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Title: The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases

In eukaryotes the bimetallic Cu/Zn superoxide dismutase (SOD) enzymes play important roles in the biology of reactive oxygen species by disproportionating superoxide anion. 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. In spite of 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. Furthermore,more » 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.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [1]
  1. Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Biochemistry and Molecular Biology
  2. St. Mary's Univ., San Antonio, TX (United States). Dept. of Biological Sciences; Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry
  3. St. Mary's Univ., San Antonio, TX (United States). Dept. of Biological Sciences
  4. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry
  5. Brookhaven National Lab. (BNL), Upton, NY (United States). Chemistry Dept.
  6. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry; South Texas Veterans Health Care System, San Antonio, TX (United States). Dept. of Veterans Affairs
Publication Date:
Report Number(s):
BNL-112573-2016-JA
Journal ID: ISSN 0021-9258; R&D Project: CO004; KC0304030
Grant/Contract Number:
SC00112704; AC02-06CH11357; AC02-98-CH10886
Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 291; Journal Issue: 40; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; copper; enzyme; fungi; superoxide dismutase (SOD); superoxide ion; x-ray crystallography
OSTI Identifier:
1336119