Issue 4, 2011
From the journal:

Molecular BioSystems

Regioselective deacetylation based on teicoplanin-complexed Orf2* crystal structures†

Hsiu-Chien Chan,abc   Yu-Ting Huang,a   Syue-Yi Lyu,a   Chuen-Jiuan Huang,a   Yi-Shan Li,a   Yu-Chen Liu,a   Chia-Cheng Chou,d   Ming-Daw Tsai*ab  and  Tsung-Lin Li*ae  

* Corresponding authors

a Genomics Research Center, Academia Sinica, Taipei, Taiwan
E-mail: tlli@gate.sinica.edu.tw
Fax: +886 2 2789 8811
Tel: +886 2 2787 1235

b Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
E-mail: mdtsai@gate.sinica.edu.tw
Fax: +886 2 2788-9759
Tel: +886 2 2785-5696 ext 1013

c Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan

d National Synchrotron Radiation Research Center, Hsinchu, Taiwan

e Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

Abstract

Lipoglycopeptide antibiotics are more effective than vancomycin against MRSA as they carry an extra aliphatic acyl side chain on glucosamine (Glm) at residue 4 (r4). The biosynthesis of the r4 N-acyl Glc moiety at teicoplanin (Tei) or A40926 has been elucidated, in which the primary amine nucleophile of Glm is freed from the r4 GlcNac pseudo-Tei precursor by Orf2* for the subsequent acylation reaction to occur. In this report, two Orf2* structures in complex with β-D-octyl glucoside or Tei were solved. Of the complexed structures, the substrate binding site and a previously unknown hydrophobic cavity were revealed, wherein r4 GlcNac acts as the key signature for molecular recognition and the cavity allows substrates carrying longer acyl side chains in addition to the acetyl group. On the basis of the complexed structures, a triple-mutation mutant S98A/V121A/F193Y is able to regioselectively deacetylate r6 GlcNac pseudo-Tei instead of that at r4. Thereby, novel analogs can be made at the r6 sugar moiety.

Graphical abstract: Regioselective deacetylation based on teicoplanin-complexed Orf2* crystal structures

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Article information

DOI
https://doi.org/10.1039/C0MB00320D
Article type
Paper
Submitted
09 Dec 2010
Accepted
06 Jan 2011
First published
25 Jan 2011

Mol. BioSyst., 2011,7, 1224-1231

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Regioselective deacetylation based on teicoplanin-complexed Orf2* crystal structures

H. Chan, Y. Huang, S. Lyu, C. Huang, Y. Li, Y. Liu, C. Chou, M. Tsai and T. Li, Mol. BioSyst., 2011, 7, 1224 DOI: 10.1039/C0MB00320D

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