Ketone reductases

Formate-FDFI system was also applied in the reduction of 6-bromotetralone to (S)-6-bromotetralol, a potential pharmaceutical precursor, with the NADFI-depen-dent ketone reductase from Trichosporon capitatum [4b]. A resin (XAD L-323) was used to bind the product (Figure 8.4). 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

The focus of this chapter is on the penetration barrier. The metabolic barrier due to esterases [39-41], aminopeptidases [38], and ketone reductase [43,51] has been reviewed elsewhere [52], The present chapter reviews and describes the... 

VHL Lee, DS Chien, H Sasaki. (1988). Ocular ketone reductase distribution and its role in the metabolism of ocularly applied levobunolol in the pigmented rabbit. J Pharmacol Exp Therap 246 871-878. 

Stewart, J.D., Rodriguez, S. and Kayser, M.M. (2001) Cloning, structure, and activity of ketone reductases from baker s yeast. Enzyme Technologies for Pharmaceutical and Biotechnological, Applications 175-207. 

Aldehyde dehydrogenase Aldehyde reductase Ketone reductases... 

The carbonyl reductases catalyze reduction of aldehydes and ketones by reduced pyridine nucleotides (NADH and/or NADPH). As mentioned earlier, alcohol dehydrogenase can perform this function in the presence of a high ratio of NADH to NAD+. Other enzymes capable of carbonyl reduction include the aldehyde and ketone reductases. The aldehyde and ketone reductases have a ubiquitous species distribution, with the enzymes present in organisms ranging from bacteria to vertebrates. The mammalian carbonyl reductases have been extensively reviewed (101). 

As with the aldehyde reductases, ketone reductases are specific for NADPH as reductant. Also, some isoenzymes of ketone reductase have not been purified to homogeneity and therefore not fully characterized. It is clear, however, that the ketone reductases catalyze reduction of aromatic, aliphatic, cyclic, and unsaturated ketones to the corresponding alcohols. The ketone reductases also catalyze reduction of aromatic and aliphatic aldehydes to primary alcohols. The distribution and specificity of ketone reductases has been reviewed (103). 

Narawane M, Podder SK, Bundgaard H, Lee VHL (1993) Segmental differences in drug permeability, esterase activity and ketone reductase activity in the albino rabbit intestine (1993). J Drug Target 1 29-39. 

The chiral compounds (/ )- and (5)-bis(trifluoromethyl)phenylethanol are particularly useful synthetic intermediates for the pharmaceutical industry, as the alcohol functionality can be easily transformed without a loss of stereospecificity and biological activity, and the trifluoromethyl functionalities slow the degradation of the compound by human metabolism. A very efficient process was recently demonstrated for the production of the (5)-enantiomer at >99% ee through ketone reduction catalyzed by the commercially available isolated alcohol dehydrogenase enzyme from Rhodococcus erythropolis (Figure 9.1). The (7 )-enantiomer could be generated at >99% ee as well using the isolated ketone reductase enzyme KRED-101. 

Diketone and Other Ketone Reductases from Microbial Sources... 

Cloning, Structure, and Activity of Ketone Reductases from Baker s Yeast... 

IV. GENERAL APPROACH TO IDENTIFYING YEAST GENES ENCODING POTENTIAL KETONE REDUCTASES... 

Table 2 Key Sequence Features of Ketone Reductases and Conservations by S. cerevisiae Open Reading Frames... 

K Ishihara, N Nakajima, S Tsuboi, M Utaka. Asymmetric reduction of l-acetoxy-2-alkanones with bakers yeast purification and characterization of a-acetoxy ketone reductase. Bull Chem Soc Jpn 67 3314-3319, 1994. 

There is, however, a further group of NADPH-dependent carbonyl reductases that transfer the 4-pro-S hydrogen [143]. These include human brain aldehyde reductase I [144], liver xenobiotic ketone reductase [145] and prostaglandin 9-ketoreductase [146], all monomeric proteins with molecular weights in the range of 30000-400000. 

Microsomes prepared from maize embryos were also shown to catalyse the reduction of various sterones to produce the corresponding 3(3-hydroxy derivatives. Based on studies concerning co-enzyme requirements and inhibitor susceptibility, the enzyme termed sterone reductase was classified as belonging to the family of ketone reductases. Since 4,4-dimethyl-sterones react poorly as compared to desmethyl- or 4a-monomethyl sterones, it was concluded... 

Narawane M, Podder SK, Bundgaard H, and Lee VHL. Segmental Differences in Drug Permeability, Esterase Activity and Ketone Reductase Activity in the Albino Rabbit Intestine./Drug Targeting 1995 1 29-39. 

P.F. Kador, N.E. Sharpless and J.D. Goosey, in Progress in Clinical and Biological Research. 114. Workshop on Enzymology of Aldehyde Dehydrogenase and Aldehyde Ketone Reductase Weiner, H. and Wermuth, B., eds (Alan R. Liss, New York, 1982) pp. 243-259. 

Aldehyde reductases and ketone reductases are families of enzymes involved in reductive metabolism of both endogenously produced and xenobiotic aldehydes and ketones (1). Aldehyde reductase activity has been detected in cell-free preparations of... 

H. diminuta, Heligmosomoides polygyrus and in the free-living nematode Panagrellus redivivus (8). Ketone reductase activity, on the other hand, appears absent from these organisms. 

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