Recombinant Candida glabrata FK506-binding protein 1 (FPR1)
Description
Introduction
Candida glabrata is an opportunistic fungal pathogen known for its increasing resistance to common antifungal drugs, such as azoles . This resistance often involves complex mechanisms, including the overexpression of drug efflux pumps and alterations in drug target enzymes . FK506-binding proteins (FKBPs) play a crucial role in regulating these resistance mechanisms and the virulence of C. glabrata . Specifically, the FK506-binding protein 1 (FPR1) is part of a family of proteins that have peptidyl-prolyl cis-trans isomerase (PPIase) activity and are involved in various cellular processes, including drug resistance and histone homeostasis .
Function and Mechanism of Action
FPR1, along with other FKBPs like CgFpr3 and CgFpr4 in C. glabrata, possesses a PPIase domain that accelerates protein folding . These proteins are involved in the regulation of the CgPDR1 regulon, which affects the expression of ATP-binding cassette multidrug transporters like CgCDR1, CgCDR2, and CgSNQ2 . These transporters actively pump drugs out of the cell, reducing the effectiveness of antifungal treatments .
A key aspect of FPR1's function is its involvement in maintaining histone H3 and H4 protein levels . Histones are essential for DNA packaging and gene regulation, and their modification can significantly impact drug resistance. For instance, reduced histone H4 levels have been associated with increased biofilm formation and diminished survival of C. glabrata .
Role in Azole Resistance
Azole resistance in C. glabrata is frequently mediated by gain-of-function mutations in the CgPDR1 gene, which encodes a transcriptional activator . CgFpr3 and CgFpr4 act redundantly to control CgPDR1 expression . Deletion of Cgfpr3 and Cgfpr4 leads to elevated expression of CgPDR1 and its target genes, resulting in increased resistance to fluconazole .
Studies have shown that disrupting genes coding for the histone demethylase CgRph1 and the histone H3K36-specific methyltransferase CgSet2 can affect fluconazole susceptibility . Loss of CgRph1 increases susceptibility to fluconazole and reduces basal expression levels of CgPDR1 and CgCDR1, while loss of CgSet2 decreases susceptibility . This highlights the role of histone methylation in modulating azole antifungal resistance .
Clinical Significance and Multidrug Resistance
Multidrug-resistant strains of C. glabrata are an increasing concern in clinical settings . In some isolates, overexpression of ERG11 (encoding lanosterol 14-alpha demethylase, the target of azoles) and CDR1 contributes to resistance to azoles like posaconazole . The Cdr1 inhibitor FK520 can reverse posaconazole resistance by downregulating ERG11 expression, indicating a potential therapeutic strategy .
Tables and Data
| Gene | Effect of Disruption | Impact on Azole Resistance |
|---|---|---|
| CgPDR1 | Overexpression | Increased |
| CgRph1 | Loss of function | Increased susceptibility |
| CgSet2 | Loss of function | Decreased |
| CgFpr3/CgFpr4 | Deletion | Increased |
| Compound | Effect on C. glabrata | Mechanism |
|---|---|---|
| Fluconazole | Antifungal | Inhibits ergosterol synthesis |
| FK506 | Immunosuppressant/Antifungal | Binds to FKBPs, affecting calcineurin and downstream signaling |
| FK520 | Cdr1 inhibitor | Reverses posaconazole resistance by downregulating ERG11 expression |
Product Specs
Note: While we prioritize shipping the format currently in stock, please specify your format preference during order placement for customized preparation.
Note: All proteins are shipped with standard blue ice packs unless dry ice shipping is requested in advance. Additional fees apply for dry ice shipping.
The tag type will be determined during production. If you require a specific tag type, please inform us, and we will prioritize its development.
Target Background
KEGG: cgr:CAGL0K09724g
STRING: 284593.XP_448641.1
