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

Joseph M. Pennington, Michael Kemp, Lauren McGarry, Yu Chen and M. Elizabeth Stroupe ()
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Joseph M. Pennington: Florida State University
Michael Kemp: University of South Florida College of Medicine
Lauren McGarry: Florida State University
Yu Chen: University of South Florida College of Medicine
M. Elizabeth Stroupe: Florida State University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14722-1

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