Squalene epoxidase encoded by ERG1 affects morphogenesis and drug susceptibilities of Candida albicans
Abstract
OBJECTIVES: Functional characterization of the erg1 mutant of ergosterol biosynthesis of Candida albicans. METHODS: We disrupted the ERG1 gene of C. albicans, which encodes squalene epoxidase (EC 1.14.99.7). Since the disruption of both alleles of ERG1 was lethal, the second allele of a heterozygous disruptant was placed under the control of a regulable promoter, MET3p, which is repressed by methionine and cysteine. RESULTS: The reverse-phase HPLC analysis of sterol, extracted from the conditional mutant strain, showed a total lack of ergosterol and instead accumulation of squalene. This imbalance in sterol composition led to defects in growth and increased susceptibilities to drugs including fluconazole, ketoconazole, cycloheximide, nystatin, amphotericin B and terbinafine. Reduced drug efflux activity of the erg1 mutant was associated with poor surface localization of Cdr1p, suggesting that enhanced passive diffusion and reduced efflux mediated by the ABC (ATP binding cassette) transporter Cdr1p increases drug susceptibility. Additionally, conditional erg1 mutant strains were unable to form hyphae in various media. CONCLUSIONS: Taken together, our results demonstrate that the absence of ergosterol, which is one of the constituents of membrane microdomains (rafts), has a direct effect on drug susceptibility and morphogenesis of C. albicans.
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ERG1, ERG7, ERG9, ERG25, ERG26, and ERG27 are essential, while ERG2, ERG3, ERG5, ERG6, and ERG24 are considered non-essential in ergosterol biosynthesis.
“By using the technology of gene disruption and controlled gene expression, ERG1 , ERG7 , ERG9 , ERG25 , ERG26 , and ERG27 have been proved to be essential, while ERG2 , ERG3 , ERG5 , ERG6 , and ERG24 are considered to be non-essential in ergosterol biosynthesis.”
From The synthesis, regulation, and functions of sterols in<i>Candida albicans</i>: Well-known but still lots to learn (2016) · cites this paper as [24]
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- Authors
- Pasrija, R., Krishnamurthy, S., Prasad, T., Ernst, J. F., & Prasad, R.
- Affiliations
- Jawaharlal Nehru University (IN)
- Corresponding author
- Pasrija, Ritu
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-04-21
- Volume
- 55
- Issue
- 6
- Pages
- 905-913
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2097147526
- Cited by
- 53
- References
- 38
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 6 · 2017: 1 · 2016: 3 · 2014: 1 · 2013: 4 · 2012: 2
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Council of Scientific and Industrial Research, India
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida albicans, ERG1, squalene epoxidase, ergosterol biosynthesis, squalene accumulation, conditional mutants, drug sensitivity, Cdr1p, ABC transporters, drug efflux, hyphal morphogenesis, lipid rafts, sterol composition, antifungal resistance
- MeSH terms
- Candida albicans, Diffusion, Ergosterol, Fungal Proteins, Morphogenesis, Mutation, Oxygenases, Membrane Transport Proteins, Squalene Monooxygenase
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