this part of the mechanism is fairly well understood. This is followed by an oxidative phase involving electron transfer reactions which remain poorly understood. In both types of dehydrogenase (containing PQQ and TTQ), electrons must pass from the reduced prosthetic group to redox centres in a second recipient protein (or protein domain), whereas in amine oxidases (containing TPQ or LTQ), electrons must be transferred to molecular oxygen by way of a redox-active copper ion in the protein.

Topics: Alcohol Oxidoreductases; Amine Oxidase (Copper-Containing); Bacterial Proteins; Binding Sites; Coenzymes; Dihydroxyphenylalanine; Disulfides; Electron Transport; Indolequinones; Lysine; Models, Chemical; Models, Molecular; Molecular Structure; Oxidation-Reduction; Oxidoreductases Acting on CH-NH Group Donors; PQQ Cofactor; Protein-Lysine 6-Oxidase; Quinolones; Quinones; Tryptophan

Topaquinone (TPQ) is a cofactor present at the active site of copper amine oxidases, derived from a Tyr residue inserted in the polypeptide chain through a copper-dependent but otherwise largely unknown mechanism. A simple model system was developed that permits to obtain the overall transformation of 4-tert-butylphenol, chosen as a model for Tyr, into a TPQ-like, para-hydroxyquinonic structure in the presence of Cu(II)-imidazole mononuclear complexes.

Topics: Amine Oxidase (Copper-Containing); Benzoquinones; Copper; Dihydroxyphenylalanine; Hydrogen-Ion Concentration; Hydroxylation; Lysine; Oxidation-Reduction; Phenols; Quinones

Topics: Amino Acid Sequence; Coenzymes; Copper; Diabetes Mellitus; Dihydroxyphenylalanine; Electron Spin Resonance Spectroscopy; Enzyme Inhibitors; Heart Failure; Humans; Indolequinones; Liver Cirrhosis; Lysine; Menkes Kinky Hair Syndrome; Metalloproteins; Mixed Function Oxygenases; Models, Molecular; Molecular Sequence Data; Oxidation-Reduction; Oxidoreductases Acting on CH-NH Group Donors; PQQ Cofactor; Protein-Lysine 6-Oxidase; Quinolones; Quinones; Semicarbazides; Sequence Homology, Amino Acid; Spectrum Analysis, Raman; Stereoisomerism; Substrate Specificity; Tryptophan