skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens

Abstract

Copper (Cu)-only superoxide dismutases (SOD) represent a newly characterized class of extracellular SODs important for virulence of several fungal pathogens. Previous studies of the Cu-only enzyme SOD5 from the opportunistic fungal pathogen Candida albicans have revealed that the active-site structure and Cu binding of SOD5 strongly deviate from those of Cu/Zn-SODs in its animal hosts, making Cu-only SODs a possible target for future antifungal drug design. C. albicans also expresses a Cu-only SOD4 that is highly similar in sequence to SOD5, but is poorly characterized. Here, we compared the biochemical, biophysical, and cell biological properties of C. albicans SOD4 and SOD5. Analyzing the recombinant proteins, we found that, similar to SOD5, Cu-only SOD4 can react with superoxide at rates approaching diffusion limits. Both SODs were monomeric and they exhibited similar binding affinities for their Cu cofactor. In C. albicans cultures, SOD4 and SOD5 were predominantly cell wall proteins. Despite these similarities, the SOD4 and SOD5 genes strongly differed in transcriptional regulation. SOD5 was predominantly induced during hyphal morphogenesis, together with a fungal burst in reactive oxygen species. Conversely, SOD4 expression was specifically up-regulated by iron (Fe) starvation and controlled by the Fe-responsive transcription factor SEF1. Interestingly, Candida tropicalis and themore » emerging fungal pathogen Candida auris contain a single SOD5-like SOD rather than a pair, and in both fungi, this SOD was induced by Fe starvation. This unexpected link between Fe homeostasis and extracellular Cu-SODs may help many fungi adapt to Fe-limited conditions of their hosts.« less

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [2];  [1];  [1]
  1. Johns Hopkins Univ., Baltimore, MD (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). Dept. of Chemistry
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1597258
Report Number(s):
[BNL-213604-2020-JAAM]
[Journal ID: ISSN 0021-9258]
Grant/Contract Number:  
[SC0012704]
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
[ Journal Volume: 295; Journal Issue: 2]; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; superoxide dismutase; superoxide ion; Candida albicans

Citation Formats

Schatzman, Sabrina S., Peterson, Ryan L., Teka, Mieraf, He, Bixi, Cabelli, Diane E., Cormack, Brendan P., and Culotta, Valeria C. Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens. United States: N. p., 2019. Web. doi:10.1074/jbc.RA119.011084.
Schatzman, Sabrina S., Peterson, Ryan L., Teka, Mieraf, He, Bixi, Cabelli, Diane E., Cormack, Brendan P., & Culotta, Valeria C. Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens. United States. doi:10.1074/jbc.RA119.011084.
Schatzman, Sabrina S., Peterson, Ryan L., Teka, Mieraf, He, Bixi, Cabelli, Diane E., Cormack, Brendan P., and Culotta, Valeria C. Thu . "Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens". United States. doi:10.1074/jbc.RA119.011084. https://www.osti.gov/servlets/purl/1597258.
@article{osti_1597258,
title = {Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens},
author = {Schatzman, Sabrina S. and Peterson, Ryan L. and Teka, Mieraf and He, Bixi and Cabelli, Diane E. and Cormack, Brendan P. and Culotta, Valeria C.},
abstractNote = {Copper (Cu)-only superoxide dismutases (SOD) represent a newly characterized class of extracellular SODs important for virulence of several fungal pathogens. Previous studies of the Cu-only enzyme SOD5 from the opportunistic fungal pathogen Candida albicans have revealed that the active-site structure and Cu binding of SOD5 strongly deviate from those of Cu/Zn-SODs in its animal hosts, making Cu-only SODs a possible target for future antifungal drug design. C. albicans also expresses a Cu-only SOD4 that is highly similar in sequence to SOD5, but is poorly characterized. Here, we compared the biochemical, biophysical, and cell biological properties of C. albicans SOD4 and SOD5. Analyzing the recombinant proteins, we found that, similar to SOD5, Cu-only SOD4 can react with superoxide at rates approaching diffusion limits. Both SODs were monomeric and they exhibited similar binding affinities for their Cu cofactor. In C. albicans cultures, SOD4 and SOD5 were predominantly cell wall proteins. Despite these similarities, the SOD4 and SOD5 genes strongly differed in transcriptional regulation. SOD5 was predominantly induced during hyphal morphogenesis, together with a fungal burst in reactive oxygen species. Conversely, SOD4 expression was specifically up-regulated by iron (Fe) starvation and controlled by the Fe-responsive transcription factor SEF1. Interestingly, Candida tropicalis and the emerging fungal pathogen Candida auris contain a single SOD5-like SOD rather than a pair, and in both fungi, this SOD was induced by Fe starvation. This unexpected link between Fe homeostasis and extracellular Cu-SODs may help many fungi adapt to Fe-limited conditions of their hosts.},
doi = {10.1074/jbc.RA119.011084},
journal = {Journal of Biological Chemistry},
number = [2],
volume = [295],
place = {United States},
year = {2019},
month = {12}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Save / Share:

Works referenced in this record:

Superoxide Dismutases and Superoxide Reductases
journal, January 2014

  • Sheng, Yuewei; Abreu, Isabel A.; Cabelli, Diane E.
  • Chemical Reviews, Vol. 114, Issue 7
  • DOI: 10.1021/cr4005296

Pathways of Oxidative Damage
journal, October 2003


Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens
journal, March 2018


Candida albicans SOD5 represents the prototype of an unprecedented class of Cu-only superoxide dismutases required for pathogen defense
journal, April 2014

  • Gleason, J. E.; Galaleldeen, A.; Peterson, R. L.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 16
  • DOI: 10.1073/pnas.1400137111

The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases
journal, August 2016

  • Peterson, Ryan L.; Galaleldeen, Ahmad; Villarreal, Johanna
  • Journal of Biological Chemistry, Vol. 291, Issue 40
  • DOI: 10.1074/jbc.M116.748251

Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains
journal, December 2017

  • Robinett, Natalie G.; Peterson, Ryan L.; Culotta, Valeria C.
  • Journal of Biological Chemistry, Vol. 293, Issue 13
  • DOI: 10.1074/jbc.TM117.000182

Computational, pulse-radiolytic, and structural investigations of lysine-136 and its role in the electrostatic triad of human C u,Z n superoxide dismutase
journal, September 1997


Decreased Metallation and Activity in Subsets of Mutant Superoxide Dismutases Associated with Familial Amyotrophic Lateral Sclerosis
journal, February 2002

  • Hayward, Lawrence J.; Rodriguez, Jorge A.; Kim, Ji W.
  • Journal of Biological Chemistry, Vol. 277, Issue 18
  • DOI: 10.1074/jbc.M112087200

Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R
journal, July 2010

  • Seetharaman, Sai V.; Winkler, Duane D.; Taylor, Alexander B.
  • Biochemistry, Vol. 49, Issue 27
  • DOI: 10.1021/bi100314n

Comprehensive Analysis of Glycosylphosphatidylinositol-Anchored Proteins in Candida albicans
journal, December 2006

  • Richard, Mathias L.; Plaine, Armêl
  • Eukaryotic Cell, Vol. 6, Issue 2
  • DOI: 10.1128/EC.00297-06

Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance
journal, January 2009


Superoxide Dismutases in Candida albicans : Transcriptional Regulation and Functional Characterization of the Hyphal-induced SOD5 Gene
journal, February 2004

  • Martchenko, Mikhail; Alarco, Anne-Marie; Harcus, Doreen
  • Molecular Biology of the Cell, Vol. 15, Issue 2
  • DOI: 10.1091/mbc.E03-03-0179

Identification and Analysis of the Role of Superoxide Dismutases Isoforms in the Pathogenesis of Paracoccidioides spp.
journal, March 2016


Extracellular Superoxide Dismutase Protects Histoplasma Yeast Cells from Host-Derived Oxidative Stress
journal, May 2012


Candida albicans FRE8 encodes a member of the NADPH oxidase family that produces a burst of ROS during fungal morphogenesis
journal, December 2017


Normal Adaptation of Candida albicans to the Murine Gastrointestinal Tract Requires Efg1p-Dependent Regulation of Metabolic and Host Defense Genes
journal, November 2012

  • Pierce, Jessica V.; Dignard, Daniel; Whiteway, Malcolm
  • Eukaryotic Cell, Vol. 12, Issue 1
  • DOI: 10.1128/EC.00236-12

NADPH Oxidases NOX-1 and NOX-2 Require the Regulatory Subunit NOR-1 To Control Cell Differentiation and Growth in Neurospora crassa
journal, June 2008

  • Cano-Domínguez, Nallely; Álvarez-Delfín, Karen; Hansberg, Wilhelm
  • Eukaryotic Cell, Vol. 7, Issue 8
  • DOI: 10.1128/EC.00137-08

Generation of reactive oxygen species by fungal NADPH oxidases is required for rice blast disease
journal, June 2007

  • Egan, M. J.; Wang, Z. -Y.; Jones, M. A.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 28
  • DOI: 10.1073/pnas.0700574104

Copper−Zinc Superoxide Dismutase:  Why Not pH-Dependent?
journal, January 1996

  • Ellerby, Lisa M.; Cabelli, Diane E.; Graden, Janet A.
  • Journal of the American Chemical Society, Vol. 118, Issue 28
  • DOI: 10.1021/ja953845x

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis
journal, December 2018

  • Robinett, Natalie G.; Culbertson, Edward M.; Peterson, Ryan L.
  • Journal of Biological Chemistry, Vol. 294, Issue 8
  • DOI: 10.1074/jbc.RA118.007095

A Gain of Superoxide Dismutase (SOD) Activity Obtained with CCS, the Copper Metallochaperone for SOD1
journal, December 1999

  • Schmidt, Paul J.; Ramos-Gomez, Minerva; Culotta, Valeria Cizewski
  • Journal of Biological Chemistry, Vol. 274, Issue 52
  • DOI: 10.1074/jbc.274.52.36952

Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS)
journal, August 2012

  • Banci, L.; Bertini, I.; Cantini, F.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 34
  • DOI: 10.1073/pnas.1207493109

Crystal Structure of the Second Domain of the Human Copper Chaperone for Superoxide Dismutase ,
journal, February 2000

  • Lamb, Audrey L.; Wernimont, Amy K.; Pufahl, Robert A.
  • Biochemistry, Vol. 39, Issue 7
  • DOI: 10.1021/bi992822i

Mechanism of Cu,Zn-Superoxide Dismutase Activation by the Human Metallochaperone hCCS
journal, October 2000

  • Rae, Tracey D.; Torres, Andrew S.; Pufahl, Robert A.
  • Journal of Biological Chemistry, Vol. 276, Issue 7
  • DOI: 10.1074/jbc.M008005200

The role of arginine 143 in the electrostatics and mechanism of Cu, Zn superoxide dismutase: Computational and experimental evaluation by mutational analysis
journal, May 1994

  • Fisher, Cindy L.; Cabelli, Diane E.; Tainer, John A.
  • Proteins: Structure, Function, and Genetics, Vol. 19, Issue 1
  • DOI: 10.1002/prot.340190105

Faster superoxide dismutase mutants designed by enhancing electrostatic guidance
journal, July 1992

  • Getzoff, Elizabeth D.; Cabelli, Diane E.; Fisher, Cindy L.
  • Nature, Vol. 358, Issue 6384
  • DOI: 10.1038/358347a0

The pH dependence of apparent binding constants between apo-superoxide dismutase and cupric ions
journal, October 1982

  • Hirose, Junzo; Ohhira, Tomoko; Hirata, Hayami
  • Archives of Biochemistry and Biophysics, Vol. 218, Issue 1
  • DOI: 10.1016/0003-9861(82)90334-4

Hyphal induction in the human fungal pathogen Candida albicans reveals a characteristic wall protein profile
journal, August 2011

  • Heilmann, Clemens J.; Sorgo, Alice G.; Siliakus, Adriaan R.
  • Microbiology, Vol. 157, Issue 8
  • DOI: 10.1099/mic.0.049395-0

Transcription Profiling of Candida albicans Cells Undergoing the Yeast-to-Hyphal Transition
journal, October 2002

  • Nantel, André; Dignard, Daniel; Bachewich, Catherine
  • Molecular Biology of the Cell, Vol. 13, Issue 10
  • DOI: 10.1091/mbc.E02-05-0272

Iron restriction-induced adaptations in the wall proteome of Candida albicans
journal, August 2013

  • Sorgo, Alice G.; Brul, Stanley; de Koster, Chris G.
  • Microbiology, Vol. 159, Issue Pt_8
  • DOI: 10.1099/mic.0.065599-0

An Iron Homeostasis Regulatory Circuit with Reciprocal Roles in Candida albicans Commensalism and Pathogenesis
journal, August 2011


The Iron-Dependent Regulation of the Candida albicans Oxidative Stress Response by the CCAAT-Binding Factor
journal, January 2017


Iron deprivation induces EFG1 -mediated hyphal development in Candida albicans without affecting biofilm formation
journal, August 2008


Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans
journal, May 2005

  • Sigle, Hans-Christian; Thewes, Sascha; Niewerth, Markus
  • Journal of Antimicrobial Chemotherapy, Vol. 55, Issue 5
  • DOI: 10.1093/jac/dki089

Candida albicans specializations for iron homeostasis: from commensalism to virulence
journal, December 2013


An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase
journal, December 2016


Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase
journal, September 2015

  • Li, Cissy X.; Gleason, Julie E.; Zhang, Sean X.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 38
  • DOI: 10.1073/pnas.1513447112

Beyond the wall: Candida albicans secret(e)s to survive
journal, November 2012

  • Sorgo, Alice G.; Heilmann, Clemens J.; Brul, Stanley
  • FEMS Microbiology Letters, Vol. 338, Issue 1
  • DOI: 10.1111/1574-6968.12049

Mass spectrometric analysis of the secretome of Candida albicans
journal, April 2010

  • Sorgo, Alice G.; Heilmann, Clemens J.; Dekker, Henk L.
  • Yeast, Vol. 27, Issue 8
  • DOI: 10.1002/yea.1775

A family of secreted pathogenesis-related proteins in Candida albicans: Pry proteins in C. albicans
journal, December 2012

  • Röhm, M.; Lindemann, E.; Hiller, E.
  • Molecular Microbiology, Vol. 87, Issue 1
  • DOI: 10.1111/mmi.12087

Genome-wide identification of fungal GPI proteins
journal, January 2003

  • de Groot, Piet W. J.; Hellingwerf, Klaas J.; Klis, Frans M.
  • Yeast, Vol. 20, Issue 9
  • DOI: 10.1002/yea.1007

Proteomic Analysis of Candida albicans Cell Walls Reveals Covalently Bound Carbohydrate-Active Enzymes and Adhesins
journal, August 2004


Trifluoromethanesulfonic acid-based proteomic analysis of cell wall and secreted proteins of the ascomycetous fungi Neurospora crassa and Candida albicans
journal, October 2009

  • Maddi, Abhiram; Bowman, Shaun M.; Free, Stephen J.
  • Fungal Genetics and Biology, Vol. 46, Issue 10
  • DOI: 10.1016/j.fgb.2009.06.005

Proteogenomics of Candida tropicalis —An Opportunistic Pathogen with Importance for Global Health
journal, April 2016

  • Datta, Keshava K.; Patil, Arun H.; Patel, Krishna
  • OMICS: A Journal of Integrative Biology, Vol. 20, Issue 4
  • DOI: 10.1089/omi.2015.0197

Candida albicans biofilm–induced vesicles confer drug resistance through matrix biogenesis
journal, October 2018


Yeast wall protein 1 of Candida albicans
journal, May 2005


Amino Acid Residues in the ω-Minus Region Participate in Cellular Localization of Yeast Glycosylphosphatidylinositol-Attached Proteins
journal, January 1999


Roles of Candida albicans Dfg5p and Dcw1p Cell Surface Proteins in Growth and Hypha Formation
journal, August 2003


A Relay Network of Extracellular Heme-Binding Proteins Drives C. albicans Iron Acquisition from Hemoglobin
journal, October 2014


Finding a Missing Gene: EFG1 Regulates Morphogenesis in Candida tropicalis
journal, March 2015

  • Mancera, Eugenio; Porman, Allison M.; Cuomo, Christina A.
  • G3: Genes|Genomes|Genetics, Vol. 5, Issue 5
  • DOI: 10.1534/g3.115.017566

Comparative Evolution of Morphological Regulatory Functions in Candida Species
journal, August 2013

  • Lackey, Erika; Vipulanandan, Geethanjali; Childers, Delma S.
  • Eukaryotic Cell, Vol. 12, Issue 10
  • DOI: 10.1128/EC.00164-13

Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris
journal, September 2015

  • Chatterjee, Sharanya; Alampalli, Shuba Varshini; Nageshan, Rishi Kumar
  • BMC Genomics, Vol. 16, Issue 1
  • DOI: 10.1186/s12864-015-1863-z

Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species
journal, December 2018


Filamentation in Candida auris , an emerging fungal pathogen of humans: passage through the mammalian body induces a heritable phenotypic switch
journal, December 2018


Early Colony Establishment in Neurospora crassa Requires a MAP Kinase Regulatory Network
journal, September 2013


Cold Shock as a Screen for Genes Involved in Cold Acclimatization in Neurospora crassa
journal, March 2018

  • Watters, Michael K.; Manzanilla, Victor; Howell, Holly
  • G3: Genes|Genomes|Genetics, Vol. 8, Issue 5
  • DOI: 10.1534/g3.118.200112

Yeast Lacking Cu-Zn Superoxide Dismutase Show Altered Iron Homeostasis: ROLE OF OXIDATIVE STRESS IN IRON METABOLISM
journal, April 2000

  • De Freitas, Jeane M.; Liba, Amir; Meneghini, Rogerio
  • Journal of Biological Chemistry, Vol. 275, Issue 16
  • DOI: 10.1074/jbc.275.16.11645

Fe Sparing and Fe Recycling Contribute to Increased Superoxide Dismutase Capacity in Iron-Starved Chlamydomonas reinhardtii
journal, June 2012

  • Page, M. Dudley; Allen, Michael D.; Kropat, Janette
  • The Plant Cell, Vol. 24, Issue 6
  • DOI: 10.1105/tpc.112.098962

Superoxide accelerates DNA damage by elevating free-iron levels
journal, November 1996

  • Keyer, K.; Imlay, J. A.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 24
  • DOI: 10.1073/pnas.93.24.13635

Oxidative Stress and the Homeodynamics of Iron Metabolism
journal, May 2015


Iron Deficiency Generates Oxidative Stress and Activation of the SOS Response in Caulobacter crescentus
journal, August 2018


Cth2 Protein Mediates Early Adaptation of Yeast Cells to Oxidative Stress Conditions
journal, January 2016


Iron starvation leads to increased expression of Cu/Zn-superoxide dismutase in Aspergillus
journal, November 2000


The oxidative stress response in yeast cells involves changes in the stability of Aft1 regulon mRNAs: Yeast iron uptake and oxidative stress
journal, May 2011


Unexpected Link between Iron and Drug Resistance of Candida spp.: Iron Depletion Enhances Membrane Fluidity and Drug Diffusion, Leading to Drug-Susceptible Cells
journal, September 2006

  • Prasad, T.; Chandra, A.; Mukhopadhyay, C. K.
  • Antimicrobial Agents and Chemotherapy, Vol. 50, Issue 11
  • DOI: 10.1128/AAC.00653-06

Flavodoxin-Like Proteins Protect Candida albicans from Oxidative Stress and Promote Virulence
journal, September 2015


Adaptive Prediction As a Strategy in Microbial Infections
journal, October 2014


An Efficient, Rapid, and Recyclable System for CRISPR-Mediated Genome Editing in Candida albicans
journal, April 2017


Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity
journal, June 2010

  • Noble, Suzanne M.; French, Sarah; Kohn, Lisa A.
  • Nature Genetics, Vol. 42, Issue 7
  • DOI: 10.1038/ng.605

Can Multidrug-Resistant Candida auris Be Reliably Identified in Clinical Microbiology Laboratories?
journal, November 2016

  • Mizusawa, Masako; Miller, Heather; Green, Rachel
  • Journal of Clinical Microbiology, Vol. 55, Issue 2
  • DOI: 10.1128/JCM.02202-16

Species-specific activation of Cu/Zn SOD by its CCS copper chaperone in the pathogenic yeast Candida albicans
journal, September 2013

  • Gleason, Julie E.; Li, Cissy X.; Odeh, Hana M.
  • JBIC Journal of Biological Inorganic Chemistry, Vol. 19, Issue 4-5
  • DOI: 10.1007/s00775-013-1045-x

Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega
journal, January 2011

  • Sievers, Fabian; Wilm, Andreas; Dineen, David
  • Molecular Systems Biology, Vol. 7, Issue 1
  • DOI: 10.1038/msb.2011.75