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CATALYSIS
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Directed evolution yields enzyme that oxidizes alkenes in a unique way
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Anti-Markovnikov
Markovnikov oxidation of terminal alkenes (left) to form ketones (center) is energetically favored, whereas anti-Markovnikov reactions leading to aldehydes are more difficult.
day convert terminal-alkene substrates to Oxidizing the end carbon atom of a termia variety of aldehyde, alcohol, and amine nal alkene to form an aldehyde, a process products for commodity and fine chemical, called anti-Markovnikov alkene oxidation, pharmaceutical, and agrochemical use. directed evolution, with styrene as a subis difficult because the reaction is energetiThe Caltech researchers started with an strate, to boost anti-Markovnikov selectivcally unfavorable. The preferred process, in iron-based cytochrome P450 enzyme called ity from 45% to aMOx’s 81%. The evolved terms of energetics, is Markovnikov selecenzyme works well because it stabilizes tivity—oxidation of the substrate’s next-to- P450LA1 because it catalyzes a related reachigh-energy radical and carbocation interlast carbon, forming a ketone instead of an tion, metal-oxo alkene oxidation, in which mediates created when its iron-oxo group aldehyde. a metal-linked oxygen attacks the double attacks styrene’s terminal alkene, Chemists have long wanted to allowing anti-Markovnikov aldehyde find better ways to achieve anformation to predominate. ti-Markovnikov selectivity in alkene It took 12 mutations distributed oxidations—for example, to convert throughout the protein to transform the aldehyde products to linear alP450LA1 into aMOx. “No one could cohols, which are commonly used in flavorings, perfumes, lubricants, and explain how these substitutions cosmetics. Catalysts exist that can confer this reaction selectivity, much perform the tricky anti-Markovnikov less predict them,” Arnold says. “This oxidations, but they are very unproillustrates the power of directed evoductive and are not enantioselective. lution to create catalysts that have Frances H. Arnold and coworkers eluded chemists.” at Caltech thought a modified enKey advantages of the evolved zyme might succeed where traditionenzyme include its enantioselectival catalysts have struggled. The team ity and its turnover number, “which now reports using directed evolution, probably still isn’t sufficient for an iterative process of protein mucommercial viability but is pretty Changing 12 amino acids (red circles) in P450LA1 tation and screening for activity, to yielded the enzyme aMOx. The heme group is a black, respectable,” says John T. Groves of identify amino acid substitutions that blue, and red stick structure. Princeton University, who specializes convert a natural enzyme into a prein biomimetic catalysis. dominantly anti-Markovnikov alkene oxiThere’s currently a push in academia and bond, typically forming an epoxide. An dation catalyst (Science 2017, DOI: 10.1126/ industry to replace conventional catalytic earlier study by another group had found science.aao1482). reactions with enzymatic processes that that P450LA1 also makes 19% aldehyde side The evolved enzyme, called aMOx, is product by opening the epoxide. In the new use aqueous solvents at ambient temperafairly productive, catalyzing about 3,800 tures and pressures, work readily in flow study, postdoc Stephan C. Hammer, now oxidation reactions, or turnovers, before systems, and don’t require catalyst separaat the University of Stuttgart, found that running out of steam, compared to fewer tions, Groves says. Biocatalysts are favored the enzyme actually makes 45% aldehyde than 10 for earlier anti-Markovnikov oxifor this reason. “The new study is an imdirectly, without going through an epoxide dation catalysts. In conjunction with other portant step in the right direction.”—STU intermediate. reagents and catalysts, aMOx could one The researchers then used 10 rounds of BORMAN
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C&EN | CEN.ACS.ORG | OCTOBER 16, 2017
C R E D I T: S CI E NC E
Enzyme beats catalysts at oxidation game
