Pathways catechol

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Metabolic pathways containing dioxygenases in wild-type strains are usually related to detoxification processes upon conversion of aromatic xenobiotics to phenols and catechols, which are more readily excreted. Within such pathways, the intermediate chiral cis-diol is rearomatized by a dihydrodiol-dehydrogenase. While this mild route to catechols is also exploited synthetically [221], the chirality is lost. In the context of asymmetric synthesis, such further biotransformations have to be prevented, which was initially realized by using mutant strains deficient in enzymes responsible for the rearomatization. Today, several dioxygenases with complementary substrate profiles are available, as outlined in Table 9.6. Considering the delicate architecture of these enzyme complexes, recombinant whole-cell-mediated biotransformations are the only option for such conversions. E. coli is preferably used as host and fermentation protocols have been optimized [222,223]. 

After reuptake into the cytosol, some noradrenaline may be taken up into the storage vesicles by the vesicular transporter and stored in the vesicles for subsequent release (see above). However, it is thought that the majority is broken down within the cytosol of the nerve terminal by monoamine oxidase (MAO ECl.4.3.4). A second degradative enzyme, catechol-O-methyl transferase (COMT EC2.1.1.6), is found mostly in nonneuronal tissues, such as smooth muscle, endothelial cells or glia. The metabolic pathway for noradrenaline follows a complex sequence of alternatives because the metabolic product of each of these enzymes can act as a substrate for the other (Fig 8.8). This could enable one of these enzymes to compensate for a deficiency in the other to some extent. 

Catechol-O-methyltransferase (COMT EC 2.1.1.6) is located in many tissues and catalyzes the methylation of polyphenols. The methylation is a well-established pathway in the metabolism of flavonoids such as those that undergo 3, 4 -dihydrox-ylation of ring B excreted as 3 -0-methyl ether metabohtes in rat bile. " Recently, the apparent methylation of both cyanidin-3-glucoside and cyanidin-3-sambubioside (cyanidin is an anthocyanin with a 3, 4 -dihydroxylation of ring B) to peonidin-3-glucoside and peonidin-3-sambubioside was reported in humans. In rats, this transformation occurred mainly in the liver and was catalyzed by COMT."°... 

Degradation of the products of hydroxylation then involves fission of the catechols (or 2,5-dihydroxybenzoates) that are produced. All three fission pathways have been observed for 3,4-dihydroxybenzoate ... 

FIGURE 3.23 Alternative dioxygenation pathways for 3-substituted catechols (a) extradiol, (b) intradiol, and (c) distal. 

This comprises a heterogeneons gronp of enzymes that is used for the degradation of snbstrates including gentisate, salicylate, and l-hydroxynaphthalene-2-carboxylate by pathways that do not involve catechols ... 

Hughes EJL, RC Bayly (1983) Control of catechol mera-cleavage pathway in Alcaligenes eutrophus. J Bacterial 154 1363-1370. 

Krooneman J, EBA Wieringa, ERB Moore, J Gerritse, RA Prins, JC Gottschal (1996) Isolation of Alcalig-enes sp. strain L6 at low oxygen concentrations and degradation of 3-chlorobenzoate via a pathway not involving (chloro)catechols. Appl Environ Microbiol 62 2427-2434. 

Barnsley EA (1976) Role and regulation of the ortho and meta pathways of catechol metabolism in pseudomonads metabolizing naphthalene and salicylate. J Bacteriol 125 404-408. 

The degradation of 2,2 -dihydroxy- 3,3 -dimethoxybiphenyl-5,5 -dicarboxylate (5,5 -dehydro-divanillate) by Sphingomonas paucimobilis SYK-6 proceeds by partial de-O-methylation followed by extradiol hssion of the catechol to 2-hydroxy-3-methoxy-5-carboxybenzoate. Diversion of this into central metabolic pathways involves decarboxylation to vanillate by two separate decarboxylases LigWl and LigW2 (Peng et al. 2005). 

The mandelate pathway in Pseudomonas putida involves successive oxidation to benzoyl formate and benzoate, which is further metabolized via catechol and the 3-ketoadipate pathway (Figure 8.35a) (Hegeman 1966). Both enantiomers of mandelate were degraded through the activity of a mandelate racemase (Hegeman 1966), and the racemase (mdlA) is encoded in an operon that includes the next two enzymes in the pathway—5-mandel-ate dehydrogenase (mdlB) and benzoylformate decarboxylase (mdlC) (Tsou et al. 1990). 

Ring fission. Ring fission of substituted catechols may take place by three pathways intradiol (ortho), extradiol (meta), or distal (1 6) fission. Although extradiol fission is generally preferred for substituted catechols, the product from extradiol fission of... 

FIGURE 9.2 Ring-cleavage pathways for the biodegradation of 3-substituted catechols. 

For 3-chlorobenzoate, an alternative pathway in Alcaligenes sp. strain BR60 may involve 3,4- or 4,5-dioxygenation. Ring fission of the catechols resulted in the production of pyruvate and oxalacetate (Nakatsu and Wyndham 1993). 

There is an additional problem that has important implications for the bioremediation of contaminated sites when two substrates such as a chlorinated and an alkylated aromatic compound are present. The extradiol fission pathway is generally preferred for the degradation of alkylbenzenes (Figure 9.17), although this may be incompatible with the degradation of chlorinated aromatic compounds since the 3-chlorocatechol produced inhibits the activity of the catechol-2,3-oxygenase (Klecka and Gibson 1981 Bartels et al. 1984). 

Sala-Trepat JM, WC Evans (1971) The meta cleavage of catechol by Azotobacter species 4-oxalocrotonatev pathway. Eur J Biochem 20 400-413. 

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