The Plasma Membrane of Candida albicans: Its Relevance to Transport Phenomenon

Prasad, R.

doi:10.1007/978-3-642-75253-7_8

Cited by 10 publications

(3 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As illustrated above, the P-type ATPases serve as effective therapeutic targets for clinically important problems. The fungal plasma membrane H + -ATPase is a proton pump that helps regulate intracellular pH (Sanders et al, 1981;Vallejo and Serrano, 1989) and maintains the transmembrane electrochemical proton gradient necessary for nutrient uptake (Prasad, 1991;Serrano, 1989). It is an essential enzyme (Serrano et al, Fink, 1986) consisting of a single large polypeptide subunit of Mr ~100 kDa that represents approximately 25% percent of the total plasma membrane protein.…”

Section: A New Mechanistic Classmentioning

confidence: 99%

Ion pumps as targets for therapeutic intervention: Old and new paradigms

Perlin¹

1998

Electron. J. Biotechnol.

View full text Add to dashboard Cite

Section: A New Mechanistic Classmentioning

confidence: 99%

Ion pumps as targets for therapeutic intervention: Old and new paradigms

Perlin¹

1998

Electron. J. Biotechnol.

View full text Add to dashboard Cite

“…It is one of the few antifungal targets that have been shown to be essential by gene disruption 8 . In addition to its role in cell growth, the H + ‐ATPase has been implicated in fungal pathogenicity through its effects on dimorphism, nutrient uptake, and medium acidification 9 . These properties, along with the availability of numerous in vivo and in vitro screens that facilitate high through‐put screening of compound libraries, make the fungal H + ‐ATPase a highly desirable drug discovery target.…”

Section: The Fungal H+‐atpase As a Novel Antifungal Targetmentioning

confidence: 99%

The Plasma Membrane H⁺‐ATPase of Fungi

Perlin¹,

Seto-Young²,

Monk

1997

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

The fungal plasma membrane H(+)-ATPase possesses important attributes that make it desirable as a target for antifungal drug discovery. First, the enzyme is essential to fungal cell physiology, being required for the formation of a large electrochemical proton gradient and the maintenance of intracellular pH. While complete inhibition of the proton pump will certainly be lethal, partial inhibition can also be lethal depending on the environment of the cell (gastrointestinal tract, etc.). Thus, an effective antagonist of the proton pump will be fungicidal, which is an important attribute for a drug being developed to treat opportunistic infections in the severely immunocompromised. Secondly, the well-characterized biochemistry and genetics of the H(+)-ATPase (encoded by the PMA1 gene) facilitate detailed analysis of interaction of lead or model compounds with the enzyme. Studies with omeprazole, which is not suitable as an antifungal but can be used under selective conditions to target H(+)-ATPase, indicate that the enzyme can be inhibited from its extramembrane surface. Detailed genetic analysis suggests that modification of amino acids in transmembrane segments 1 and 2 can either enhance or diminish the omeprazole sensitivity of the H(+)-ATPase, depending on the nature and location of the amino acid substitution. This region in mammalian P-type enzymes has been implicated in the interaction of cardiac glycosides and reversible gastric pump inhibitors. Our results suggest that this region in the H(+)-ATPase may be valuable as a potential interaction domain for antifungal agents. Finally, a number of primary and secondary screens are available to identify compounds that are targeted to the H(+)-ATPase and affect one or more functional properties. These screens assess enzyme functionality in the cell as well as in vitro and can be used in 96-well microplate format to facilitate high through-put screening. These screens have already yielded promising H(+)-ATPase-directed antagonists. In conclusion, the plasma membrane H(+)-ATPase is a highly desirable target for the development of novel antifungal therapeutics.

show abstract

“…C. albicans infections are treated with antifungal agents, particularly with the triazole derivative fluconazole. In order to combat the effects of antifungals, Candida has evolved a variety of mechanisms to acquire resistance to these drugs (Prasad, 1991;Prasad et al, 1996;Joseph-Horne and Hollomon, 1997;White et al, 1998;Marichal, 1999). The resistance to azoles in C. albicans, was earlier thought to occur primarily through an alteration or an overexpression of the 14a-lanosterol demethylase (P45014DM) involved in sterol biosynthesis (Lamb et al, 1997;White, 1997).…”

Section: Introductionmentioning

confidence: 99%

ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators

Smriti

Krishnamurthy

Dixit

et al. 2002

Yeast

Self Cite

View full text Add to dashboard Cite

We have used fluorescent 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-tagged phospholipid analogues, NBD-PE (phosphatidylethanolamine), NBD-PC (phosphatidylcholine) and NBD-PS (phosphatidylserine), to demonstrate that Cdr1p and its other homologues, Cdr2p and Cdr3p, belonging to the ATP-binding cassette (ABC) superfamily behave as general phospholipid translocators. Interestingly, CDR1 and CDR2, whose overexpression leads to azole resistance in C. albicans, elicit in-to-out transbilayer phospholipid movement, while CDR3, which is not involved in drug resistance, carries out-to-in translocation of phospholipids between the two monolayers of plasma membrane. Cdr1p, Cdr2p and Cdr3p could be further distinguished on the basis of their sensitivities to different inhibitors. For example, the in-to-out activity associated with Cdr1p and Cdr2p is energy-dependent and sensitive to sulphydryl blocking agents such as N-ethylmaleimide (NEM) and cytoskeleton disrupting agent cytochalasin E, while Cdr3p-associated out-to-in activity is energydependent but insensitive to NEM and cytochalasin E. We found that certain drugs, such as fluconazole, cycloheximide and miconazole, to which Cdr1p confers resistance could also affect in-to-out transbilayer movement of NBD-PE, while the same drugs had no effect on Cdr3p-mediated out-to-in translocation of NBD-PE. The ineffectiveness of these drugs to affect Cdr3p mediated out-to-in phospholipid translocation further confirms the inherent difference in the directionality of phospholipid translocation between these pumps. Notwithstanding the role of some of the Cdrps in drug resistance, this study clearly demonstrates that these ABC transporters of C. albicans are phospholipid translocators and this function could represent one of the physiological functions of such large family of proteins.

show abstract

The Plasma Membrane of Candida albicans: Its Relevance to Transport Phenomenon

Cited by 10 publications

References 100 publications

Ion pumps as targets for therapeutic intervention: Old and new paradigms

Ion pumps as targets for therapeutic intervention: Old and new paradigms

The Plasma Membrane H⁺‐ATPase of Fungi

ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators

Contact Info

Product

Resources

About

The Plasma Membrane of Candida albicans: Its Relevance to Transport Phenomenon

Cited by 10 publications

References 100 publications

Ion pumps as targets for therapeutic intervention: Old and new paradigms

Ion pumps as targets for therapeutic intervention: Old and new paradigms

The Plasma Membrane H+‐ATPase of Fungi

ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators

Contact Info

Product

Resources

About

The Plasma Membrane H⁺‐ATPase of Fungi