A New Antifungal Substance of Fungal Origin

Delmotte, P.; Delmotte-Plaquee, J.

doi:10.1038/171344a0

Cited by 252 publications

(154 citation statements)

References 2 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…RD is the more potent binder of the two. Radicicol, also known as monorden, was originally discovered as an antifungal substance of fungal origin in 1953 13 and is a specific Hsp90 inhibitor 14 . The co-crystal structures of radicicol bound to the Hsp90 N-terminal domains from various species have been determined, and they show numerous hydrogen bonds with the ATP-binding pocket of the Nterminal domain 15; 16 .…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Zubrienė¹,

Gutkowska²,

Matulienė³

et al. 2010

Biophysical Chemistry

View full text Add to dashboard Cite

Radicicol is a natural antibiotic that specifically inhibits chaperone Hsp90 activity and binds to its active site with nanomolar affinity. Radicicol has been widely used as a lead compound to generate synthetic analogs with reduced toxicity and increased stability that could be employed clinically. Here we present a detailed thermodynamic description of radicicol binding to human Hsp90 and yeast Hsc82 studied by isothermal titration calorimetry and thermal shift assay.Titrations as a function of pH showed a linked protonation event upon radicicol binding. The intrinsic binding constant and the thermodynamic parameters (including the enthalpy, entropy, and heat capacity) were determined for yeast Hsc82, and human alpha and beta Hsp90. Recent experimental evidence in literature shows that yeast Hsc82 has significant differences from human Hsp90 isozymes. Here we support this by demonstrating differences in radicicol binding thermodynamics to these proteins. The intrinsic enthalpy of radicicol binding to Hsc82 was -46.7 kJ/mol, to Hsp90alpha -70.7 kJ/mol, and to Hsp90beta was -66.8 kJ/mol. The enthalpies of binding were significantly different, while the intrinsic dissociation constants were quite similar,

show abstract

Section: Introductionmentioning

confidence: 99%

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Zubrienė¹,

Gutkowska²,

Matulienė³

et al. 2010

Biophysical Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition to its activity as an antifungal antibiotic [23] and a tranquilizer, [24] radicicol was particurlarly intensively examined for its selective and potent PTK-inhibitory activity. [25] Since the natural substance is difficult to isolate, development of an efficient total synthesis (only one is published so far [26] ) provides the opportunity to produce enough material for biological and medical studies.…”

Section: Figurementioning

confidence: 99%

Organic Synthesis and Biological Signal Transduction

Schmittberger¹,

Waldmann²

1998

Synlett

View full text Add to dashboard Cite

“…This strategy has been successfully employed in identifying the target molecules of several natural products such as fumagillin (16), didemnin (17), rapamycin (18), and leptomycin (19). We show here that radicicol binds not only Hsp90 but also ATP citrate lyase (ACL), 1 a key enzyme that produces acetyl-CoA in the cytosolic compartment. ACL is required for both fatty acid and sterol syntheses.…”

mentioning

confidence: 98%

“…Radicicol (also known as monorden), a 14-membered macrolide originally isolated from Monosporium bonorden as an antifungal antibiotic in 1953 (1), is a compound showing a variety of biological activities. It was reported again as a potent tranquilizer with low toxicity in 1964 (2).…”

mentioning

confidence: 99%

Radicicol Binds and Inhibits Mammalian ATP Citrate Lyase

Ki¹,

Ishigami²,

Kitahara³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

Six different biotinylated radicicol derivatives were synthesized as affinity probes for identification of cellular radicicol-binding proteins. Derivatives biotinylated at the C-17 (BR-1) and C-11 (BR-6) positions retained the activity of morphological reversion in v-src-transformed 3Y1 fibroblasts. Two radicicol-binding proteins, 120 and 90-kDa in size, were detected in HeLa cell extracts by employing BR-1 and BR-6, respectively. The 90-kDa protein bound to BR-6 was identified to be Hsp90 by immunoblotting. The 120-kDa protein bound to BR-1 was purified from rabbit reticulocyte lysate, and its internal amino acid sequence was identical to that of human and rat ATP citrate lyase. The identity of the 120-kDa protein as ATP citrate lyase was confirmed by immunoblotting. Interaction between BR-1 and ATP citrate lyase was blocked by radicicol but not by herbimycin A that interacts with Hsp90. These results suggest that radicicol binds the two proteins through different molecular portions of its structure. BR-1-bound ATP citrate lyase isolated from rabbit reticulocyte lysate showed no enzymatic activity. The activity of rat liver ATP citrate lyase was inhibited by radicicol and BR-1 but not by BR-6. Kinetic analysis demonstrated that radicicol was a noncompetitive inhibitor of ATP citrate lyase with K i values for citrate and ATP of 13 and 7 M, respectively.Radicicol (also known as monorden), a 14-membered macrolide originally isolated from Monosporium bonorden as an antifungal antibiotic in 1953 (1), is a compound showing a variety of biological activities. It was reported again as a potent tranquilizer with low toxicity in 1964 (2). We rediscovered radicicol as a potent inducer of reversal of the transformed phenotype in v-src-transformed fibroblasts to the normal one (3, 4). We also showed that radicicol caused cell cycle arrest in G 1 and G 2 phases, and Oikawa et al. (5) demonstrated that it inhibited in vivo angiogenesis. Furthermore, radicicol was reported to induce morphological reversion of not only src but also ras, mos, raf, fos, and SV40-transformed cell lines and inhibited the expression of mitogen-inducible cyclooxygenase in macrophages (6 -8). Some of leukemia cell lines were differentiated in response to radicicol (4, 9). Recently, KF25706, a novel oxime derivative of radicicol, was reported to show potent antitumor activity and is currently under consideration as an anticancer drug (10). The in vivo inhibition of tyrosine kinases and MAP kinases has been suggested to be involved in these characteristic phenotypes elicited by radicicol (6, 7). Increased expression of gelsolin, an actin regulatory protein, has also been observed during the induction of morphological changes in various transformed cells (11). Recent studies showed that radicicol disrupted the Ras-activated signaling pathway by selectively depleting Raf kinase or reducing Ras/Raf molecular interaction (12, 13). The target molecule of radicicol was proposed to be Hsp90, because it strongly binds Hsp90 in a manner competitive with ATP and...

show abstract

A New Antifungal Substance of Fungal Origin

Cited by 252 publications

References 2 publications

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Organic Synthesis and Biological Signal Transduction

Radicicol Binds and Inhibits Mammalian ATP Citrate Lyase

Contact Info

Product

Resources

About