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Domain Fusion of Two Oxygenases Affords Organophosphonate Degradation in Pathogenic Fungi

  • Michelle Langton
    Michelle Langton
    Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States
  • Matthew Appell
    Matthew Appell
    Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States
  • Jeremy Koob
    Jeremy Koob
    Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States
    More by Jeremy Koob
  • , and 
  • Maria-Eirini Pandelia*
    Maria-Eirini Pandelia
    Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States
    *Maria-Eirini Pandelia. Email: [email protected]
Cite this: Biochemistry 2022, 61, 11, 956–962
Publication Date (Web):May 4, 2022
https://doi.org/10.1021/acs.biochem.2c00163
Copyright © 2022 American Chemical Society

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    Abstract

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    Proteins of the HD-domain superfamily employ a conserved histidine-aspartate (HD) dyad to coordinate diverse metallocofactors. While most known HD-domain proteins are phosphohydrolases, new additions to this superfamily have emerged such as oxygenases and lyases, expanding their functional repertoire. To date, three HD-domain oxygenases have been identified, all of which employ a mixed-valent FeIIFeIII cofactor to activate their substrates and utilize molecular oxygen to afford cleavage of C–C or C–P bonds via a diferric superoxo intermediate. Phylogenetic analysis reveals an uncharacterized multidomain protein in the pathogenic soil fungus Fonsecaea multimorphosa, herein designated PhoF. PhoF consists of an N-terminal FeII/α-ketoglutarate-dependent domain resembling that of PhnY and a C-terminal HD-domain like that of PhnZ. PhnY and PhnZ are part of an organophosphonate degradation pathway in which PhnY hydroxylates 2-aminoethylphosphonic acid, and PhnZ cleaves the C–P bond of the hydroxylated product yielding phosphate and glycine. Employing electron paramagnetic resonance and Mössbauer spectroscopies in tandem with activity assays, we determined that PhoF carries out the O2-dependent degradation of two aminophosphonates, demonstrating an expanded catalytic efficiency with respect to the individual, but mechanistically coupled PhnY and PhnZ. Our results recognize PhoF as a new example of an HD-domain oxygenase and show that domain fusion of an organophosphonate degradation pathway may be a strategy for disease-causing fungi to acquire increased functional versatility, potentially important for their survival.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biochem.2c00163.

    • Materials and methods, table of organisms containing the PhyH and HD-domain fusion gene, genomic neighborhood network for GmPhnZ1, EPR spectra of PhoF with nonhydroxylated substrates (PDF)

    Accession Codes

    NCBI: XP_016629182. Uniprot ID: D0E8I5.1. Uniprot ID: D0E8I4.1.

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    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 1 publications.

    1. Sining Sun, Richard Wang, Maria-Eirini Pandelia. Vibrio cholerae V-cGAP3 Is an HD-GYP Phosphodiesterase with a Metal Tunable Substrate Selectivity. Biochemistry 2022, 61 (17) , 1801-1809. https://doi.org/10.1021/acs.biochem.2c00269

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