Nicotinamide adenine dinucleotide phosphate NADPH oxidase

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an enzymatic complex considered the most important source of superoxide... 

Production of ROS, factors involved in the aging process (Finkel and Holbrook, 2000), is elevated in AD brain and may be an important cause of AD (Martins et al., 1986). Elevated levels of oxicUzed hpids (lipid peroxidation, maloncUaldehyde, 4-hydroxynonenal) (Markesbery and Carney, 1999), proteins (advanced glycation end product mocUfications, tyrosine nitration) (Good et al., 1996 Takeda et al., 1998), and nucleic acids (8-hydroxy-deoxyguanosine) have been documented in AD brains (Lyras et al., 1997). Mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex... 

Two major sensors have been proposed that could act as physiological sources of the AOS and fulhll the sensor role, namely, nicotinamide adenine dinucleotide phosphate (NADPH oxidase) (67,68) and the mitochondrial ETC (35). What is the evidenee for eaeh potential souree of signaling AOS ... 

Figure 6 Molecular model of O2 sensor complex in NEB cell. Shown is the a-jS potassium (K+) channel complex with tetramer of a-subunits forming the ionic pore, -subiuiits interact with the assembly domains T1 in the cytosol. A positively chaiged amino terminal ball domain of the a-subunit (and possibly of the -subunit) underlies fast inactivation. The reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex is shown to be associated with this K+-channel complex in NEB cells. Reactive oxygen intermediates produced by the NADPH oxidase modulate the inactivation process by oxidizing specific cysteine residues in the amino terminus, forming disulfide bridges with other cysteines located in the channel and thus immobilizing the inactivation balls. (From Ref 78, Courtesy of Dr. Honore.)...

Hexachloroethane is metabolized by the mixed function oxidase system by way of a two-step reduction reaction involving cytochrome P-450 and either reduced nicotinamide adenine dinucleotide phosphate (NADPH) or cytochrome b5 as an electron donor. The first step of the reduction reaction results in the formation of the pentachloroethyl free radical. In the second step, tetrachloroethene is formed as the primary metabolite. Two chloride ions are released. Pentachloroethane is a minor metabolic product that is generated from the pentachloroethyl free radical. 

Enzymes responsible for metabolism are located at various subcellular sites, for example the cytosol, mitochondria and smooth endoplasmic reticulum. However, it is enzymes derived from endoplasmic reticulum, called mixed function oxidases or monooxygenases , which have been most intensely studied in the past two or three decades. These enzyme systems, which utilize a family of haemoprotein cytochromes, or P-450 as terminal oxidases, require molecular oxygen and reduced nicotinamide adenine dinucleotide phosphate (NADPH) for activity. The overall stoichiometry of the reactions catalyzed by these enzymes is normally represented by equation (1). 

The hepatic endoplasmic reticulum possesses oxidative enzymes called mixed-function oxidases or monooxygenase with a specific requirement for both molecular oxygen and a reduced concentration of nicotinamide adenine dinucleotide phosphate (NADPH). Essential in the mixed-function oxidase system is P-450 (Figure 1.12). The primary electron donor is NADPH, whereas the electron transfer involved P-450, a flavoprotein. The presence of a heat-stable fraction is necessary for the operation of the system. 

Conditions for cytosolic incubations depend on the aim of the assay e.g. to cover specific enzymatic activity present in the cytosol. For this purpose it is essential to fortify the incubation medium with the specific cofactor for the reaction-if needed (Ekins 1999). (J> -Nicotinamide adenine dinucleotide (NAD) is needed for alcohol and aldehyde dehydrogenases, flavin adenine dinucleotide (FAD) for polyamine oxidase, P-nicotinamide adenine dinucleotide phosphate (NADPH) for Dihydropyrimidine dehydrogenase. Phase II reactions depend on PAPS (sulfotransferases,... 

In vitro metabolic studies with rodent and human liver microsomal prepara- tions have established that MPTP undergoes both oxidative N-demethylation and C-6 (allylic) oxidation in reactions that are -nicotinamide adenine dinucleotide phosphate (NADPH) dependent and therefore likely to be cytochrome P-450 catalyzed (Weissman et al. 1985 Ottoboni et al. 1990). Although the latter transformation can lead to the toxic pyridinium metabolite MPP, the cytochrome P450-catalyzed pathway is unlikely to contribute significantly to the neurotoxicity of MPTP. As mentioned above, liver aldehyde oxidase diverts the inter-mediate dihydropyridinium metabolite away from pyridinium ion formation by catalyzing the conversion of structure 40 to the nontoxic lactim structure 41. Further-more, even if formed in the periphery, the polar pyridinium metabolite would have limited access to the central nervous system (CNS). The low... 

Phase I metabolism Phase I reactions (mainly oxidation, reduction, and hydrolysis) act as a preparation of the drug for the phase II reactions, i.e., a chemically reactive group is produced or uncovered on which the phase II reactions can occur, e.g., -OH, -NH2, -SH, -COOH. Most toxic metabolites are produced by phase I reactions. The P-450 isoenzymes (CYP enzymes), known collectively as the mixed function oxidase system, are found in the endoplasmic reticulum of many cells (notably those of liver, kidney, lung, and intestine) and perform many of these different functionalization reactions. The system requires the presence of molecular oxygen and co-factor nicotinamide adenine dinucleotide phosphate (NADPH) as well as cytochrome P450, NADPH-cytochrome P450 reductase, and lipid. 

The co-hydroxylation of fatty acids, which involves the addition of a hydroxyl group at or near the co-terminal carbon, was first shown to be catalyzed by the liver microsomal enzyme system in the 1960s [38], In particular, the CO pigment of CYP was recognized as a constituent of the microsomal mixed function oxidase system that contributes to the co-hydroxylation of steroids [39], Substrates that are susceptible to co-hydroxylation include laurate and AA [38], Early reports showed that CYP enzymes catalyze the CO (C-20) and co-1 (C-19) hydroxy lation of AA [40], In 1990, Faick et al. demonstrated that CYP enzymes also hydroxy late the C-16 (co-4), C-17 (co-3), and C-18 (co-2) carbons of A A [41], Thus, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen, CYPs mediate the hydroxylation of AA to generate a variety of co-terminal HETEs including 16-, 17-, 18-, 19-, and 20-HETR (Fig. 13.2). 

The answers are 34-g, 33-a, 36-d. (Katzung, pp 53-56.) There are four major components to the mixed-function oxidase system (1) cytochrome P450, (2) NADPH, or reduced nicotinamide adenine dinucleotide phosphate, (3) NADPH-cytochrome P450 reductase, and (4) molecular oxygen. The figure that follows shows the catalytic cycle for the reactions dependent upon cytochrome P450. 

Overproduction of superoxide ( Op has been implicated in the pathogenesis of various cardiovascular diseases. The main sources of human superoxide include the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) enzyme complex, cyclooxygenase, mitochondrial oxidases, xanthine oxidase, and nitric... 

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