ClusterCAD 2.0: an updated computational platform for chimeric type I polyketide synthase and nonribosomal peptide synthetase design

Tao, Xavier B.; LaFrance, Sarah; Xing, Yifei; Nava, Alberto A.; Martin, Hector Garcia; Keasling, Jay D.; Backman, Tyler W. H.

doi:10.1093/nar/gkac1075

ClusterCAD 2.0: an updated computational platform for chimeric type I polyketide synthase and nonribosomal peptide synthetase design

Journal Article · Tue Nov 22 23:00:00 EST 2022 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkac1075· OSTI ID:1899641

Tao, Xavier B.; LaFrance, Sarah; Xing, Yifei; Nava, Alberto A.; Martin, Hector Garcia; Keasling, Jay D.;

Abstract

Megasynthase enzymes such as type I modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) play a central role in microbial chemical warfare because they can evolve rapidly by shuffling parts (catalytic domains) to produce novel chemicals. If we can understand the design rules to reshuffle these parts, PKSs and NRPSs will provide a systematic and modular way to synthesize millions of molecules including pharmaceuticals, biomaterials, and biofuels. However, PKS and NRPS engineering remains difficult due to a limited understanding of the determinants of PKS and NRPS fold and function. We developed ClusterCAD to streamline and simplify the process of designing and testing engineered PKS variants. Here, we present the highly improved ClusterCAD 2.0 release, available at https://clustercad.jbei.org. ClusterCAD 2.0 boasts support for PKS-NRPS hybrid and NRPS clusters in addition to PKS clusters; a vastly enlarged database of curated PKS, PKS-NRPS hybrid, and NRPS clusters; a diverse set of chemical ‘starters’ and loading modules; the new Domain Architecture Cluster Search Tool; and an offline Jupyter Notebook workspace, among other improvements. Together these features massively expand the chemical space that can be accessed by enzymes engineered with ClusterCAD.

View Journal Article

Sponsoring Organization:: USDOE

Grant/Contract Number:: EE0008926; AC02-05CH11231

OSTI ID:: 1899641

Alternate ID(s):: OSTI ID: 2246955
OSTI ID: 1987508

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: D1 Vol. 51; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

References (29)

Nonribosomal Peptide Synthesis-Principles and Prospects Süssmuth, Roderich D.; Mainz, Andi Angewandte Chemie International Edition, Vol. 56, Issue 14 https://doi.org/10.1002/anie.201609079	journal	March 2017
A Unique Amino Transfer Mechanism for Constructing the β-Amino Fatty Acid Starter Unit in the Biosynthesis of the Macrolactam Antibiotic Cremimycin Amagai, Keita; Takaku, Ryoma; Kudo, Fumitaka ChemBioChem, Vol. 14, Issue 15 https://doi.org/10.1002/cbic.201300370	journal	September 2013
Nonribosomal Peptides Produced by Minimal and Engineered Synthetases with Terminal Reductase Domains Tietze, Andreas; Shi, Yan‐Ni; Kronenwerth, Max ChemBioChem, Vol. 21, Issue 19 https://doi.org/10.1002/cbic.202000176	journal	June 2020
Structural insights into dehydratase substrate selection for the borrelidin and fluvirucin polyketide synthases Barajas, Jesus F.; McAndrew, Ryan P.; Thompson, Mitchell G. Journal of Industrial Microbiology & Biotechnology, Vol. 46, Issue 8 https://doi.org/10.1007/s10295-019-02189-z	journal	May 2019
The FK520 gene cluster of Streptomyces hygroscopicus var. ascomyceticus (ATCC 14891) contains genes for biosynthesis of unusual polyketide extender units Wu, Kai; Chung, Loleta; Revill, W. Peter Gene, Vol. 251, Issue 1 https://doi.org/10.1016/S0378-1119(00)00171-2	journal	June 2000
The bacitracin biosynthesis operon of Bacillus licheniformis ATCC 10716: molecular characterization of three multi-modular peptide synthetases Konz, Dirk; Klens, Andrea; Schörgendorfer, Kurt Chemistry & Biology, Vol. 4, Issue 12 https://doi.org/10.1016/S1074-5521(97)90301-X	journal	December 1997
Engineering DNA-Templated Nonribosomal Peptide Synthesis Huang, Hsin-Mei; Stephan, Philipp; Kries, Hajo Cell Chemical Biology, Vol. 28, Issue 2 https://doi.org/10.1016/j.chembiol.2020.11.004	journal	February 2021
Engineering modular polyketide synthases for production of biofuels and industrial chemicals Cai, Wenlong; Zhang, Wenjun Current Opinion in Biotechnology, Vol. 50 https://doi.org/10.1016/j.copbio.2017.08.017	journal	April 2018
Isolation and characterization of meridamycin biosynthetic gene cluster from Streptomyces sp. NRRL 30748 He, Min; Haltli, Bradley; Summers, Mia Gene, Vol. 377 https://doi.org/10.1016/j.gene.2006.03.021	journal	August 2006
Biosynthesis of polycyclopropanated high energy biofuels Cruz-Morales, Pablo; Yin, Kevin; Landera, Alexander Joule, Vol. 6, Issue 7 https://doi.org/10.1016/j.joule.2022.05.011	journal	July 2022
Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path Campodonico, Miguel A.; Andrews, Barbara A.; Asenjo, Juan A. Metabolic Engineering, Vol. 25 https://doi.org/10.1016/j.ymben.2014.07.009	journal	September 2014
RetroPath2.0: A retrosynthesis workflow for metabolic engineers Delépine, Baudoin; Duigou, Thomas; Carbonell, Pablo Metabolic Engineering, Vol. 45 https://doi.org/10.1016/j.ymben.2017.12.002	journal	January 2018
The Uncommon Enzymology of Cis-Acyltransferase Assembly Lines Keatinge-Clay, Adrian T. Chemical Reviews, Vol. 117, Issue 8 https://doi.org/10.1021/acs.chemrev.6b00683	journal	April 2017
Proof-Reading Thioesterase Boosts Activity of Engineered Nonribosomal Peptide Synthetase Pourmasoumi, Farzaneh; De, Sayantan; Peng, Huiyun ACS Chemical Biology, Vol. 17, Issue 9 https://doi.org/10.1021/acschembio.2c00341	journal	August 2022
Engineering a Polyketide Synthase for In Vitro Production of Adipic Acid Hagen, Andrew; Poust, Sean; Rond, Tristan de ACS Synthetic Biology, Vol. 5, Issue 1 https://doi.org/10.1021/acssynbio.5b00153	journal	November 2015
Comprehensive in Vitro Analysis of Acyltransferase Domain Exchanges in Modular Polyketide Synthases and Its Application for Short-Chain Ketone Production Yuzawa, Satoshi; Deng, Kai; Wang, George ACS Synthetic Biology, Vol. 6, Issue 1 https://doi.org/10.1021/acssynbio.6b00176	journal	September 2016
Formylation Domain: An Essential Modifying Enzyme for the Nonribosomal Biosynthesis of Linear Gramicidin Schoenafinger, Georg; Schracke, Nadine; Linne, Uwe Journal of the American Chemical Society, Vol. 128, Issue 23 https://doi.org/10.1021/ja0611240	journal	June 2006
Chemoinformatic-Guided Engineering of Polyketide Synthases Zargar, Amin; Lal, Ravi; Valencia, Luis Journal of the American Chemical Society, Vol. 142, Issue 22 https://doi.org/10.1021/jacs.0c02549	journal	May 2020
The Amipurimycin and Miharamycin Biosynthetic Gene Clusters: Unraveling the Origins of 2-Aminopurinyl Peptidyl Nucleoside Antibiotics Romo, Anthony J.; Shiraishi, Taro; Ikeuchi, Hideo Journal of the American Chemical Society, Vol. 141, Issue 36 https://doi.org/10.1021/jacs.9b03021	journal	May 2019
Combinatorial biosynthesis of reduced polyketides Weissman, Kira J.; Leadlay, Peter F. Nature Reviews Microbiology, Vol. 3, Issue 12 https://doi.org/10.1038/nrmicro1287	journal	December 2005
Efficient rational modification of non-ribosomal peptides by adenylation domain substitution Calcott, Mark J.; Owen, Jeremy G.; Ackerley, David F. Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-18365-0	journal	September 2020
Recent advances in engineering nonribosomal peptide assembly lines Winn, M.; Fyans, J. K.; Zhuo, Y. Natural Product Reports, Vol. 33, Issue 2 https://doi.org/10.1039/C5NP00099H	journal	January 2016
The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Schwecke, T.; Aparicio, J. F.; Molnar, I. Proceedings of the National Academy of Sciences, Vol. 92, Issue 17 https://doi.org/10.1073/pnas.92.17.7839	journal	August 1995
Exploring the diversity of complex metabolic networks Hatzimanikatis, V.; Li, C.; Ionita, J. A. Bioinformatics, Vol. 21, Issue 8 https://doi.org/10.1093/bioinformatics/bti213	journal	December 2004
RedEx: a method for seamless DNA insertion and deletion in large multimodular polyketide synthase gene clusters Song, Chaoyi; Luan, Ji; Li, Ruijuan Nucleic Acids Research, Vol. 48, Issue 22 https://doi.org/10.1093/nar/gkaa956	journal	October 2020
antiSMASH 6.0: improving cluster detection and comparison capabilities Blin, Kai; Shaw, Simon; Kloosterman, Alexander M. Nucleic Acids Research, Vol. 49, Issue W1 https://doi.org/10.1093/nar/gkab335	journal	May 2021
antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification Blin, Kai; Wolf, Thomas; Chevrette, Marc G. Nucleic Acids Research, Vol. 45, Issue W1 https://doi.org/10.1093/nar/gkx319	journal	April 2017
ClusterCAD: a computational platform for type I modular polyketide synthase design Eng, Clara H.; Backman, Tyler W. H.; Bailey, Constance B. Nucleic Acids Research, Vol. 46, Issue D1 https://doi.org/10.1093/nar/gkx893	journal	October 2017
RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne S.; Nguyen, Bernard; Pinar, Ali BMC Bioinformatics, Vol. 20, Issue 1 https://doi.org/10.1186/s12859-019-3025-9	journal	September 2019

Similar Records

ClusterCAD: a computational platform for type I modular polyketide synthase design

Journal Article · Wed Oct 11 00:00:00 EDT 2017 · Nucleic Acids Research · OSTI ID:1433111

ClusterCAD 2.0: an updated computational platform for chimeric type I polyketide synthase and nonribosomal peptide synthetase design

Citation Formats

References (29)

Similar Records

Related Subjects