NADPH dependent reduction

FIGURE 25.32 A reaction mechanism for HMGCoA reductase. Two successive NADPH-dependent reductions convert the thioester, HMGCoA, to a primary alcohol. 

Romanov V, RP Hausinger (1996) NADPH-dependent reductive ortho dehalogenation of 2,4-dichlorobenzoic acid in Corynebacterium sepedonicum KZ-4 and coryneform bacterium strain NTB-1 via 2,4-dichlo-robenzoyl coenzyme A. J Bacteriol 178 2656-2661. 

DHFR has been the object of intense research for the last few decades. The enzyme catalyses the NADPH-dependent reduction of 7,8-dihydrofolate to 5,6,7,8 tetrahydrofolate, a chemical which participates in the thymidilate synthesis cycle. Thus, the enzyme is crucial in the synthesis of thymidine monophosphate as well as in various one-carbon unit transfer reactions. 

III. Glutathione reductase (EC 1.6.4.2) It is a flavoprotein that catalyzes the NADPH-dependent reduction of oxidized glutathione (GSSG) to glutathione (GSH). This enzyme is essential for the GSH redox cycle which maintains adequate levels of reduced cellular GSH. A high GSH/GSSG ratio is essential for protection against oxidative stress. 

Mammalian thioredoxin reductases are a family of selenium-containing pyridine nucleotide-disulfide oxidoreductases. These enzymes catalyze NADPH-dependent reduction of the redox protein thioredoxin (Trx), which contains a redox-active disulfide and dithiol group and by itself may function as an efficient cytosolic antioxidant [77]. One of the functions of Trx/ thioredoxin reductase system is the NADPH-catalyzed reduction of protein disulfide [78] ... 

Dietrichs D, Meyer M, Rieth M, Andreesen JR. 1991. Interaction of selenoprotein PA and the thioredoxin system, components of the NADPH-dependent reduction of glycine in Eubacterium acidaminophilum and Clostridium litorale. J Bacteriol 173 5983-91. 

In a collaboration between the Abelson and Hecht labs [56b], a series of noncoded amino acids were introduced into dihydrofolate reductase (DHFR) to probe substrate binding and the requirement of an aspartic acid residue for catalytic competence. When aspartic acid analogs mono- or disubstituted at the )0-carbon were substituted for the active site aspartic acid residue, the mutant DHFRs were still able to catalyze the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate at 74 - 86 % of the wild-type rate. While hydride transfer from NADPH is not the rate-limiting step for the wild-type enzyme at physiological pH, a kinetic isotope experiment with NADPD indicated that hydride transfer had likely become the rate-limiting step for the mutant containing the )0,)0-dimethylaspartic acid. 

This enzyme [EC 1.1.1.189], also known as prostaglandin E2 9-reductase, catalyzes the NADPH-dependent reduction of prostaglandin E2 to prostaglandin F2 and NADP ... 

This enzyme [EC 2.5.1.21], officially known as farnesyl-diphosphate farnesyltransferase (and also referred to as farnesyltransferase and presqualene-diphosphate synthase), catalyzes the conversion of two molecules of farnesyl diphosphate to yield presqualene diphosphate and pyrophosphate (or, diphosphate). In its polymeric form, the enzyme then catalyzes the NADPH-dependent reduction of presqualene diphosphate to form squalene. See also Farnesyl Diphosphate Farnesyltransferase... 

Dihydroflavonol 4-reductase (DFR) catalyzes the stereospecific conversion of 2R,3R)-trans-DHFs to the respective (2R,35, 45)-flavan-2,3-traKi-3,4-cA-diols (leucoanthocyanidins) through a NADPH-dependent reduction at the 4-carbonyl. DNA sequences for DFR were first identified from A. majus and Z. mays, and the identity of the Z. mays sequence confirmed by in vitro transcription and translation of the cDNA and assay of the resultant protein. DNA sequences have now been cloned from many species, with the size of the predicted protein averaging about 38kDa. Stereospecificity to (2R,3R)-dihydroquercetin (DHQ) has been shown for some recombinant DFR proteins. ... 

Schematic of the polyol pathway showing the NADPH-dependent reduction of open chain D-glucose to sorbitol, which is catalyzed by ALR2. This step is followed by the NAD+-dependent oxidation of sorbitol by sorbitol dehydrogenase to yield D-fructose.

In the presence of oxygen, NADPH and rat liver microsomes, 1,1,1,2-tetrachloroethane undergoes little dechlorination. In contrast, NADPH-dependent reductive metabolism of 1,1,1,2-tetrachloroethane by hepatic microsomal fractions from rats yields 1,1-dichloroethylene as the major metabolite and 1,1,2-trichloroethane as a minor metabolite (lARC, 1986). 

Komura, I., T. Funaba, and K. Izaki. 1971. Mechanism of mercuric chloride resistance in microorganisms. II. NADPH-dependent reduction of mercuric chloride and vaporization of mercury from mercuric chloride by a multiple drug-resistant strain of Escherichia coli. J. Biochem. (Tokyo) 70 895-901. 

Fig. 7.4 Reactions associated with the thioredoxin system. Thioredoxin is a redox-regulating protein with a redox-active disulfide/dithiol within the conserved active site sequence -Cys-Gly-pro-Cys-. Thioredoxin reductase, a 55 kDa flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin (1) and thioredoxin oxidase (2), a flavin-dependent sulfhydry 1 oxidase that catalyzes the oxidative protein folding with the generation of disulfides...

In ergosterol biosynthesis, side chain alkylation of lanosterol normally takes place to build 24-methylenedihydrolanosterol, which itself is then the substrate for demethylation reactions at and C. The C -demethylation has been studied in detail. It is an oxidative demethylation catalyzed by a cytochrome P -system. The first step involved in this reaction is the hydroxylation of the Cj -methy1-group to form the C -hydroxymethyl derivative. A second hydroxylation and loss of water lead to the C -formyl intermediate, which is hydroxylized a third time to form the corresponding carboxylic acid. Decarboxylation does not directly take place, but proceeds instead by abstraction of a proton from C, followed by elimination and formation of a A 4-double bond. The NADPH-dependent reduction of the A14 -double bond finishes the demethylation reaction. Subsequently, demethylation at has to take place twice, followed by a dehydrogenation reaction in A" -position and isomerization from A8 to A7 and A24(28) to A22. respectively. 

TrxRs are homodimeric flavoproteins [80] that catalyze the NADPH-dependent reduction of thioredoxin (Trx), a ubiquitous 12 kDa protein that is the major protein disulfide reductase in cells [81], and belongs to the pyridine nucleotide-disulfide oxidoreductase family [82]. Each monomer includes an FAD prosthetic group, a NADPH binding site and an active site containing a redox-active selenol group. Electrons are transferred from NADPH via FAD to the active-site selenol of TrxR, which then reduces the substrate Trx [83]. The crystal structure of TrxR is shown in Fig. 13 [84],... 

The Unear tetrapyrrole biUverdin IXa that is a product of the heme oxygenase reaction is the substrate for biliverdin reductase, which catalyzes the NADPH-dependent reduction of biUverdin IXa at the y-methene bridge to form bilirubin IXa (Fig. 22-1). Many of the pathological problems associated with excess production or diminished eUmination of biUrubin are... 

Treatment of E. coli sulfite reductase with p-mercuriphenyl sulfonate results in the specific release of FMN from the enzyme (390). FMN-depleted sulfite reductase can be prepared also by photodestruction of FMN. The enzyme-FMN dissociation constant is 10 nAf at 25°, and light irradiation can deplete the enzyme of FMN by destroying the released flavin. These treatments do not lead to removal or destruction of other components of the enzyme. The FMN-depleted enzyme is no longer capable of NADPH-dependent reduction of sulfite, nitrite, hydroxylamine. 

The NADPH-dependent reduction of vitamin K quinone to the hydroquinone is not inhibited by warfarin. In the presence of adequate amounts of vitamin K, the carboxylation of glutamate residues can proceed normally, despite the presence of warfarin, with the stoichiometric formation of vitamin K epoxide that cannot be reutilized. Small amounts of vitamin K epoxide, and hydroxides formed by its reduction by other enzymes, are normally found in plasma. In warfarin-treated animals and patients, there is a significant increase in the plasma concentration of both. There is also an increase in the urinary excretion of the products of side-chain oxidation of the epoxide and hydroxides. 

Pinoresinol/lariciresinol reductase (PLR) catalyses the stereospecific NADPH-dependent reduction of first pinoresinol to lariciresinol and afterwards lariciresinol to secoisolariciresinol (Fig. 4.8). The first PLR forming... 

This enzyme catalyses the reduction of the A -double bond of the A -sterols into A -sterols in vertebrates and higher plants. A microsomal preparation from seedlings of Zea mays catalysed the NADPH-dependent reduction of the A -bond of A -cholestadienol, providing the first in vitro evidence for the intermediacy of A -sterols in plant sterol biosynthesis (Taton and Rahier, 1996). The potent inhibition of the enzyme by ammonium-containing fungicides suggests a cationic mechanism involved in this reduction reaction (Taton and Rahier, 1991). 

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