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Title: Paradigm Shift for Radical S -Adenosyl- l -methionine Reactions: The Organometallic Intermediate Ω Is Central to Catalysis

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/jacs.8b04061· OSTI ID:1459248
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  1. Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana 59717, United States
  2. Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  3. Institute of Microbiology, Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 4, Zürich 8093, Switzerland
  4. Cassia, LLC, 3030 Bunker Hill Street, Ste. 214, San Diego, California 92109, United States
  5. Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
+ Show Author Affiliations

Radical S-adenosyl-L-methionine (SAM) enzymes comprise a vast superfamily catalyzing diverse reactions essential to all life through homolytic SAM cleavage to liberate the highly reactive 5'-deoxyadenosyl radical (5'-dAdo·). Our recent observation of a catalytically competent organometallic intermediate Ω that forms during reaction of the radical SAM (RS) enzyme pyruvate formate-lyase activating-enzyme (PFL-AE) was therefore quite surprising, and led to the question of its broad relevance in the superfamily. We now show that Ω in PFL-AE forms as an intermediate under a variety of mixing order conditions, suggesting it is central to catalysis in this enzyme. We further demonstrate that Ω forms in a suite of RS enzymes chosen to span the totality of superfamily reaction types, implicating Ω as essential in catalysis across the RS superfamily. Finally, EPR and electron nuclear double resonance spectroscopy establish that Ω involves an Fe-C5' bond between 5'-dAdo· and the [4Fe-4S] cluster. An analogous organometallic bond is found in the well-known adenosylcobalamin (coenzyme B12) cofactor used to initiate radical reactions via a 5'- dAdo· intermediate. Liberation of a reactive 5'-dAdo· intermediate via homolytic metal-carbon bond cleavage thus appears to be similar for Ω and coenzyme B12. However, coenzyme B12 is involved in enzymes catalyzing only a small number (~12) of distinct reactions, whereas the RS superfamily has more than 100 000 distinct sequences and over 80 reaction types characterized to date. The appearance of Ω across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.

Research Organization:
Montana State Univ., Bozeman, MT (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
SC0005404
OSTI ID:
1459248
Alternate ID(s):
OSTI ID: 1508581
Journal Information:
Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Vol. 140 Journal Issue: 28; ISSN 0002-7863
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 49 works
Citation information provided by
Web of Science

References (26)

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Figures / Tables (6)

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Chart 1(p. 3)figure Chart 1
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Figure 4.(p. 3)figure Figure 4.
Figure 5.(p. 4)figure Figure 5.

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