@article{e53079db4a3549bcbd37fd44436e3ee8,
title = "The phylogeny and active site design of eukaryotic copper-only superoxide dismutases",
abstract = "In eukaryotes the bimetallic Cu/Zn superoxide dismutase (SOD) enzymes play important roles in the biology of reactive oxygen species by disproportionating superoxide anion. Recently, we reported that the fungal pathogen Candida albicans expresses a novel copper-only SOD, known as SOD5, that lacks the zinc cofactor and electrostatic loop (ESL) domain of Cu/Zn-SODs for substrate guidance. Despite these abnormalities, C. albicans SOD5 can disproportionate superoxide at rates limited only by diffusion. Here we demonstrate that this curious copper-only SOD occurs throughout the fungal kingdom as well as in phylogenetically distant oomycetes or {"}pseudofungi{"} species. It is the only form of extracellular SOD in fungi and oomycetes, in stark contrast to the extracellular Cu/Zn-SODs of plants and animals. Through structural biology and biochemical approaches we demonstrate that these copper-only SODs have evolved with a specialized active site consisting of two highly conserved residues equivalent to SOD5 Glu-110 and Asp-113. The equivalent positions are zinc binding ligands in Cu/Zn-SODs and have evolved in copper-only SODs to control catalysis and copper binding in lieu of zinc and the ESL. Similar to the zinc ion in Cu/Zn-SODs, SOD5 Glu-110 helps orient a key copper-coordinating histidine and extends the pH range of enzyme catalysis. SOD5 Asp-113 connects to the active site in a manner similar to that of the ESL in Cu/Zn-SODs and assists in copper cofactor binding. Copper-only SODs are virulence factors for certain fungal pathogens; thus this unique active site may be a target for future anti-fungal strategies.",
author = "Peterson, {Ryan L.} and Ahmad Galaleldeen and Johanna Villarreal and Taylor, {Alexander B.} and Cabelli, {Diane E.} and Hart, {P. John} and Culotta, {Valeria C.}",
note = "Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants RO1 GM50016 (to V. C. C.), F32 GM112320 (to R. L. P.), and T32 CA009110 (to R. L. P.). This work was also supported in part by United States Department of Veterans Affairs Merit Review Award I01 BX002580 (to P. J. H.) and Robert A. Welch Foundation grant AQ-1399 (to P. J. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Supported by the Biaggini Research Program, Faculty Research Grant and the Honors Program at St. Mary's University. We thank Drs. Julie Gleason and Brian Learn for helpful discussions and Professor Jiou Wang for assistance with protein purification. Support for Northeastern Collaborative Access Team beamline 24-ID-E was provided by National Institutes of Health Grant P41 GM103403 and United States Department of Energy Grant DE-AC02-06CH11357. The X-Ray Crystallography Core Laboratory at the University of Texas Health Science Center at San Antonio is supported in part by the Office of the Vice President for Research and by National Institutes of Health Grant P30 CA054174 (Cancer Therapy and Research Center). Pulse radiolysis studies were carried out using the Van de Graaff facilities of the BNL Accelerator Center for Energy Research, which is supported by United States Department of Energy, Office of Science, Office of Basic Energy Sciences through Grant DE-AC02-98-CH10886. Publisher Copyright: {\textcopyright} 2016, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.",
year = "2016",
month = sep,
day = "30",
doi = "10.1074/jbc.M116.748251",
language = "English (US)",
volume = "291",
pages = "20911--20923",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "40",
}