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Title: Crystal structure of SgcJ, an NTF2-like superfamily protein involved in biosynthesis of the nine-membered enediyne antitumor antibiotic C-1027

Abstract

Comparative analysis of the enediyne biosynthetic gene clusters revealed sets of conserved genes serving as outstanding candidates for the enediyne core. Here we report the crystal structures of SgcJ and its homologue NCS-Orf16, together with gene inactivation and site-directed mutagenesis studies, to gain insight into enediyne core biosynthesis. Gene inactivation in vivo establishes that SgcJ is required for C-1027 production in Streptomyces globisporus. SgcJ and NCS-Orf16 share a common structure with the nuclear transport factor 2-like superfamily of proteins, featuring a putative substrate binding or catalytic active site. Site-directed mutagenesis of the conserved residues lining this site allowed us to propose that SgcJ and its homologues may play a catalytic role in transforming the linear polyene intermediate, along with other enediyne polyketide synthase-associated enzymes, into an enzyme-sequestered enediyne core intermediate. In conclusion, these findings will help formulate hypotheses and design experiments to ascertain the function of SgcJ and its homologues in nine-membered enediyne core biosynthesis.

Authors:
 [1];  [2];  [3];  [2];  [4];  [5];  [2];  [2];  [2];  [2];  [5];  [5];  [6];  [7];  [4];  [4];  [8];  [2]
  1. The Scripps Research Institute, Jupiter, FL (United States); Shanghai Jiao Tong Univ., Shanghai (China)
  2. The Scripps Research Institute, Jupiter, FL (United States)
  3. The Scripps Research Institute, Jupiter, FL (United States); Purdue Univ., West Lafayette, IN (United States)
  4. Univ. of Chicago, Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
  5. Argonne National Lab. (ANL), Argonne, IL (United States)
  6. Univ. of Wisconsin, Madison, WI (United States)
  7. Rice Univ., Houston, TX (United States); Jaypee Univ. of Information Technology, Himachal Pradesh (India)
  8. Rice Univ., Houston, TX (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Scripps Research Institute; German Research Foundation (DFG); National Institutes of Health (NIH), National Institute of General Medical Sciences; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1374053
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
The Journal of Antibiotics
Additional Journal Information:
Journal Volume: 69; Journal Issue: 10; Journal ID: ISSN 0021-8820
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Huang, Tingting, Chang, Chin -Yuan, Lohman, Jeremy R., Rudolf, Jeffrey D., Kim, Youngchang, Chang, Changsoo, Yang, Dong, Ma, Ming, Yan, Xiaohui, Crnovcic, Ivana, Bigelow, Lance, Clancy, Shonda, Bingman, Craig A., Yennamalli, Ragothaman M., Babnigg, Gyorgy, Joachimiak, Andrzej, Phillips, Jr., George N., and Shen, Ben. Crystal structure of SgcJ, an NTF2-like superfamily protein involved in biosynthesis of the nine-membered enediyne antitumor antibiotic C-1027. United States: N. p., 2016. Web. doi:10.1038/ja.2016.88.
Huang, Tingting, Chang, Chin -Yuan, Lohman, Jeremy R., Rudolf, Jeffrey D., Kim, Youngchang, Chang, Changsoo, Yang, Dong, Ma, Ming, Yan, Xiaohui, Crnovcic, Ivana, Bigelow, Lance, Clancy, Shonda, Bingman, Craig A., Yennamalli, Ragothaman M., Babnigg, Gyorgy, Joachimiak, Andrzej, Phillips, Jr., George N., & Shen, Ben. Crystal structure of SgcJ, an NTF2-like superfamily protein involved in biosynthesis of the nine-membered enediyne antitumor antibiotic C-1027. United States. doi:10.1038/ja.2016.88.
Huang, Tingting, Chang, Chin -Yuan, Lohman, Jeremy R., Rudolf, Jeffrey D., Kim, Youngchang, Chang, Changsoo, Yang, Dong, Ma, Ming, Yan, Xiaohui, Crnovcic, Ivana, Bigelow, Lance, Clancy, Shonda, Bingman, Craig A., Yennamalli, Ragothaman M., Babnigg, Gyorgy, Joachimiak, Andrzej, Phillips, Jr., George N., and Shen, Ben. Sat . "Crystal structure of SgcJ, an NTF2-like superfamily protein involved in biosynthesis of the nine-membered enediyne antitumor antibiotic C-1027". United States. doi:10.1038/ja.2016.88. https://www.osti.gov/servlets/purl/1374053.
@article{osti_1374053,
title = {Crystal structure of SgcJ, an NTF2-like superfamily protein involved in biosynthesis of the nine-membered enediyne antitumor antibiotic C-1027},
author = {Huang, Tingting and Chang, Chin -Yuan and Lohman, Jeremy R. and Rudolf, Jeffrey D. and Kim, Youngchang and Chang, Changsoo and Yang, Dong and Ma, Ming and Yan, Xiaohui and Crnovcic, Ivana and Bigelow, Lance and Clancy, Shonda and Bingman, Craig A. and Yennamalli, Ragothaman M. and Babnigg, Gyorgy and Joachimiak, Andrzej and Phillips, Jr., George N. and Shen, Ben},
abstractNote = {Comparative analysis of the enediyne biosynthetic gene clusters revealed sets of conserved genes serving as outstanding candidates for the enediyne core. Here we report the crystal structures of SgcJ and its homologue NCS-Orf16, together with gene inactivation and site-directed mutagenesis studies, to gain insight into enediyne core biosynthesis. Gene inactivation in vivo establishes that SgcJ is required for C-1027 production in Streptomyces globisporus. SgcJ and NCS-Orf16 share a common structure with the nuclear transport factor 2-like superfamily of proteins, featuring a putative substrate binding or catalytic active site. Site-directed mutagenesis of the conserved residues lining this site allowed us to propose that SgcJ and its homologues may play a catalytic role in transforming the linear polyene intermediate, along with other enediyne polyketide synthase-associated enzymes, into an enzyme-sequestered enediyne core intermediate. In conclusion, these findings will help formulate hypotheses and design experiments to ascertain the function of SgcJ and its homologues in nine-membered enediyne core biosynthesis.},
doi = {10.1038/ja.2016.88},
journal = {The Journal of Antibiotics},
number = 10,
volume = 69,
place = {United States},
year = {Sat Oct 01 00:00:00 EDT 2016},
month = {Sat Oct 01 00:00:00 EDT 2016}
}

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Works referenced in this record:

MUSCLE: multiple sequence alignment with high accuracy and high throughput
journal, March 2004

  • Edgar, R. C.
  • Nucleic Acids Research, Vol. 32, Issue 5, p. 1792-1797
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A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis
journal, January 2008

  • Zhang, J.; Van Lanen, S. G.; Ju, J.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 5, p. 1460-1465
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