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Title: Siroheme synthase orients substrates for dehydrogenase and chelatase activities in a common active site

Abstract

Siroheme is the central cofactor in a conserved class of sulfite and nitrite reductases that catalyze the six-electron reduction of sulfite to sulfide and nitrite to ammonia. In Salmonella enterica serovar Typhimurium, siroheme is produced by a trifunctional enzyme, siroheme synthase (CysG). A bifunctional active site that is distinct from its methyltransferase activity catalyzes the final two steps, NAD+-dependent dehydrogenation and iron chelation. How this active site performs such different chemistries is unknown. Here, we report the structures of CysG bound to precorrin-2, the initial substrate; sirohydrochlorin, the dehydrogenation product/chelation substrate; and a cobalt-sirohydrochlorin product. We identified binding poses for all three tetrapyrroles and tested the roles of specific amino acids in both activities to give insights into how a bifunctional active site catalyzes two different chemistries and acts as an iron-specific chelatase in the final step of siroheme synthesis.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [1]; ORCiD logo [2]; ORCiD logo [1]
  1. Florida State Univ., Tallahassee, FL (United States)
  2. Univ. of South Florida, Tampa, FL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF)
OSTI Identifier:
1601850
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Pennington, Joseph M., Kemp, Michael, McGarry, Lauren, Chen, Yu, and Stroupe, M. Elizabeth. Siroheme synthase orients substrates for dehydrogenase and chelatase activities in a common active site. United States: N. p., 2020. Web. https://doi.org/10.1038/s41467-020-14722-1.
Pennington, Joseph M., Kemp, Michael, McGarry, Lauren, Chen, Yu, & Stroupe, M. Elizabeth. Siroheme synthase orients substrates for dehydrogenase and chelatase activities in a common active site. United States. https://doi.org/10.1038/s41467-020-14722-1
Pennington, Joseph M., Kemp, Michael, McGarry, Lauren, Chen, Yu, and Stroupe, M. Elizabeth. Thu . "Siroheme synthase orients substrates for dehydrogenase and chelatase activities in a common active site". United States. https://doi.org/10.1038/s41467-020-14722-1. https://www.osti.gov/servlets/purl/1601850.
@article{osti_1601850,
title = {Siroheme synthase orients substrates for dehydrogenase and chelatase activities in a common active site},
author = {Pennington, Joseph M. and Kemp, Michael and McGarry, Lauren and Chen, Yu and Stroupe, M. Elizabeth},
abstractNote = {Siroheme is the central cofactor in a conserved class of sulfite and nitrite reductases that catalyze the six-electron reduction of sulfite to sulfide and nitrite to ammonia. In Salmonella enterica serovar Typhimurium, siroheme is produced by a trifunctional enzyme, siroheme synthase (CysG). A bifunctional active site that is distinct from its methyltransferase activity catalyzes the final two steps, NAD+-dependent dehydrogenation and iron chelation. How this active site performs such different chemistries is unknown. Here, we report the structures of CysG bound to precorrin-2, the initial substrate; sirohydrochlorin, the dehydrogenation product/chelation substrate; and a cobalt-sirohydrochlorin product. We identified binding poses for all three tetrapyrroles and tested the roles of specific amino acids in both activities to give insights into how a bifunctional active site catalyzes two different chemistries and acts as an iron-specific chelatase in the final step of siroheme synthesis.},
doi = {10.1038/s41467-020-14722-1},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {2}
}

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