Characterization and Structural Determination of CmnG-A, the Adenylation Domain That Activates the Nonproteinogenic Amino Acid Capreomycidine in Capreomycin Biosynthesis

I-Hsuan Chen; Ting Cheng; Yung-Lin Wang; Szu-Jo Huang; Yu-Hsuan Hsiao; Yi-Ting Lai; Shu-Ing Toh; John Chu; Jeffrey D Rudolf; Chin-Yuan Chang

doi:10.1002/cbic.202200563

Characterization and Structural Determination of CmnG-A, the Adenylation Domain That Activates the Nonproteinogenic Amino Acid Capreomycidine in Capreomycin Biosynthesis

Chembiochem. 2022 Dec 16;23(24):e202200563. doi: 10.1002/cbic.202200563. Epub 2022 Nov 16.

Authors

I-Hsuan Chen^{1

2}, Ting Cheng¹, Yung-Lin Wang³, Szu-Jo Huang¹, Yu-Hsuan Hsiao¹, Yi-Ting Lai¹, Shu-Ing Toh², John Chu⁴, Jeffrey D Rudolf⁵, Chin-Yuan Chang^{1

6

7}

Affiliations

¹ Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan, ROC.
² Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan, ROC.
³ Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan ROC.
⁴ Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan, ROC.
⁵ Department of Chemistry, University of Florida, Gainesville, Florida, 32611-7011, USA.
⁶ Center for Intelligent Drug Systems and Smart Bio-devices, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan ROC.
⁷ Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan ROC.

PMID: 36278314
DOI: 10.1002/cbic.202200563

Abstract

Capreomycidine (Cap) is a nonproteinogenic amino acid and building block of nonribosomal peptide (NRP) natural products. We report the formation and activation of Cap in capreomycin biosynthesis. CmnC and CmnD catalyzed hydroxylation and cyclization, respectively, of l-Arg to form l-Cap. l-Cap is then adenylated by CmnG-A before being incorporated into the nonribosomal peptide. The co-crystal structures of CmnG-A with l-Cap and adenosine nucleotides provide insights into the specificity and engineering opportunities of this unique adenylation domain.

Keywords: CmnG; adenylation domains; capreomycidine; capreomycin; nonproteinogenic amino acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids*
Capreomycin
Peptide Synthases* / metabolism
Peptides / chemistry
Substrate Specificity

Substances

Amino Acids
Peptide Synthases
Capreomycin
capreomycidine
Peptides