Studies on new phosphate ester antifungal antibiotics phoslactomycins. I. Taxonomy, fermentation, purification and biological activities.

According to the chemical genetic approach, small molecules that bind directly to proteins are used to analyze protein function, thereby enabling the elucidation of complex mechanisms in mammal cells. Thus, it is very important to identify the molecular targets of compounds that induce a unique phenotype in a target cell. Phoslactomycin A (PLMA) is known to be a potent inhibitor of protein Ser/Thr phosphatase 2A (PP2A); however, the inhibitory mechanism of PP2A by PLMA has not yet been elucidated. Here, we demonstrated that PLMA directly binds to the PP2A catalytic subunit (PP2Ac) in cells by using biotinylated PLMA, and the PLMA-binding site was identified as the Cys-269 residue of PP2Ac. Moreover, we revealed that the Cys-269 contributes to the potent inhibition of PP2Ac activity by PLMA. These results suggest that PLMA is a PP2A-selective inhibitor and is therefore expected to be useful for future investigation of PP2A function in cells.

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“…[8][9][10][11]. Previously, we reported that PLMs are potent protein Ser/Thr phosphatase 2A (PP2A) inhibitors in vitro [12].…”

Section: Introductionmentioning

confidence: 99%

Phoslactomycin targets cysteine‐269 of the protein phosphatase 2A catalytic subunit in cells

et al. 2005

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“…HA81-2 exhibited antifungal activity against Aspergillus fumigatus IFO 5840 accompanied by hyphal abnormalities. The isolated active fraction was identified as phoslactomycin E (PLME) [5] based on LC-MS and NMR spectral data. We herein report the isolation procedures for PLME, its molecular characteristics, and its induction of morphological changes in fungal cells.…”

mentioning

confidence: 99%

“…Lit. [5] [a] D 25 ϩ61°(c 0.2, MeOH) [7,8]. PLME was then evaluated for in vitro antifungal activity.…”

mentioning

confidence: 99%

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

et al. 2007

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In our survey for antifungal compounds, a fermentation broth of Streptomyces sp. HA81-2 was found to inhibit the in vitro growth of Aspergillus fumigatus IFO 5840 accompanied by hyphal morphological abnormalities. One of the isolated antibiotics was identified as phoslactomycin E based on LC-MS and NMR spectral data. In a preliminary assay using the membrane fractions of A. fumigatus, phoslactomycin E was found to inhibit the activity of 1,3-b glucan synthase.Keywords antifungal activity, phoslactomycin E, Aspergillus fumigatus, hyphal morphological abnormalities, 1,3-b glucan synthase Opportunistic fungal infections are a major cause of serious morbidity and mortality in immunocompromised patients. However, there are few drugs for antifungal chemotherapy of deep-seated mycosis. As both human and fungal cells are eukaryotes, it is difficult to develop antifungal drugs without side effects in human hosts. Current targets are limited to ergosterol, cell wall components, biosynthetic pathways of cell wall and cytosine deaminase [1,2]. Therefore, there is a great need for novel antifungal drugs with new mechanisms of action. Morphological deformation of fungal hyphae is often induced by antifungal drugs [3]. As this phenomenon is specific to fungi, it could be used to screen for selective antifungal antibiotics [4]. In addition, this hyphal deformation is expected to reflect the disruption of cell wall biosynthesis, which is a specific target of antifungal agents. Moreover, investigating the mechanism of antifungal-induced hyphal morphological abnormalities is potentially useful for understanding the morphogenesis of fungal hyphae.In the course of our search for antifungal antibiotics, we found that a fermentation broth of Streptomyces sp. HA81-2 exhibited antifungal activity against Aspergillus fumigatus IFO 5840 accompanied by hyphal abnormalities. The isolated active fraction was identified as phoslactomycin E (PLME) [5] based on LC-MS and NMR spectral data. We herein report the isolation procedures for PLME, its molecular characteristics, and its induction of morphological changes in fungal cells.Active principles were isolated as follows; fermentation broth was filtered, the filtrate was applied on Diaion HP-20 column, and then eluted using an increasing gradient of aq MeOH (10ϳ100%). The 80ϳ90% MeOH fractions were concentrated in vacuo to afford crude extract, which was partitioned between water and CHCl 3 . Purification of

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“…The structure of bitungolide A (22) was elucidated by X-ray and the rest by spectroscopic correlation. Although bitungolides are the first such compounds from marine sources, they share the same structural elements with those of microbial metabolites, pironetin (28) known as a microtubule-targeting drug [9] and phoslactomycin (29), a phosphatase inhibitor [10]. Bitungolides showed moderate and selective activity against dual-specificity phosphatase, but no activity against microtubules.…”

Section: Polyketides From Spongesmentioning

confidence: 99%

“…The structures were determined by spectroscopic and X-ray analysis [13]. These compounds are related to the class of compounds known as longithorones and longithorols, but their unique features are in the presence of an ε-lactone bridging the aromatic ring and a [10]metacyclophane band and of a double bond or an epoxy function at the bridgehead, confining the cyclophane ring into a relatively rigid system. Floresolides showed moderate cytotoxicity against KB cells.…”

Section: Metabolites From An Ascidianmentioning

confidence: 99%

Diverse metabolites of coral reef organisms

Tanaka

Kuniyoshi

Tanaka

et al. 2005

Pure and Applied Chemistry

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A detailed mechanism for the spontaneous transformation of 2-chloro-1-hydroxyoctoda-3(8),5-dien-4-one, a metabolite of Portieria hornemanni, into 4,5-dimethylbenzo[b]-furan was presented. Five new terpenoids have been isolated from the red alga Laurencia luzonensis. Five species of sponges yielded various metabolites: furanosesterterpenes from Ircinia sp., scalarane derivatives from Phyllospongia sp., polyketides from Theonella cf. swinhoei, a polyacetylene from Callyspongia sp., and cyclic depsipeptides from Suberites japonicus. Other new metabolites were sponge-derived secomanoalide derivative and imidazole alkaloids from nudibranchs, briarane class diterpenes from octocorals, and cyclofarnesylated hydroquinones, floresolides A-C, from an ascidian, Aplidium sp. Many of these compounds showed cytotoxicity.

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Studies on new phosphate ester antifungal antibiotics phoslactomycins. I. Taxonomy, fermentation, purification and biological activities.

Cited by 90 publications

References 11 publications

Phoslactomycin targets cysteine‐269 of the protein phosphatase 2A catalytic subunit in cells

Phoslactomycin targets cysteine‐269 of the protein phosphatase 2A catalytic subunit in cells

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

Diverse metabolites of coral reef organisms

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