Molecular Basis of Substrate Polyspecificity of the Candida albicans Mdr1p Multidrug/H+ Antiporter

Redhu, Archana Kumari; Banerjee, Atanu; Shah, Abdul Haseeb; Moréno, Alexis; Rawal, Manpreet Kaur; Nair, Remya; Falson, Pierre; Prasad, Rajendra

doi:10.1016/j.jmb.2018.01.005

Cited by 20 publications

(43 citation statements)

References 29 publications

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“…Similar to the study on CaCdr1, Redhu et al performed alanine (glycine substitution in places where alanine is present) scanning mutagenesis for all the residues present within the TMDs of CaMdr1 [74]. The library of 252 mutants (created by overexpressing all the alanine or glycine variants in the AD1-8u − host strain) was screened against different drug substrates of CaMdr1 [74]. The results showed that around 33% (84/252) of the variants with alanine (or glycine) substitutions gave total or selective loss of drug resistance [74].…”

Section: Camdr1mentioning

confidence: 99%

Directed Mutational Strategies Reveal Drug Binding and Transport by the MDR Transporters of Candida albicans

Banerjee

Pata

Sharma

et al. 2021

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Multidrug resistance (MDR) transporters belonging to either the ATP-Binding Cassette (ABC) or Major Facilitator Superfamily (MFS) groups are major determinants of clinical drug resistance in fungi. The overproduction of these proteins enables the extrusion of incoming drugs at rates that prevent lethal effects. The promiscuity of these proteins is intriguing because they export a wide range of structurally unrelated molecules. Research in the last two decades has used multiple approaches to dissect the molecular basis of the polyspecificity of multidrug transporters. With large numbers of drug transporters potentially involved in clinical drug resistance in pathogenic yeasts, this review focuses on the drug transporters of the important pathogen Candida albicans. This organism harbors many such proteins, several of which have been shown to actively export antifungal drugs. Of these, the ABC protein CaCdr1 and the MFS protein CaMdr1 are the two most prominent and have thus been subjected to intense site-directed mutagenesis and suppressor genetics-based analysis. Numerous results point to a common theme underlying the strategy of promiscuity adopted by both CaCdr1 and CaMdr1. This review summarizes the body of research that has provided insight into how multidrug transporters function and deliver their remarkable polyspecificity.

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Section: Camdr1mentioning

confidence: 99%

Directed Mutational Strategies Reveal Drug Binding and Transport by the MDR Transporters of Candida albicans

Banerjee

Pata

Sharma

et al. 2021

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“…Mutagenesis of the glycine residue of the GP dipeptide within motif-C has been shown to alter tetracycline resistance conferred by TetA(C), a tetracycline/H + antiporter (Varela et al 1995). Much recently, mutational analyses of a MFS transporter of C. albicans, Mdr1, revealed that both these helices (TMH4 and TMH5) contains quite a significant number of residues which are important for the transport function (Redhu et al 2018). To get an insight into the distribution of the high scoring residues on a 3D-structure, top 20 residues with the maximum scores were mapped on to the crystal structure of the lactose permease (LacY) of Escherichia coli (PDB ID: 1pv6) ( Fig.…”

Section: Prediction Of Fold-specific Residues: Results Of Re Calculationmentioning

confidence: 99%

Phylogenetic and conservation analyses of MFS transporters

et al. 2018

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Major facilitator superfamily is one of the largest superfamily of secondary transporters present across the kingdom of life. Considering the physiological and clinical importance of MFS proteins, we attempted to explore the phylogenetic and structural aspects of the superfamily. To achieve the objectives, we performed global sequence-based analyses of MFS proteins encompassing multiple taxa. Notably, phylogenetic analysis of MFS proteins resulted in the clustering of MFS proteins based on their function, rather than lineage of the respective organisms. Additionally, we employed information theoretic measures, Relative entropy (RE) and Cumulative relative entropy (CRE) to decipher fold-specific and function-specific residues, respectively, in the MFS proteins. The residues with high RE score when mapped on to the 3D-structure of MFS transporter LacY, were found to be distributed throughout the tertiary structure of the protein. On the other hand, CRE calculation was employed to contrast two subfamilies Drug H + antiporter 1 and 3 (DHA1 and DHA3). The particular analysis unveiled certain differentially conserved residues in DHA1 as compared to DHA3 highlighting family-specific importance of them. Remarkably, a number of high scoring CRE residues have already established functional roles, for instance, the arginine residue present in TMH4. Altogether, the current study apart from providing an insight into the functional clustering of MFS proteins also identifies residues with established or plausible roles in the transport mechanism. Thus, the study lays a platform for future structure-function studies of these proteins.

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“…It is possible that the use of certain fungicides for crop disease, notably azoles, may cause elevated resistant to this class of antifungals in medical settings [ 240 ]. Resistance can occur by multiple mechanisms, including mutations in the target enzyme and via the overexpression of multidrug efflux pumps, such as the MFS transporter Mdr1 in C. albicans or various ABC transporters in A. fumigatus [ 241 , 242 ]. Encouragingly, structural aspects of these membrane transporters may be unique to fungi, such as the presence of two extracellular loops between transmembrane spanning regions in fungal ABC transporters [ 242 ].…”

Section: Surviving In the Communitymentioning

confidence: 99%

“…Resistance can occur by multiple mechanisms, including mutations in the target enzyme and via the overexpression of multidrug efflux pumps, such as the MFS transporter Mdr1 in C. albicans or various ABC transporters in A. fumigatus [ 241 , 242 ]. Encouragingly, structural aspects of these membrane transporters may be unique to fungi, such as the presence of two extracellular loops between transmembrane spanning regions in fungal ABC transporters [ 242 ]. Thus, the chemical inhibition of efflux pumps should theoretically have minimal toxicity to humans and may act to improve efficacy of existing antifungals when used in combinational therapy.…”

Section: Surviving In the Communitymentioning

confidence: 99%

Turning Inside Out: Filamentous Fungal Secretion and Its Applications in Biotechnology, Agriculture, and the Clinic

Cairns

Zheng

et al. 2021

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Filamentous fungi are found in virtually every marine and terrestrial habitat. Vital to this success is their ability to secrete a diverse range of molecules, including hydrolytic enzymes, organic acids, and small molecular weight natural products. Industrial biotechnologists have successfully harnessed and re-engineered the secretory capacity of dozens of filamentous fungal species to make a diverse portfolio of useful molecules. The study of fungal secretion outside fermenters, e.g., during host infection or in mixed microbial communities, has also led to the development of novel and emerging technological breakthroughs, ranging from ultra-sensitive biosensors of fungal disease to the efficient bioremediation of polluted environments. In this review, we consider filamentous fungal secretion across multiple disciplinary boundaries (e.g., white, green, and red biotechnology) and product classes (protein, organic acid, and secondary metabolite). We summarize the mechanistic understanding for how various molecules are secreted and present numerous applications for extracellular products. Additionally, we discuss how the control of secretory pathways and the polar growth of filamentous hyphae can be utilized in diverse settings, including industrial biotechnology, agriculture, and the clinic.

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Molecular Basis of Substrate Polyspecificity of the Candida albicans Mdr1p Multidrug/H+ Antiporter

Cited by 20 publications

References 29 publications

Directed Mutational Strategies Reveal Drug Binding and Transport by the MDR Transporters of Candida albicans

Directed Mutational Strategies Reveal Drug Binding and Transport by the MDR Transporters of Candida albicans

Phylogenetic and conservation analyses of MFS transporters

Turning Inside Out: Filamentous Fungal Secretion and Its Applications in Biotechnology, Agriculture, and the Clinic

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