Three Related Enzymes in Candida albicans Achieve Arginine- and Agmatine-Dependent Metabolism That Is Essential for Growth and Fungal Virulence

Katja Schaefer, Jeanette Wagener, Ryan M Ames, Stella Christou, Donna M MacCallum, Steven Bates* (Corresponding Author), Neil A R Gow

*Corresponding author for this work

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Abstract

Amino acid metabolism is crucial for fungal growth and development. Ureohydrolases produce amines when acting on l-arginine, agmatine, and guanidinobutyrate (GB), and these enzymes generate ornithine (by arginase), putrescine (by agmatinase), or GABA (by 4-guanidinobutyrase or GBase). Candida albicans can metabolize and grow on arginine, agmatine, or guanidinobutyrate as the sole nitrogen source. Three related C. albicans genes whose sequences suggested that they were putative arginase or arginase-like genes were examined for their role in these metabolic pathways. Of these, Car1 encoded the only bona fide arginase, whereas we provide evidence that the other two open reading frames, orf19.5862 and orf19.3418, encode agmatinase and guanidinobutyrase (Gbase), respectively. Analysis of strains with single and multiple mutations suggested the presence of arginase-dependent and arginase-independent routes for polyamine production. CAR1 played a role in hyphal morphogenesis in response to arginine, and the virulence of a triple mutant was reduced in both Galleria mellonella and Mus musculus infection models. In the bloodstream, arginine is an essential amino acid that is required by phagocytes to synthesize nitric oxide (NO). However, none of the single or multiple mutants affected host NO production, suggesting that they did not influence the oxidative burst of phagocytes.IMPORTANCE We show that the C. albicans ureohydrolases arginase (Car1), agmatinase (Agt1), and guanidinobutyrase (Gbu1) can orchestrate an arginase-independent route for polyamine production and that this is important for C. albicans growth and survival in microenvironments of the mammalian host.

Original languageEnglish
Article numbere01845-20
Number of pages15
JournalmBio
Volume11
Issue number4
DOIs
Publication statusPublished - 11 Aug 2020

Bibliographical note

We thank Jane Usher (University of Exeter) for constructive criticism of the manuscript. We thank Valmik K. Vyas and Gerald R. Fink from the Whitehead Institute for Biomedical Research, Cambridge, United Kingdom, for providing the Candida CRISPR plasmid (CaCas9 Solo system pV1200 vector).

N.A.R.G. acknowledges support provided by Wellcome as a Senior Investigator Award (101873/Z/13/Z), Collaborative Award (200208/A/15/Z), and Strategic Award (097377/Z11/Z) and by the MRC Centre for Medical Mycology (MR/N006364/2). R.M.A. acknowledges support from an EPSRC/BBSRC Interface Innovation Fellowship (EP/S001352/1).

K.S., N.A.R.G., S.B., and J.W. conceived the study. N.A.R.G. was awarded the grant that served as a resource for this study. K.S., S.C., D.M.M., and S.B. performed experiments. K.S., N.A.R.G., S.B., and R.M.A. analyzed and interpreted results. K.S., N.A.R.G., and S.B. wrote the paper, and all of us provided comments.

Keywords

  • candida
  • arginase
  • guanidinobutyrase
  • agmatinase
  • immunity
  • morphogenesis
  • candida albicans
  • macrophages
  • Candida albicans
  • Arginase
  • Agmatinase
  • Macrophages
  • Immunity
  • Morphogenesis
  • Guanidinobutyrase
  • Candida
  • DECARBOXYLASE
  • PUTRESCINE BIOSYNTHETIC ENZYME
  • NITRIC-OXIDE
  • POLYAMINE BIOSYNTHESIS
  • DEIMINASE
  • ASPERGILLUS-NIGER
  • MECHANISMS
  • IDENTIFICATION
  • GENE
  • UREOHYDROLASE

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