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Oxygen-responsive transcriptional regulation of lipid homeostasis in fungi: Implications for anti-fungal drug development.

ABSTRACT: Low oxygen adaptation is essential for aerobic fungi that must survive in varied oxygen environments. Pathogenic fungi in particular must adapt to the low oxygen host tissue environment in order to cause infection. Maintenance of lipid homeostasis is especially important for cell growth and proliferation, and is a highly oxygen-dependent process. In this review, we focus on recent advances in our understanding of the transcriptional regulation and coordination of the low oxygen response across fungal species, paying particular attention to pathogenic fungi. Comparison of lipid homeostasis pathways in these organisms suggests common mechanisms of transcriptional regulation and points toward untapped potential to target low oxygen adaptation in antifungal development.

SUBMITTER: Burr R

PROVIDER: S-EPMC5826825 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Oxygen-responsive transcriptional regulation of lipid homeostasis in fungi: Implications for anti-fungal drug development.

Burr Risa R Espenshade Peter J PJ

Seminars in cell & developmental biology 20170826

Low oxygen adaptation is essential for aerobic fungi that must survive in varied oxygen environments. Pathogenic fungi in particular must adapt to the low oxygen host tissue environment in order to cause infection. Maintenance of lipid homeostasis is especially important for cell growth and proliferation, and is a highly oxygen-dependent process. In this review, we focus on recent advances in our understanding of the transcriptional regulation and coordination of the low oxygen response across f ...[more]

PMID: 28851600

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Project description:Cytochrome P450 monooxygenases (CYPs/P450s) are heme-thiolate proteins whose role as a drug target against pathogenic microbes has been explored because of their stereo- and regio-specific oxidation activity. We aimed to assess the CYP53 family's role as a common alternative drug target against animal (including human) and plant pathogenic fungi and its role in fungal-mediated wood degradation. Genome-wide analysis of fungal species revealed the presence of CYP53 members in ascomycetes and basidiomycetes. Basidiomycetes had a higher number of CYP53 members in their genomes than ascomycetes. Only two CYP53 subfamilies were found in ascomycetes and six subfamilies in basidiomycetes, suggesting that during the divergence of phyla ascomycetes lost CYP53 P450s. According to phylogenetic and gene-structure analysis, enrichment of CYP53 P450s in basidiomycetes occurred due to the extensive duplication of CYP53 P450s in their genomes. Numerous amino acids (103) were found to be conserved in the ascomycetes CYP53 P450s, against only seven in basidiomycetes CYP53 P450s. 3D-modelling and active-site cavity mapping data revealed that the ascomycetes CYP53 P450s have a highly conserved protein structure whereby 78% amino acids in the active-site cavity were found to be conserved. Because of this rigid nature of ascomycetes CYP53 P450s' active site cavity, any inhibitor directed against this P450 family can serve as a common anti-fungal drug target, particularly toward pathogenic ascomycetes. The dynamic nature of basidiomycetes CYP53 P450s at a gene and protein level indicates that these P450s are destined to acquire novel functions. Functional analysis of CYP53 P450s strongly supported our hypothesis that the ascomycetes CYP53 P450s ability is limited for detoxification of toxic molecules, whereas basidiomycetes CYP53 P450s play an additional role, i.e. involvement in degradation of wood and its derived components. This study is the first report on genome-wide comparative structural (gene and protein structure-level) and evolutionary analysis of a fungal P450 family.

Dataset Information

Oxygen-responsive transcriptional regulation of lipid homeostasis in fungi: Implications for anti-fungal drug development.

Publications

Oxygen-responsive transcriptional regulation of lipid homeostasis in fungi: Implications for anti-fungal drug development.

Similar Datasets

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