The Factors Governing Metal Dependence of an Emergent Superfamily of Bimetallic Oxygenases

Liu, Chang; Nguyen, Jessica; Britt, R. David; Rittle, Jonathan

doi:10.1021/jacs.6c01173

Title: The Factors Governing Metal Dependence of an Emergent Superfamily of Bimetallic Oxygenases

Journal Article · Thu Apr 23 00:00:00 UTC 2026 · Journal of the American Chemical Society

DOI: https://doi.org/10.1021/jacs.6c01173 · OSTI ID:3371950

^[1]; Nguyen, Jessica ^[1];

^[1];

^[1]

Department of Chemistry; University of California

Metalloenzyme superfamilies are typically defined by their protein scaffolds and active sites. Owing to the high tunability of protein structures, members of a single superfamily can catalyze diverse reactions with the same metallocofactor. Some superfamilies, such as amidohydrolase-related dinuclear oxygenases (AROs), display further versatility by utilizing multiple metallocofactors. We have shown that certain AROs catalyze monooxygenation reactions with diiron, dimanganese, and/or mixed manganese−iron cofactors, but the molecular factors governing the selection of a particular cofactor remain unknown, and the extent of this superfamily in biology is unclear. Here, we report bioinformatic analyses that expand the ARO superfamily to approximately 17,000 unique UniProt sequences, far exceeding the number of previously characterized enzymes. Through the integration of structural, spectroscopic, and thermodynamic analyses of representative proteins with a bioinformatic pipeline that identifies key secondary- and tertiary-sphere residues, we can predict in silico the metal preference for the majority of reported ARO sequences. These annotations were validated via the characterization of multiple new AROs, including ones implicated in key oxidative steps of natural product biosyntheses. This study establishes the key structure−function relationships governing metal preferences in AROs and highlights their vastly underappreciated role in myriad biological processes.

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Research Organization:: US Department of Energy (USDOE), Washington, DC (United States). Office of Science, Basic Energy Sciences (BES)

Sponsoring Organization:: Basic Energy Sciences; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 3371950

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 17 Vol. 148; ISSN 0002-7863; ISSN 1520-5126

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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