Substrate stereoselectivity

Haining RL, Hunter AP, Veronese ME, et al. Allelic variants of human cytochrome P450 2C9 baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996 333(2) 447 t58. 

K. Adachi, S. Kobayashi, M. Ohno, Chiral Synthons by Enantioselective Hydrolysis of meso-Diesters with Pig Liver Esterase Substrate-Stereoselectivity Relationships , Chi-mia 1986, 40, 311-314. 

All of the above examples are acetates of active alcohols. Here, we also mention the acetate of a phenol, namely the provitamin a-tocopheryl acetate, whose natural enantiomer of absolute configuration (2R,47 ,87 ) is shown as 8.73. a-Tocopheryl acetate is a substrate of cholesterol esterase (EC 3.1.1.13), and was hydrolyzed in rats faster than its (2S,47 ,87 )-epimer. In vitro experiments required a-tocopheryl acetate to be dispersed as a micellar pseudosolution, and the nature of the bile salt used to prepare micelles had a profound effect on the substrate stereoselectivity of the reaction [95] [96], Only when the micelle composition approximated that of the gastrointestinal tract did the in vitro substrate stereoselectivity resemble that seen in vivo. 

The same model indicates, of course, that only (S)-lactate [not (R)-lactate] is formed in the reduction. By the same token it explains why, in the reverse reaction, the enzyme is substrate stereoselective for (S)-lactate (R)-lactate, if locked into the enzyme cavity, would have CH3 rather than C—H juxtaposed with the NAD+ and could thus not be oxidized. 

In 1996, Feringa < /< /.198,198a reported the use of monodentate phosphoramidites of type 257 in Michael additions of diethylzinc to several enones (Scheme 63). These reactions are catalyzed by copper(i) salts and also by copper(n) triflate when cyclohex-2-enone was used as substrate, stereoselectivities of 60% ee (with CuOTf) and 63% ee (with Cu(OTf)2) were obtained, whereas a much higher value of 81% ee resulted with 4,4-dimethylcyclohex-2-enone in the... 

The ability of baker s yeast to transform unconventional substrates stereoselectively is well known, as one can judge from the considerable amount of work in this area reported in the early literature 1). 

V. Sundaresan and R. Abrol,Towards a general model for protein-substrate stereoselectivity, Protein Sci. 11 (2002), 1330. 

Generally speaking, conclusions regarding stereoselective sulfation in vivo are difficult to draw, because of competition between (stereoselective) glucuronidation and sulfation of the same substrates. Stereoselective sulfation of 4 -hydroxypiopranol enantiomers was demonstrated in vitro in hepatic tissue of various species (Christ and Walle, 1985). Enantiomeric (-/-l-)-4 -hydroxypropranolol sulfate ratios varied from 1.07 in the rat and... 

As for stereoselectivity, relatively little is known as yet, except that the natural R configuration in the cysteine residue is a prerequisite for a cysteine conjugate to be a substrate of p-lyase. This fact has been used as a tool to ascertain the role of p-lyase in the development of nephrotoxicity by cysteine conjugates. No data are presently available with regard to the substrate-stereoselective effects of the noncysteine part of the thioether substrates of p-lyase (Commandeur and Vermeulen, 1990). Such stereoselective effects may be anticipated, however, since, for example, the regioisomeric 1,2- and 2,2-dichlorovinyl-LrCysteine conjugates have also... 

There must be enantiopure chiral information in the stereoselective step. This can be achieved either by using covalent attachment to one of the substrates (stereoselective auxiliary-based methods) or by creating a complex that is cleaved after the stereoselective elementary step under the reaction conditions and reused for the next molecule (stereoselective catalytic methods). Substrate control is observed when the substrates themselves are chiral,... 

Probably of more significance are chiral effects in metabolism which can be divided into (i) substrate stereoselectivity (the effect of... 

Chirality may feature in one of the following ways (a) substrate stereoselectivity (b) product stereoselectivity (c) inversion of configuration (d) loss of chirality. 

The substrates being metabolized at different rates may share various types of relationships. They may be chemically dissimilar or similar (e.g., analogs), in which case the term of substrate selectivity is used in a narrow sense. Alternatively, the substrates may be isomers such as positional isomers (regioiso-mers) or stereoisomers, resulting in substrate regioselectivity or substrate stereoselectivity. Substrate enantioselectivity is a particular case of the latter (see Section 5.1.2). 

Stereoselective metabolism is the most important process responsible for the stereoselectivity observed in pharmacokinetics. Verapamil has received considerable attention as an example of substrate stereoselective pharmacokinetics in humans. After oral administration, the drug undergoes an important stereoselective first pass metabolism, so that (— )-verapamil, the active enantiomer, has a two to three times lower bioavailability than its antipode. The (— )/(-f) plasma concentration ratio is therefore higher after intravenous than after oral administration. 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

Reactions of oxidoreduction are an example of chiral inversion that takes place by the intermediacy of two opposing metabolic processes. The alcohol/ketone equilibrium mediated by alcohol dehydrogenase enzyme is an abundant reaction. The dehydrogenation of secondary alcohols to a ketone proceeds with substrate stereoselectivity in oxidation, while the hydrogenation of the ketone metabolite is product selective to one face of the carbonyl group. The consequence of the metabolism of the secondary alcohols may involve chiral inversion of this center, which can result in an altered proportion of the two enantiomers or epimers. 

The stereoselectivity of the methylation of ketone enolates is determined by the structure of the substrate. Stereoselective methylation of cyclic ketone enolates has been examined in detail and current models reliably predict the stereochemical outcome (eqs 9-11). Diastereoselective methylation of acyclic ketone and ester enolates has been accomplished employing a variety of chiral auxiliaries (eq 12). Efficient catalytic enantioselective methylation of 6,7-dichloro-5-methoxy-l-indanone has been accomplished via a chiral phase-transfer catalyst (eq 13). An enantiomeric excess of 92% was observed when employing Chloromethane as the methylating agent, whereas... 

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