The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

TY - JOUR

T1 - The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

AU - Grogan, Gideon James

AU - Petchey, Mark

AU - Cuetos, Anibal

AU - Rowlinson, Benjamin

AU - Dannevald, Stephanie

AU - Frese, Amina

AU - Sutton, Peter

AU - Lovelock, Sarah

AU - Lloyd, Richard

AU - Fairlamb, Ian James Stewart

N1 - © 2018 Wiley-VCH Verlag GmbH &Co. KGaA,Weinheim. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2018/9/3

Y1 - 2018/9/3

N2 - Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods of 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 has been 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 has 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.

AB - Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods of 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 has been 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 has 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.

KW - ATP

KW - adenylation

KW - amides

KW - biocatalysis

KW - ligases

UR - http://www.scopus.com/inward/record.url?scp=85052384806&partnerID=8YFLogxK

U2 - 10.1002/anie.201804592

DO - 10.1002/anie.201804592

M3 - Article

SN - 1433-7851

VL - 57

SP - 11584

EP - 11588

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 36

ER -