Enzymatic biotransformation

Figure 4.1 Comparison of metabolic bioconversions and enzymatic biotransformations...

Next to the metabolic bioconversions there are enzymatic biotransformations, which are characterized by a low number of fundamental well-defined reactions [11], However, there are often inherent limitations that need to be addressed the crucial ones are the following ... 

L-Ascorbic acid serves as a reductant for several important enzymatic biotransformations. These characteristic biological activities result from its enediol structure, which confers a strong electron-donating ability. In addition, there is considerable evidence that biological antioxidants, including ascorbic acid, play an important role in the prevention of a large number of chronic diseases such as cancer, cerebral apoplexy, diabetes, myocardial damage, and AIDS.367,368... 

The esterases, lipases, and proteases are often used to prepare chiral intermediates when the reactions are carried out in the synthetic mode. Selected examples of these enzymatic biotransformations will be discussed in the respective sections later in this chapter. The reader is directed to the following reviews and textbooks for additional information, especially regarding resolutions 5,19,26,72,156-159... 

In this context, Hoshino et al. have recently reported the cyclization of (3S)-2,3-oxidosqualene catalyzed by a Gly600-deletion mutant (AG600SHC) of the enzyme squalene-hopene cyclase (SHC) from Alicyclobacillus acidocal-darius (Scheme 31) [108]. The enzymatic biotransformation gave monocyclic (9) and tricyclic triterpenoids (38 and 44-47), but no detectable bicychc products [108]. Despite the authors biogenetic proposal of a conventional carbocationic pathway, the skeletal profile of products reported closely resembles that expected for a radical-type cyclization. 

After intravenous administration of oxaliplatin, about 33% and 40% of the dose is bound to erythrocytes and plasma proteins. The half-life averages 26 days, which is in accordance with the normal life expectancy of erythrocytes (12-50 days). Oxaliplatin undergoes rapid non-enzymatic biotransformation to form a variety of reactive platinum intermediates, which bind rapidly and extensively to plasma proteins and erythrocytes. The antineoplastic and toxic properties appear to reside in the non-protein bound fraction, whereas platinum bound to plasma proteins or erythrocytes is considered to be pharmacologically inactive. Biotransformation produces DACH-platinum dichloride, 12-DACH-platinum dicysteinate, 1,2-DACH-platinum diglutathionate, 1,2-DACH-platinum mono-glutathionate, and 1,2-DACH-platinum methionine. The erythrocyte contains only thiol derivatives, whereas all derivatives can be recovered from the plasma. 

MeHg accumulates in the brain where it is slowly converted to inorganic Hg. Whether CNS damage is due to MeHg per se, to its biotransformation to inorganic Hg, or to both is still controversial. The mechanisms and cellular site for the biotransformation in humans are not well understood. Both free-radical and enzymatic biotransformation has been proposed. 

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

Parmar A, Kumar H, Marwaha SS et al. (1998) Recent trends in the enzymatic conversion of cephalosporin C to 7-aminocephalosporanic add (7-ACA). Critic Rev Biotechnol 18(1) 1-12 Parmar A, Kumar H, Marwaha S et til. (2(XX)) Advances in enzymatic biotransformation of peni-dllins to 6-aminopenicillanic add (6-APA). Biotechnol Adv 18 289—301... 

The acidic form of classical sophorolipid (a deacetylated compound) produced by alkaline hydrolysis of the native lactonic form (Fig. 2) was successfully converted by enzymatic biotransformation (glycosidase catalysis) to an acidic glucose lipid [44]. Another modification was performed with alkyl-amines leading to alkylamides of the acidic sophorolipid [123]. Bisht et al. [128] reported an efficient chemoenzymatic route that led to an 6-O-acryloyl-sophorolipid macrolactone analog. The homopolymerization of this monomer as well as its copolymerization with acrylic acid and acrylamide led in maximum to a molecular weight of 4.2 x 10" Da. The first total synthesis of a major component of the microbial classical lactonic sophorolipid was described by Fiirstner et al. [129]. 

Nowadays, numerous yeast or bacterial or enzymatic biotransformations, biodegenerations, or bioconversions are known, and, as Chaleff [4] pointed out, in the initial excess of enthusiasm [5] that invariably accompanies the birth of a new field [6], biotransformations were hailed as a panacea that would ultimately displace tiaditional organic chemistry [7,8]. However, bioconversions should be employed when a given reaction step is not easily accomplished by classical chemical methods [9] thus, the role of biotransformations is one of support rather than replacement. 

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