IPC Synthase as a Useful Target for Antifungal Drugs

Sugimoto, Yuichi; Sakoh, Hiroki; Yamada, Koji

doi:10.2174/1568005043340597

Cited by 53 publications

(37 citation statements)

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“…The scale is a log transformed base 2. Sugimoto et al, 2004). In contrast, the major sterol species is ergosterol, and other species are probably just intermediates in its biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Functional Interactions between Sphingolipids and Sterols in Biological Membranes Regulating Cell Physiology

Guan

Souza²,

Pichler

et al. 2009

MBoC

198

203

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Sterols and sphingolipids are limited to eukaryotic cells, and their interaction has been proposed to favor formation of lipid microdomains. Although there is abundant biophysical evidence demonstrating their interaction in simple systems, convincing evidence is lacking to show that they function together in cells. Using lipid analysis by mass spectrometry and a genetic approach on mutants in sterol metabolism, we show that cells adjust their membrane composition in response to mutant sterol structures preferentially by changing their sphingolipid composition. Systematic combination of mutations in sterol biosynthesis with mutants in sphingolipid hydroxylation and head group turnover give a large number of synthetic and suppression phenotypes. Our unbiased approach provides compelling evidence that sterols and sphingolipids function together in cells. We were not able to correlate any cellular phenotype we measured with plasma membrane fluidity as measured using fluorescence anisotropy. This questions whether the increase in liquid order phases that can be induced by sterol-sphingolipid interactions plays an important role in cells. Our data revealing that cells have a mechanism to sense the quality of their membrane sterol composition has led us to suggest that proteins might recognize sterol-sphingolipid complexes and to hypothesize the coevolution of sterols and sphingolipids.

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“…The scale is a log transformed base 2. Sugimoto et al, 2004). In contrast, the major sterol species is ergosterol, and other species are probably just intermediates in its biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Functional Interactions between Sphingolipids and Sterols in Biological Membranes Regulating Cell Physiology

Guan

Souza²,

Pichler

et al. 2009

MBoC

198

203

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“…Other IPC synthase inhibitors include khafrefungin, rustmicin and galbonolide A, both presenting antifungal activity against Candida spp., C. neoformans and to a lesser extent against Aspergillus spp. [115]. Ipc1 inhibitors are highly desirable because of their specificity (Ipc1 is not present in mammalian cells) and because Ipc1 is essential in fungi.…”

Section: Sphingolipids As Targets For Treatment Of Fungal Infections mentioning

confidence: 99%

Sphingolipids as Targets for Treatment of Fungal Infections

et al. 2016

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Invasive fungal infections have significantly increased in the last few decades. Three classes of drugs are commonly used to treat these infections: polyenes, azoles and echinocandins. Unfortunately each of these drugs has drawbacks; polyenes are toxic, resistance against azoles is emerging and echinocandins have narrow spectrum of activity. Thus, the development of new antifungals is urgently needed. In this context, fungal sphingolipids have emerged as a potential target for new antifungals, because their biosynthesis in fungi is structurally different than in mammals. Besides, some fungal sphingolipids play an important role in the regulation of virulence in a variety of fungi. This review aims to highlight the diverse strategies that could be used to block the synthesis or/and function of fungal sphingolipids.

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“…Sphingolipids are essential for the survival of many fungi as evidenced by their sensitivity to aureobasidin A, an IPC synthase inhibitor (Sugimoto et al, 2004). In S. cerevisiae IPCs are supposed to localize within lipid rafts, distinct sphingolipid-rich membrane areas that are essential for the correct localization of proteins, the organization of the cortical actin cytoskeleton and the endocytic uptake (Wachtler and Balasubramanian, 2005).…”

Section: Discussionmentioning

confidence: 99%