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The broad aryl acid specificity of the amide bond synthetase McbA suggests potential for the biocatalytic synthesis of amides

DOI: 10.1002/anie.201804592 DOI Help

Authors: Mark Petchey (University of York) , Anibal Cuetos (University of York) , Benjamin Rowlinson (University of York) , Stephanie Dannevald (University of York) , Amina Frese (University of York) , Peter W. Sutton (GSK Medicines Research Centre) , Sarah Lovelock (GSK Medicines Research Centre) , Richard C. Lloyd (GSK Medicines Research Centre) , Ian J. S. Fairlamb (University of York) , Gideon Grogan (University of York)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition , VOL 57 , PAGES 11584 - 11588

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 9948

Abstract: Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.

Journal Keywords: adenylation; amides; ATP; biocatalysis; ligases

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 05/09/2018 14:41

Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)