NADPH-dependent cleavage

Coenzyme M was shown to function as the central cofactor of aliphatic epoxide carboxylation in Xanthobacter strain Py2, an aerobe from the Bacteria domain (AUen et al. 1999). The organism metabolizes short-chain aliphatic alkenes via oxidation to epoxyalkanes, followed by carboxylation to p-ketoacids. An enzyme in the pathway catalyzes the addition of coenzyme M to epoxypropane to form 2-(2-hydroxypropylthio)ethanesulfonate. This intermediate is oxidized to 2-(2-ketopropylthio)ethanesulfonate, followed by a NADPH-dependent cleavage and carboxylation of the P-ketothioether to form acetoacetate and coenzyme M. This is the only known function for coenzyme M outside the methanoarchaea. 

Figure 2.1 NADPH-dependent cleavage of la by hepatic microsomes (rat, dog human)...

Concerning the metabolism of triterpenes and steroids, quite a number of P450 catalyzed transformations are very important, namely the 14a-demethyla-tion of lanosterol [50], the side-chain cleavage of cholesterol [51]and pregnenes [52], and the desaturation of ring A of androgens with concomitant oxidative removal of C(19) [53]. The latter reaction is catalyzed by human placental aromatase, associated with a NADPH-dependent reductase, and requires three moles of oxygen and three moles of NADPH in order to oxidize andro-stenedione 45 to formic acid and estrone 46, Fig. 10. 

We have examined the hydrogen-isotope effect for cyclohexenol formation as a probe of the nature of C-H bond cleavage in the NADPH-dependent and cumene-hydroperoxide-dependent oxidation of cyclohexene. 

In conclusion the final route to raumacHne (70) has not been completely understood. It is proposed that this side route starts with an oxidative cleavage of 1 to form 72, followed by a NADPH-dependent reduction to dehver the alkaloid 70 (Figure 35). 

Baeyer-VilUger Reactions. Baeyer-Villiger oxidation is the oxidative cleavage of a carbon-carbon bond adjacent to a carbonyl, and converts ketones to esters and cyclic ketones to lactones (Figure 1.46). The enzymes that catalyze these reactions are Baeyer-Villiger monooxygenases (BVMOs), which are NADPH-dependent flavo-... 

The compounds 96-99, shown in Scheme 3.26, are all metabolites of arachidonic acid (8) produced in a NADPH-dependent cytochrome P-450-meditated oxidative pathways. Falck and coworkers [77] prepared these from Corey s epoxide methyl ester 89a as shown in Scheme 3.26. Hydrolysis of the epoxide ester 89a using perchloric acid, followed by oxidative cleavage of the resulting diol 100, provided aldehyde 101. Next, a Wittig reaction with aldehyde 101 followed by Jones oxidation and/or saponification... 

The route shown in Scheme 12.7 has been confirmed for some poppy plants [26]. However, a more common route from thebaine (35) toward morphine is outlined in Scheme 12.8 [27]. Cleavage of the enol ether, most probably via a hydroxylation step (38), affords neopinone (39). Migration of the double bond to the more stable conjugated position gives codeinone (40), which is converted to codeine (41) by means of an NADPH-dependent reduction. Morphine is obtained after cleavage of the phenolic methyl ether, probably via the same hydroxylation mechanism, which delivers neopinone (39) a few steps earlier. 

It has been established that the enzymic cleavage of Maillard-type compounds depends on the concentration of cytochrome P-450 and of the coenzyme NADPH (j3) (Fig. 3). The mechanism suggested for the enzymic cleavage of deoxyfructoserotonin is shown in Figure 4. Therefore, factors interfering with this enzyme system may prevent the detrimental effects of the Maillard reaction in diabetes. 

Oxidative cleavage of the O-alkyl linkage in glycerolipids is catalyzed by a microsomal tetrahydropteridine (Pte-H4)-dependent alkyl monooxygenase (Fig. 12) (T.-C. Lee, 1981). The required cofactor, Pte H4, is regenerated from Pte-Hj by an NADPH-linked pteridine reductase, a cytosolic enzyme. Oxidative attack on the ether bond in lipids is similar to the enzymatic mechanism described for the hydroxylation of phenylalanine. Fatty aldehydes produced via the cleavage reaction can be either oxidized to the corresponding acid or reduced to the alcohol by appropriate enzymes. 

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