A new cubic-space section model for predicting the specificity of horse liver alcohol dehydrogenase-catalyzed oxidoreductions

Abstract

A new active site model for predicting and interpreting the stiuctural-and stereospecificity of horse liver alcohol dehydrogenase-catalyzed oxidations and reductions has been formulated from the specificity, X-ray, and kinetic data now available. The new model is based on a cubic-space system and is convenient and easy to use. The model is completely reliable and permits HLADH specificity towards all of its currently known substrates to be predicted with confidence. Its application is illustrated by analyses of representative examples of major substrate types.J. BRYAN JONES et IGNAC J. JAKOVAC. Can. J. Chem. 60, 19 (1982) A partir des donnees de specicite, de diffraction de rayons X et de cinetique disponibles. on a elabore un nouveau modele de site actif pour predire et interpreter la structure et la stereospecifite des oxydations et des reductions catalysee par la deshydrogenase de l'alcool du foie de cheval (DHAFC). Le nouveau modele est fonde sur un systeme d'espace cubique et est d'emploi facile. Le modele est completement fiable et permet de predire en toute confiance la specifite de la DHAFC envers tous ses substrats connus. On illustre son utilisation par I'analyse d'exemples representatifs des principaux types de substrats.[Traduit par le journal]The asymmetric synthetic opportunities provided by the chiral catalytic properties of enzymes are becoming increasingly recognized (2a,b). Alcohol dehydrogenases, which catalyze oxidoreductions of the type depicted in reaction are among the most useful enzymes for organic synthetic purposes, with the commercially available enzyme from horse liver the best documented.HLADH is an extremely versatile alcohol dehydrogenase, capable of effecting highly stereospecific oxidoreductions on a broad structural range of aldehyde, ketone, and alcohol substrates (2-6).In order for any enzyme to become widely adopted as a practical synthetic catalyst, it is essential that a reliable active site model be available for predicting the structural-and stereospecificity of the enzyme towards both known and potential substrate structures. Predictive systems of varying degrees of sophistication have been developed for a number of enzymes, including proteases (2a), mono-oxygenases (7, 8), and some alcohol dehydrogenases (2a, 3 , 4 , 9 ) . For HLADH, the diamond lattice section approach devised by Prelog ( 3 , and subsequently refined ( 2 a , 4 ) , has been very successful for interpreting the steric course of catalyses of cyclohexane and decalin substrates. However, for many of the other types of cyclic structures now known to be substrates ( 2 ) , stereochemical predictions based on diamond lattice analyses have become increasingly subjective and ~n c e r t a i n .~ It is clear that, after serving as a valuable active site model for nearly twenty years, the diamond lattice section has become totally inadequate for interpreting the stereochemical course of HLADH-catalyzed oxidoreductions of many of the recently identified, and still expanding, range of substrate structures (2, 6b)....

Enzymes in organic synthesis. 32. Stereospecific horse liver alcohol dehydrogenase-catalyzed oxidations of exo- and endo-oxabicyclic meso diols

“…The spectral data did not permit unequivocal isomeric Can Cubic active-site section analysis of the stereospecificity of HLADH-catalyzed oxidation of the exo-diol 1. The model, the analytical procedure applied, and the alphanumeric assignments of the cube locations are as described previously (6). In this analysis, the top elevation perspective is used to depict the substrate orientations.…”

Metallation of Phosphorylated Aliphatic Alcohols to Configurationally Stable α-Oxyalkyllithium Compounds − Use of the Phosphoryl Group as an Activating Group and Electrophile

“…[17] Ethyl hexanoate (20) was reduced with LiAlD 4 (D Ն 98%) in diethyl ether to form the dideuterated hexanol 21 (D Ն 98%) in 94% yield, which was oxidised to the deuterated hexanal 22 (D Ն 99%, yield 48%) with PCC in the presence of 3 Å molecular sieves. [18] The aldehyde was reduced stereospecifically with horse liver alcohol dehydrogenase/NAD ϩ /EtOH in a phosphate buffer pH 6.9 at 30°C for 16 h to give (S)-(ϩ)-1-deuteriohexanol (23) in 69% yield.…”

“…[19] The absolute configuration of the alcohol was assigned on the basis of precedence for the reduction of other aldehydes. [17,19] Its enantiomeric excess (ee Ն 98%) was determined by derivatisation with (S)-(ϩ)-MTPACl/pyridine and 1 H NMR spectroscopy with decoupling of the hydrogen substituents at C-2. Phosphorylation of the deuterated hexanol 23 with perdeuterated diisopropyl bromophosphate in the same way as hexanol furnished phosphate (S)-(ϩ)-24.…”

Enantioselective Syntheses and Absolute Configurations of Viridiene and Aucantene, Two Constitutents of Algae Pheromone Bouquets

“…This high ee is remarkable, since the oxidation of a number of racemic trans-diols with HLADH yields only lactones of low optical purity (1-16% ee) [7]. The stereochemical outcome in both cases corresponds to the side-specificity of HLADH as deduced from the 'cubic-site model' of the enzyme's active center [24]. Hence, on reduction of the aldehydes rac-5a and rac-15, the same spatial conformation of the substrates is involved as on oxidation of the diols rac-1 and 12 (cf.…”

“…Scheme I and 3). By following the 'cubic-site analysis' [24], this allows prediction of the absolute configuration of the products obtained.…”