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Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases

Dunham, Noah P. and Arnold, Frances H. (2020) Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases. ACS Catalysis, 10 (20). pp. 12239-12255. ISSN 2155-5435. PMCID PMC7710332. doi:10.1021/acscatal.0c03606.

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Iron is an especially important redox-active cofactor in biology because of its ability to mediate reactions with atmospheric O₂. Iron-dependent oxygenases exploit this earth-abundant transition metal for the insertion of oxygen atoms into organic compounds. Throughout the astounding diversity of transformations catalyzed by these enzymes, the protein framework directs reactive intermediates toward the precise formation of products, which, in many cases, necessitates the cleavage of strong C–H bonds. In recent years, members of several iron-dependent oxygenase families have been engineered for new-to-nature transformations that offer advantages over conventional synthetic methods. In this Perspective, we first explore what is known about the reactivity of heme-dependent cytochrome P450 oxygenases and nonheme iron-dependent oxygenases bearing the 2-His-1-carboxylate facial triad by reviewing mechanistic studies with an emphasis on how the protein scaffold maximizes the catalytic potential of the iron-heme and iron cofactors. We then review how these cofactors have been repurposed for abiological transformations by engineering the protein frameworks of these enzymes. Finally, we discuss contemporary challenges associated with engineering these platforms and comment on their roles in biocatalysis moving forward.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Dunham, Noah P.0000-0001-8006-9566
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2020 American Chemical Society. Received: August 17, 2020; Revised: September 26, 2020; Published: September 28, 2020. This work was supported by the US Army Research Office Institute for Collaborative Biotechnologies contract W911NF-19-D-0001 and the Joseph J. Jacobs Institute for Molecular Engineering for Medicine. N.P.D. was supported by the Ruth L. Kirschstein NIH Postdoctoral Fellowship (F32GM131620). We thank Professor Haoming Zhang for providing the open- and closed-state coordinates resulting from the full-length P450_(BM3) cryo-EM structures. We also thank Dr. S. V. Athavale, Dr. D. C. Miller, and Dr. Z. Liu for providing helpful comments on the manuscript. The authors declare no competing financial interest.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funding AgencyGrant Number
Army Research Office (ARO)W911NF-19-D-0001
Joseph J. Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
NIH Postdoctoral FellowshipF32GM131620
Subject Keywords:biocatalysis, enzymology, directed evolution, mechanism, oxygenase, cytochrome P450
Issue or Number:20
PubMed Central ID:PMC7710332
Record Number:CaltechAUTHORS:20200929-124227563
Persistent URL:
Official Citation:Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases. Noah P. Dunham and Frances H. Arnold. ACS Catalysis 2020 10 (20), 12239-12255; DOI: 10.1021/acscatal.0c03606
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105637
Deposited By: Tony Diaz
Deposited On:29 Sep 2020 20:11
Last Modified:12 Feb 2022 00:26

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