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Enzymatyczne utlenianie typu Baeyera-Villgera

Kołek T., Świzdor A., Panek A.

Wiadomości Chemiczne

2009

[Z] 63, 9-10

819-845

Baeyer-Villiger (BV) reaction is oxidation of ketones, leading to cleavage of one of the C-CO-C bonds with simultaneous insertion of an oxygen atom into the cleaved bond. Resulting products obtained from cyclic ketones are lactones, while esters are obtained from acyclic ketones. Numerous strains of microorganisms produce enzymes catalyzing BV oxidation. These enzymes participate in the processes of degradation of natural and synthetic ketones, which can be used by the microorganisms as carbon source (Scheme 3 and 4). The enzymes are monooxygenases (Baeyer-Villigerases, BVMOs), usually containing flavinoadenine nucleotide and cooperating with NAD(P)H reductases. Research on the role of BV oxidation in degradation processes has evolved into intensive studies on the mechanism of this reaction and its use in synthesis, especially after isolation (in 1976) of cyclohexane monooxygenase from Acinetobacter sp. NCIB9871(CHMOAcineto 1) [9]. Subsequently, further strains were identified which produced BVMOs catalyzing oxidation of ketones of diverse structures. In addition to the best-characterized cyclohexane monooxygenase, there are: cyclopentanone, phenylacetone, cyclododecanone, aliphatic ketone and 2-oxo-3-en-4,5,5-trimethyl-cyclopentenylacetic acid monooxygenases. The adjective characterizing a given BVMO is derived from the ketone constituting carbon source, or from the ketone which is oxidized with the highest yield. In addition to these ketones, the enzymes accept their various structural analogues, therefore it is possible to select a biocatalyst which carries out oxidation of a given substrate. Among BVMOs, particularly selective are the enzymes carrying out BV oxidation of steroidal ketones: these enzymes operate only on steroid substrates, mostly containing 3-oxo--4-en moiety, but also they exhibit regioselectivity as well - the oxidation of ketones takes place only at C-17. During the regioselective enzymatic oxidation, "atypical" lactones [2, 4], which are not produced in chemical BV oxidation processes, are sometimes formed. Products of stereoselective enzymatic reactions are optically pure lactones and esters, which are starting points for further asymmetric synthesis of biologically active compounds, including medicines. The application of genetic engineering allows obtaining recombinant microbial strains, which are non-pathogenic and produce larger amounts of the enzyme than the wild-type strains. The recombinants are also able to produce mutated BVMOs exhibiting higher selectivity and/or lifetime, as well as activity towards different spectrum of substrates than the parent enzymes [2]. However, reaction yields of transformations carried out by the recombinants are still not significantly better than the results obtained with the wild-type strains. The recombinants usually require an expensive reagent, isopropyl-? --D-tiogalactopyranoside (ITPG), to induce their BVMOs [23]. Enzymatic BV oxidation, due to the selectivity of the enzymatic action, is competitive to the chemical oxidation. The enzyme selectivity allows for using pure products, including enantiopure compounds, with high yield. The process is environmentally friendly, because the oxidizer in the enzymatic BV reaction is molecular oxygen, and the amount of byproducts is limited. Synthetic application of BVMOs is limited by three principal factors: isolation of the enzyme in amounts suitable for large-scale applications, decrease in the enzymatic activity in the presence of the substrate and/or the product, and the isolation of the product. Separation of the unreacted enantiomer of the substrate in the process of kinetic separation of the racemic mixture, or separation of regioisomeric lactones are costly and time-consuming operations. Another possible problem is the fact that some strains producing useful BVMOs are pathogenic. Therefore, multidirectional research efforts are devoted to overcome the aforementioned barriers with the goal of establishing economically viable methods of biotransformations [4].