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Rationalization of stereoselectivity in enzyme reactions

Advanced Review

H. C. Stephen Chan, Lu Pan, Yi Li, Shuguang Yuan

Published Online: Dec 05 2018

DOI: 10.1002/wcms.1403

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Enzymes are responsible for more than 5,000 different types of biochemical reactions. Enzymes speed up various chemical reactions in cell that would otherwise take millions of years to occur in milliseconds. The ability to discriminate between optical isomers is vital for living systems. The selective formation of only one product stereoisomer from achiral substrates is one of the most sophisticated tasks for enzymes. Because of the importance of stereoselectivity in biology, the structural and mechanistic basis underlying these phenomena has become the subject of intensive research. Enzymatic reactions provide the basis of cellular biochemistry and typically display high stereoselectivity. With the advances of enzyme engineering, in vitro evolution and, especially, computational rational design, scientists start to provide various methods and tools to manipulate the stereoselective properties of enzymes. To gain an insightful view of stereoselectivity in enzyme reactions, we present an extensive discussion on the latest progresses in this area. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Reaction Mechanisms and Catalysis Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods

Scheme of enzyme catalysis. (a) The catalytic process and induced fit effect of enzyme. (b) The activation energy of enzyme catalysis compared to that of no enzyme reactions

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Calculated activation energy barrier and substrate−water distances of LEH variant SZ719. (a) The catalysis scheme of LEH. (b) The activation energy barrier of SZ719–CYO1. Distance in blue was calculated by QM methods. (c) Distances of C1O2 and C2O2 along MD simulations of SZ719–CYO1. (d) The activation energy barrier of SZ719–CYO3. Distance in blue was calculated by QM methods. (e) Distances of C1O2 and C2O2 along MD simulations of SZ719–CYO3. (Reprinted with permission from Reference . Copyright 2018 American Chemical Society)

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Two dominant binding modes of fluoroacetate dehalogenases (FAcD) substrates and their relative ligand binding energies. (a) The reaction scheme of FAcD. (b) The binding mode 1 of (S)‐1, with ΔG_S1 = −60.1 ± 1.1 kcal/mol (−35.4 ± 0.7, monomer). (c) The binding mode 2 of (S)‐1, with ΔG_S2 = −28.1 ± 0.4 kcal/mol (−14.4 ± 0.9, monomer). (d) The binding mode 1 of (R)‐1, with ΔG_R1 = −35.7 ± 0.7 kcal/mol (−16.4 ± 0.8, monomer). (e) The binding mode 2 of (R)‐1, with ΔG_S2 = −17.5 ± 1.1 kcal/mol (−6.4 ± 0.9, monomer). (Reprinted with permission from Reference . Copyright 2017 American Chemical Society)

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One‐pot consecutive two‐enzyme sequential cascade. 4‐Oxo‐pentenoate derivatives are first hydrogenated 4‐oxo‐pentanoate via enoate reductase (ER). The cis‐ or trans‐ of the precursors affect the anti‐ or syn‐configurations of the immediate products. The ketone is further reduced to hydroxyl group via alcohol dehydrogenase (ADH). ADH produced from various bacterial species such as Thermoanaerobacter sp. (ADH_T) or Lactobacillus brevis (ADH_LK) stereoselectively produces the alcohol semiproducts. The closure of lactone ring is achieved by simple acidification

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Engineering of CYP260A1 for stereoselective hydroxylation of progesterone. (a) S276 in the engineered enzyme corresponds to S326 in the native CYP260A1. S276I and S276N mutants selectively catalyze 1α‐ and 17α‐hydroxylation, respectively. (b) The binding mode of progesterone in S276I‐progesterone complex (PDB ID: 6F8C) corresponds to the predicted docking pose I. (c) The binding mode of progesterone in S276N‐progesterone complex (PDB ID: 6F88) corresponds to the predicted docking pose II

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Diels–Alder reaction. (a) The de novo designed diels‐alderase, DA_20_10, catalyzes the formation of nearly pure 3R,4S‐product. (b) True catalysis by ribozyme: the oligo(ethylene glycol) anthracene derivatives enters the active site via a wider opening. The resulting orientation favors the formation of R,R‐product. (c) Tethered catalysis: the anthracene moiety is tethered near the narrower backdoor openings on the ribozyme. A short ethylene glycol tether of 2–8 units long forces the substrate to enter the active site with opposite orientation, leading to S,S‐product

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Further Reading

Antonaccio, MJ. Angiotensin converting enzyme (ACE) inhibitors. Annu Rev Pharmacol Toxicol. 1982;22:57–87.
Blake, K, Raissy, H. Chiral switch drugs for asthma and allergies: True benefit or marketing hype. Pediatr Allergy Immunol Pulmonol. 2013;26:157–160.
Brossi, A, Pei, X‐F. Biological activity of unnatural alkaloid enantiomers. In: Cordell, GA, editor. The alkaloids: Chemistry and biology. Volume 50. Academic Press, 1998; p. 109–139.
Dinis‐Oliveira, RJ. Metabolic profile of oxazepam and related benzodiazepines: Clinical and forensic aspects. Drug Metab Rev. 2017;49:451–463.
Flesch, G, Müller, P, Lloyd, P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol. 1997;52:115–120.
Gascon, AR, Campo, E, Hernandez, RM, Calvo, B, Errasti, J, Pedraz Munoz, JL. Pharmacokinetics of ofloxacin enantiomers after intravenous administration for antibiotic prophylaxis in biliary surgery. J Clin Pharmacol. 2000;40:869–874.
Greenblatt, DJ, Zammit, GK. Pharmacokinetic evaluation of eszopiclone: Clinical and therapeutic implications. Expert Opin Drug Metab Toxicol. 2012;8:1609–1618.
Jeon, SH, Kim, M, Han, HK, Lee, W. Direct enantiomer separation of thyroxine in pharmaceuticals using crown ether type chiral stationary phase. Arch Pharm Res. 2010;33:1419–1423.
Korhonova, M, Doricakova, A, Dvorak, Z. Optical isomers of atorvastatin, rosuvastatin and fluvastatin enantiospecifically activate Pregnane X receptor PXR and induce CYP2A6, CYP2B6 and CYP3A4 in human hepatocytes. PLoS One. 2015;10:e0137720.
Landoni, MF, Soraci, A. Pharmacology of chiral compounds 2‐arylpropionic acid derivatives. Curr Drug Metab. 2001;2:37–51.
Lukša, J, Josić, D, Podobnik, B, Furlan, B, Kremser, M. Semi‐preparative chromatographic purification of the enantiomers S‐(−)‐amlodipine and R‐(+)‐amlodipine. J Chromatogr B Biomed Sci Appl. 1997;693:367–375.
Mehvar, R, Brocks, DR. Stereospecific pharmacokinetics and pharmacodynamics of beta‐adrenergic blockers in humans. J Pharm Pharm Sci. 2001;4:185–200.
Mitra, S, Chopra, P. Chirality and anaesthetic drugs: A review and an update. Indian J Anaesth. 2011;55:556–562.
Weinberg, ED, Tonnis, SM. Action of chloramphenicol and its isomers on secondary biosynthetic processes of bacillus. Appl Microbiol. 1966;14:850–856.

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