Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9UIJ5 (Rec)
 58,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitochondrial outer membrane enzyme kynurenine 3-hydroxylase (K3H) is an NADPH-dependent flavin mono-oxygenase involved in the tryptophan pathway, where it catalyzes the hydroxylation of kynurenine. K3H was transiently expressed in COS-1 cells as a glutathione S-transferase (GST) fusion protein, and the pure recombinant protein (rec-K3H) was obtained with a specific activity of about 2000 nmol.min-1.mg-1. Rec-K3H was shown to have an optimum pH at 7.5, to use NADPH more efficiently than NADH, and to contain one molecule of non-covalently bound FAD per molecule of enzyme. The mechanism of the rec-K3H-catalyzed reaction was investigated by overall initial-rate measurements, and a random mechanism in which combination of the enzyme with one substrate does not influence its affinity for the other is proposed. Further kinetic studies revealed that K3H activity was inhibited by both pyridoxal phosphate and Cl-, and that NADPH-catalyzed oxidation occurred even in the absence of kynurenine if 3-hydroxykynurenine was present, suggesting an uncoupling effect of 3-hydroxykynurenine with peroxide formation. This observation could be of clinical interest, as peroxide formation could explain the neurotoxicity of 3-hydroxykynurenine in vivo.
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PMID:Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase. 1067 18

Until recently, it was generally believed that enzymatic oxidation and reduction requires the participation of either a nicotinamide (NAD(P)+) or a flavin (FAD, FMN), in agreement with the existence of NAD(P)/H-dependent dehydrogenases/reductases and flavoprotein dehydrogenases/reductases/oxidases. However, during the past 20 years, the unraveling of the enzymology of the oxidation and reduction of C1-compounds by bacteria has led to the discovery of many new redox cofactors, some of them discussed here as they have a wider physiological significance than just enabling enzymatic C1-conversions to occur. A good example is the quinone cofactors, encompassing PQQ (2,7,9-tricarboxy-1H-pyrrolo[2,3-f]-quinoline-4,5-dione), TTQ (tryptophyl tryptophanquinone), TPQ (topaquinone), LTQ (lysyl topaquinone), and several others whose structures have still to be elucidated. Another example is mycothiol (1-O-(2'-[N-acetyl-L-cysteinyl]amido-2'-deoxy-alpha-D-glucopyranosyl)-D-myo-inosoitol), the counterpart of glutathione, once thought to be a universal coenzyme. Because these novel cofactors assist in reactions that can also be catalyzed by already known enzyme "classic cofactor" combinations, and first indications suggest that the chemistry of the reactions is not unique, one may wonder about the evolutionary background for this cofactor diversity. However, as will be illustrated by examples, from a practical point of view the diversity is beneficial, as it has increased the arsenal of enzymes suitable for application.
Chem Rec 2001
PMID:Cofactor diversity in biological oxidations: implications and applications. 1189 60

The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.
Chem Rec 2007
PMID:Human D-amino acid oxidase: an update and review. 1792 43