Domain Fusion of Two Oxygenases Affords Organophosphonate Degradation in Pathogenic Fungi
- Michelle LangtonMichelle LangtonDepartment of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United StatesMore by Michelle Langton
- Matthew AppellMatthew AppellDepartment of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United StatesMore by Matthew Appell
- Jeremy KoobJeremy KoobDepartment of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United StatesMore by Jeremy Koob
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- Maria-Eirini Pandelia*
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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This article is cited by 1 publications.
- 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
, 1801-1809. https://doi.org/10.1021/acs.biochem.2c00269