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Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic yeast Candida albicans

Zameitat, Elke ; Gojkovic, Z. ; Knecht, W. LU ; Piskur, Jure LU and Löffler, Monica (2006) In The FEBS Journal 273(14). p.3183-3191
Abstract
Candida albicans is the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), which catalyzes the fourth step of de novo pyrimidine synthesis, as a new target for controlling infection. We propose that the enzyme is a member of the DHODH family 2, which comprises mitochondrially bound enzymes, with quinone as the direct electron acceptor and oxygen as the final electron acceptor. Full-length DHODH and N-terminally truncated DHODH, which lacks the targeting sequence and the transmembrane domain, were subcloned from C. albicans, recombinantly expressed in Escherichia coli,... (More)
Candida albicans is the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), which catalyzes the fourth step of de novo pyrimidine synthesis, as a new target for controlling infection. We propose that the enzyme is a member of the DHODH family 2, which comprises mitochondrially bound enzymes, with quinone as the direct electron acceptor and oxygen as the final electron acceptor. Full-length DHODH and N-terminally truncated DHODH, which lacks the targeting sequence and the transmembrane domain, were subcloned from C. albicans, recombinantly expressed in Escherichia coli, purified, and characterized for their kinetics and substrate specificity. An inhibitor screening with 28 selected compounds was performed. Only the dianisidine derivative, redoxal, and the biphenyl quinoline-carboxylic acid derivative, brequinar sodium, which are known to be potent inhibitors of mammalian DHODH, markedly reduced C. albicans DHODH activity. This study provides a background for the development of antipyrimidines with high efficacy for decreasing in situ pyrimidine nucleotide pools in C. albicans. (Less)
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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DHODase, pathogenes, nucleic acid precursors, yeast
in
The FEBS Journal
volume
273
issue
14
pages
3183 - 3191
publisher
Wiley-Blackwell
external identifiers
  • wos:000238747000006
  • scopus:33745623955
  • pmid:16774642
ISSN
1742-464X
DOI
10.1111/j.1742-4658.2006.05327.x
language
English
LU publication?
yes
id
a6894c52-8ac6-42ca-9f80-b40587054ec0 (old id 745136)
date added to LUP
2016-04-01 11:48:30
date last changed
2021-02-17 05:41:40
@article{a6894c52-8ac6-42ca-9f80-b40587054ec0,
  abstract     = {Candida albicans is the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), which catalyzes the fourth step of de novo pyrimidine synthesis, as a new target for controlling infection. We propose that the enzyme is a member of the DHODH family 2, which comprises mitochondrially bound enzymes, with quinone as the direct electron acceptor and oxygen as the final electron acceptor. Full-length DHODH and N-terminally truncated DHODH, which lacks the targeting sequence and the transmembrane domain, were subcloned from C. albicans, recombinantly expressed in Escherichia coli, purified, and characterized for their kinetics and substrate specificity. An inhibitor screening with 28 selected compounds was performed. Only the dianisidine derivative, redoxal, and the biphenyl quinoline-carboxylic acid derivative, brequinar sodium, which are known to be potent inhibitors of mammalian DHODH, markedly reduced C. albicans DHODH activity. This study provides a background for the development of antipyrimidines with high efficacy for decreasing in situ pyrimidine nucleotide pools in C. albicans.},
  author       = {Zameitat, Elke and Gojkovic, Z. and Knecht, W. and Piskur, Jure and Löffler, Monica},
  issn         = {1742-464X},
  language     = {eng},
  number       = {14},
  pages        = {3183--3191},
  publisher    = {Wiley-Blackwell},
  series       = {The FEBS Journal},
  title        = {Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic yeast Candida albicans},
  url          = {http://dx.doi.org/10.1111/j.1742-4658.2006.05327.x},
  doi          = {10.1111/j.1742-4658.2006.05327.x},
  volume       = {273},
  year         = {2006},
}