Biotransformation processes acetylation

Major differences exist between species In biotransformation processes. For example, most animal species display either rapid (e.g. hamster) or slow (e.g. rat) acetylation activity, whereas hvimons are endowed with a genetically determined polymorphism (7). Differences In biotransformation activities account for many differences In susceptibility to carcinogenesis. For example. It has been demonstrated that differences In acetylation activity Influence the genotoxicity of aromatic amines (8). 

PEA and TYR are substrates for W-acetyltransferase (NAT)-mediated biotransformation process. NATs metabolize agents that contain an aromatic amine or hydrazine group. Addition of an acetyl group leads to a less soluble molecule, altering its pharmacokinetics [37]. Therefore, W-acetylation is used by cells as an inactivation process of excess amines. Substrate specificity of NAT for biogenic amines was investigated in Fasciola Hepatica. TYR and PEA were found to be the best substrates with a relative rate of 98-100 % as compared to serotonin, norepinephrine, and DOP [38]. 

Biotransformation reactions can be classified as phase 1 and phase 11. In phase 1 reactions, dmgs are converted to product by processes of functionalization, including oxidation, reduction, dealkylation, and hydrolysis. Phase 11 or synthetic reactions involve coupling the dmg or its polar metaboHte to endogenous substrates and include methylation, acetylation, and glucuronidation (Table 1). 

Since there is no commercially available D-aminoacylase, the production process of D-amino acids involves cloning of the D-aminoacylase and the whole cells containing the recombinant d-aminoacylase are used in biotransformation of /V-acetyl-D-amino acid, d-Amino acids can be generated in large quantities at low cost using whole-cell biotransformation [23]. 

Figure 19.9 Metabolic possibilities for model compounds having representative functionality. Selected phase 1 reactions (1) Hydrolysis of various types of esters, in this case mediated by a carboxylesterase (2) N-dealkylation mediated by certain of the Cytochrome P-450 (CYP) enzymes (3) O-dealkylation mediated by certain of the CYPs and (4) Aromatic hydroxylation also mediated by certain of the CYPs. Depending upon the subtleties of their electronic and steric environments, the relative competitive biotransformation rates for these processes will generally be (1) (2) > (3) (4). Selected phase 2 reactions (5) Formation of a glucuronic acid conjugate (or in some cases a sulfate conjugate) and (6) N-acetylation. In terms of relative biotransformation rates in general (5) >> (6).

Historically, the biocatalytic acyloin condensation was first observed by Liebig in 1913 during studies on baker s yeast [1460]. A few years later, Neuberg and Hirsch reported the formation of 3-hydroxy-3-phenylpropan-2-one (phenyl acetyl carbinol, PAC) from benzaldehyde by fermenting baker s yeast [1461]. Without knowledge on the actual enzyme(s) involved, this biotransformation assumed early industrial importance when it was shown that the acyloin thus obtained could be converted into (-)-ephedrine by diastereoselective reductive amination, a process which is still utilized in almost unchanged form at a capacity of 120 t/year [1462, 1463] (Scheme 2.199). Subsequent studies revealed that this yeast-based protocol can be extended to a broad range of aldehydes [1464, 1465]. 

To start with the first option of such a chemoenzymatic process sequence, namely initial biotransformation and subsequent chemocatalytic or classical chemical reaction(s), an early example from the Gijsen and Wong [40] already in 1995 demonstrated a one-pot process for the synthesis of a cyclitol, which is based on an initial enzymatic aldol reaction of aldehyde 37 with 0-monophosphorylated dihy-droxyacetone, followed by a subsequent spontaneous cyclization via intramolecular Horner-Wadsworth-Emmons olefination reaction (Scheme 19.14). Furthermore, the resulting functionalized cyclopentene derivative 39 was deprotected in situ in the presence of an added phosphatase. By means of this one-pot three-step process, the desired trihydroxylated cyclopentene derivative 40 was formed, which was then further transformed via acetylation into the desired product 41 with an overall yield of 71%. A closely related process represents the combination of an enzymatic aldol reaction with a subsequent nitroaldol reaction (Henry reaction). Examples for such a type of process were developed independently by the Wong [41] and Lemaire [42] groups. 

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