Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase

Shan Wang; William D.G. Brittain; Qian Zhang; Zhou Lu; Ming Him Tong; Kewen Wu; Kwaku Kyeremeh; Matthew Jenner; Yi Yu; Steven L. Cobb; Hai Deng

doi:10.1038/s41467-021-27512-0

Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase

Shan Wang, William D.G. Brittain, Qian Zhang, Zhou Lu, Ming Him Tong, Kewen Wu, Kwaku Kyeremeh, Matthew Jenner^* (Corresponding Author), Yi Yu^* (Corresponding Author), Steven L. Cobb^* (Corresponding Author), Hai Deng^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

4 Downloads (Pure)

Abstract

Non-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity. Herein, we report the first biochemically characterized example of a type II thioesterase (TE_II) domain capable of catalysing aminoacyl chain transfer between thiolation (T) domains on two separate NRPS subunits responsible for installation of a dehydrobutyrine moiety. Biochemical dissection of this process reveals the central role of the TE_II-catalysed chain translocation event and expands the enzymatic scope of TE_II domains beyond canonical (amino)acyl chain hydrolysis. The apparent co-evolution of the TE_II domain with the NRPS subunits highlights a unique feature of this enzymatic cassette, which will undoubtedly find utility in biosynthetic engineering efforts.

Original language	English
Article number	62
Number of pages	14
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	10 Jan 2022
DOIs	https://doi.org/10.1038/s41467-021-27512-0
Publication status	Published - 10 Jan 2022

Bibliographical note

Funding Information:
This work was supported by the Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, W.B. and S.L.C., BB/P003656/1). S.W and H.D. are grateful for SFC Covid-19 Grant extension and bridging Fund and UKRI Covid-19 Extension Allocation Fund. Q.Z. and Y.Y. are grateful for financial support from the National Key Research and Development Program of China (2018YFA0900400), the National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y.). H.D. and Y.Y. are recipients of a Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617). M.J. is the recipient of a BBSRC Discovery Fellowship (BB/R012121/1). The Bruker MaXis II instrument used in this study was funded by the BBSRC (BB/M017982/1). K.K. and H.D. thank Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council-UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1).

Publisher Copyright:
© 2022, The Author(s).

Keywords

Biosynthesis
Enzyme mechanisms
Enzymes

Access to Document

10.1038/s41467-021-27512-0Licence: CC BY

Wang_etal_NC_Aminoacyl_Chain_Translocation_VoRFinal published version, 1.96 MBLicence: CC BY

Cite this

@article{bf0215bc850345de828dd3481870aa35,

title = "Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase",

abstract = "Non-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity. Herein, we report the first biochemically characterized example of a type II thioesterase (TEII) domain capable of catalysing aminoacyl chain transfer between thiolation (T) domains on two separate NRPS subunits responsible for installation of a dehydrobutyrine moiety. Biochemical dissection of this process reveals the central role of the TEII-catalysed chain translocation event and expands the enzymatic scope of TEII domains beyond canonical (amino)acyl chain hydrolysis. The apparent co-evolution of the TEII domain with the NRPS subunits highlights a unique feature of this enzymatic cassette, which will undoubtedly find utility in biosynthetic engineering efforts.",

keywords = "Biosynthesis, Enzyme mechanisms, Enzymes",

author = "Shan Wang and Brittain, {William D.G.} and Qian Zhang and Zhou Lu and Tong, {Ming Him} and Kewen Wu and Kwaku Kyeremeh and Matthew Jenner and Yi Yu and Cobb, {Steven L.} and Hai Deng",

note = "Funding Information: This work was supported by the Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, W.B. and S.L.C., BB/P003656/1). S.W and H.D. are grateful for SFC Covid-19 Grant extension and bridging Fund and UKRI Covid-19 Extension Allocation Fund. Q.Z. and Y.Y. are grateful for financial support from the National Key Research and Development Program of China (2018YFA0900400), the National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y.). H.D. and Y.Y. are recipients of a Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617). M.J. is the recipient of a BBSRC Discovery Fellowship (BB/R012121/1). The Bruker MaXis II instrument used in this study was funded by the BBSRC (BB/M017982/1). K.K. and H.D. thank Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council-UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jan,

day = "10",

doi = "10.1038/s41467-021-27512-0",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase

AU - Wang, Shan

AU - Brittain, William D.G.

AU - Zhang, Qian

AU - Lu, Zhou

AU - Tong, Ming Him

AU - Wu, Kewen

AU - Kyeremeh, Kwaku

AU - Jenner, Matthew

AU - Yu, Yi

AU - Cobb, Steven L.

AU - Deng, Hai

N1 - Funding Information: This work was supported by the Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, W.B. and S.L.C., BB/P003656/1). S.W and H.D. are grateful for SFC Covid-19 Grant extension and bridging Fund and UKRI Covid-19 Extension Allocation Fund. Q.Z. and Y.Y. are grateful for financial support from the National Key Research and Development Program of China (2018YFA0900400), the National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y.). H.D. and Y.Y. are recipients of a Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617). M.J. is the recipient of a BBSRC Discovery Fellowship (BB/R012121/1). The Bruker MaXis II instrument used in this study was funded by the BBSRC (BB/M017982/1). K.K. and H.D. thank Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council-UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1). Publisher Copyright: © 2022, The Author(s).

PY - 2022/1/10

Y1 - 2022/1/10

N2 - Non-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity. Herein, we report the first biochemically characterized example of a type II thioesterase (TEII) domain capable of catalysing aminoacyl chain transfer between thiolation (T) domains on two separate NRPS subunits responsible for installation of a dehydrobutyrine moiety. Biochemical dissection of this process reveals the central role of the TEII-catalysed chain translocation event and expands the enzymatic scope of TEII domains beyond canonical (amino)acyl chain hydrolysis. The apparent co-evolution of the TEII domain with the NRPS subunits highlights a unique feature of this enzymatic cassette, which will undoubtedly find utility in biosynthetic engineering efforts.

AB - Non-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity. Herein, we report the first biochemically characterized example of a type II thioesterase (TEII) domain capable of catalysing aminoacyl chain transfer between thiolation (T) domains on two separate NRPS subunits responsible for installation of a dehydrobutyrine moiety. Biochemical dissection of this process reveals the central role of the TEII-catalysed chain translocation event and expands the enzymatic scope of TEII domains beyond canonical (amino)acyl chain hydrolysis. The apparent co-evolution of the TEII domain with the NRPS subunits highlights a unique feature of this enzymatic cassette, which will undoubtedly find utility in biosynthetic engineering efforts.

KW - Biosynthesis

KW - Enzyme mechanisms

KW - Enzymes

U2 - 10.1038/s41467-021-27512-0

DO - 10.1038/s41467-021-27512-0

M3 - Article

AN - SCOPUS:85122862316

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 62

ER -

Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this