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Featured researches published by Anke Krebber.


Science | 2010

Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture

Christopher Savile; Jacob Janey; Emily Mundorff; Jeffrey C. Moore; Sarena Tam; William R. Jarvis; Jeffrey C. Colbeck; Anke Krebber; Fred J. Fleitz; Jos Brands; Paul N. Devine; Gjalt Huisman; Gregory Hughes

Biocatalytic Boost Enzymes tend to direct reactions toward specific products much more selectively than synthetic catalysts. Unfortunately, this selectivity has evolved for cellular purposes and may not promote the sorts of reactions chemists are seeking to enhance (see the Perspective by Lutz). Siegel et al. (p. 309) now describe the design of enzymes that catalyze the bimolecular Diels-Alder reaction, a carbon-carbon bond formation reaction that is central to organic synthesis but unknown in natural metabolism. The enzymes display high stereoselectivity and substrate specificity, and an x-ray structure of the most active enzyme confirms that the structure matches the design. Savile et al. (p. 305, published online 17 June) applied a directed evolution approach to modify an existing transaminase enzyme so that it recognized a complex ketone in place of its smaller native substrate, and could tolerate the high temperature and organic cosolvent necessary to dissolve this ketone. This biocatalytic reaction improved the production efficiency of a drug that treats diabetes. An engineered enzyme offers substantial efficiency advantages in the production-scale synthesis of a drug. Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.


Current Opinion in Chemical Biology | 2010

Practical chiral alcohol manufacture using ketoreductases

Gjalt W. Huisman; Jack Liang; Anke Krebber

Over the past two years the application of ketoreductases in the commercial synthesis of chiral alcohols has undergone a revolution. Biocatalysts are now often the preferred catalyst for the synthesis of chiral alcohols via ketone reduction and are displacing reagents and chemocatalysts that only recently were considered break-through process solutions themselves. Tailor-made enzymes can now be generated from advanced, non-natural variants using HTP screening and modern molecular biology techniques. At the same time, global economic and environmental pressures direct industrial process development toward versatile platforms that can be applied to the different stages of product development. We will discuss the technologies that have emerged over the past years that have guided biocatalysis from the bottom of the toolbox, to the power tool of choice.


Organic Process Research & Development | 2010

Highly Enantioselective Reduction of a Small Heterocyclic Ketone: Biocatalytic Reduction of Tetrahydrothiophene-3-one to the Corresponding (R)-Alcohol

Jack Liang; Emily Mundorff; Rama Voladri; Stephan Jenne; Lynne Gilson; Aaron Conway; Anke Krebber; John Wing Wong; Gjalt Huisman; Susan Jane Truesdell; James Lalonde


Archive | 2004

Ketoreductase polypeptides and related polynucleotides

Simon Christopher Davis; Gjalt W. Huisman; Stephane J. Jenne; Anke Krebber; Lisa M. Newman


Metabolic Engineering | 2005

Semi-synthetic DNA shuffling of aveC leads to improved industrial scale production of doramectin by Streptomyces avermitilis.

Kim Jonelle Stutzman-Engwall; Steve Conlon; Ronald Fedechko; Hamish McArthur; Katja Pekrun; Yan Chen; Stephane J. Jenne; Charlene La; Na Trinh; Seran Kim; Ying-Xin Zhang; Richard J. Fox; Claes Gustafsson; Anke Krebber


Archive | 2004

Improved ketoreductase polypeptides and related polynucleotides

S. Christopher Davis; Stephane J. Jenne; Anke Krebber; Gjalt W. Huisman; Lisa M. Newman


Archive | 2010

Glucose dehydrogenase polypeptides and related polynucleotides

S. Christopher Davis; Stephane J. Jenne; Anke Krebber; Lisa M. Newman


Archive | 2008

Ketoreductase Polypeptides for the Reduction of Acetophenones

Jack Liang; Stephane J. Jenne; Emily Mundorff; Charlene Ching; John M. Gruber; Anke Krebber; Gjalt W. Huisman


Trends in Pharmacological Sciences | 1979

Structure-activity relationships

Emily Mundorff; Simon Christopher Davis; Gjalt W. Huisman; Anke Krebber; John H. Grate; Richard J. Fox


Archive | 2004

Improved glucose dehydrogenase polypeptides and related polynucleotides

Anke Krebber; Lisa M. Newman; S. Christopher Davis; Stephane J. Jenne

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