Targeting the fungal plasma membrane proton pump

• Autorzy: Monk B. C. , Mason A.B. , Kardos T.B. , Perlin D.S.
• Języki publikacji: EN

Abstrakty

EN

The need for new mechanistic classes of broad spectrum antifungal agents has prompted development of the membrane sector and ectodomain of the plasma membrane proton pumping ATPase as an antifungal target. The fungal proton pump is a highly abundant, essential enzyme in Saccharomyces cerevisiae. It belongs to the family of P-type ATPases, a class of enzymes that includes the Na+,K+-ATPase and the gastric H+,K+-ATPase. These enzymes are cell surface therapeutic targets for the cardiac glycosides and several anti-ulcer drugs, respectively. The effects of acid- -activated omeprazole show that extensive inhibition of the S. cerevisiae ATPase is fungicidal. Fungal proton pumps possess elements within their transmembrane loops that distinguish them from other P-type ATPases. These loops, such as the conformationally sensitive transmembrane loop 1+2, can attenuate the activity of the enzyme. Expression in S. cerevisiae of fully functional chimeric ATPases that contain a foreign target comprising transmembrane loops 1+2 and/or 3+4 from the fungal pathogen Candida albicans suggests that these loops operate as a domain. The chimera containing C. albicans transmembrane loops 1+2 and 3+4 provides a prototype for mutational analysis of the target region and the screening of inhibitors directed against opportunistic fungal pathogens. Panels of mutants with modified ATPase regulation or with altered cell surface cysteine residues are also described. Information about the ATPase membrane sector and ectodomain has been integrated into a model of this region.

Słowa kluczowe

EN

omeprazole; plasma membrane; chimera; ATPase; proton pump; antifungal agent; Candida albicans; fungal infection; Saccharomyces cerevisiae

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 1995
• Tom: 42
• Numer: 4
• Opis fizyczny: p.481-496,fig.

Twórcy

autor

Monk B. C.

• University of Otago, PO Box 647, Dunedin, New Zeyland

autor

Mason A.B.

autor

Kardos T.B.

autor

Perlin D.S.

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