Biotransformation pathways oxidative enzymes

Finally, the yeast Yarrowia lipolytica is able to transform ricinoleic acid (12-hydroxy oleic acid) into y-decalactone, a desirable fruity and creamy aroma compound however, the biotransformation pathway involves fi-oxidation and requires the lactonisation at the CIO level. The first step of fi-oxidation in Y. lipolytica is catalysed by five acyl-CoA oxidases (Aox), some of which are long-chain-specific, whereas the short-chain-specific enzymes are also involved in the degradation of the lactone. Genetic constructions have been made to remove these lactone-degrading activities from the yeast strain [49, 50]. A strain displaying only Aox2p activity produced 10 times more lactone than the wild type in 48 h but still showed the same growth behaviour as the wild type. 

Microsomal oxidative reactions constitute the most prominent phase I biotransformation pathway for a wide variety of structurally unrelated drugs (Table 1.4). Some drugs (e.g. amphetamine, diazepam, propranolol, lignocaine) simultaneously undergo more than one type of microsomal-mediated oxidative reaction. Microsomal enzymes are located primarily in liver cells, where they are associated with the smooth-surface (without ribosomes) endoplasmic reticulum (Fouts, 1961). Lipid solubility is a prerequisite for drug access to the... 

One of the first laboratories to proactively use LC-MS-based methods to screen drug discovery candidates for drug-drug interactions was GlaxoSmithKline in 1998 [97], These assays can be performed either in vitro as described by Ayrton et al. [97] and Bu et al. [98] or in vivo [99,100], The methods feature the use of CYP enzymes that are involved in oxidative biotransformation pathways via hydroxyla-tion, iV-demethylalion, or O-desethylation. 

Still another experimental route to introducing otherwise excluded molecules into the brain is to chemically modify them so that they are lipophilic and therefore can passively diffuse. The brain, just as most other organs and tissues of the body, has enzymes to metabolize or biotransform metabolites in order to use and then get rid of them. Many of these pathways are oxidative. A reduced species or derivative which is lipophilic can enter the brain by simple passive diffusion there to be oxidatively transformed into an active state. Compounds which have been tested in animals include derivatives of 2-PAM (an antidote for organophosphate insecticide poisoning) and phenylethylamine (similar to amphetamine type molecules). Figure 5 illustrates the general concept behind this method. 

In some cases. Phase I metabolites may not be detected, owing to their instability or high chemical reactivity. The latter type are often electrophilic substances, called reactive intermediates, which frequently react non-enzymically as well as enzymically with conjugating nucleophiles to produce a Phase II metabolite. A common example of this type is the oxidative biotransformation of an aromatic ring and conjugation of the resulting arene oxide (epoxide) with the tripeptide glutathione. Detection of metabolites derived from this pathway often points to the formation of precursor reactive electrophilic Phase I metabolites, whose existence is nonetheless only inferred. 

Phase I oxidation generally is described as the addition of an oxygen atom (e.g., as an hydroxyl moiety) to the parent molecule. Phase I oxidation is carried out by multiple enzyme pathways, including the various isoforms of the cytochrome P450 (CYP) family and the non-P450 biotransformation enzymes such as flavin-containing monooxygenase (FMO) and monamine oxidase (MAO). 

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