Studies on the mode of antifungal action of pradimicin antibiotics. I.Lectin-mimic binding of BMY-28864 to yeast mannan in the presence of calcium.

Ueki, Tomokazu; Numata, Kei-Ichi; Sawada, Yosuke; Nakajima, Tatsuo; Fukagawa, Yasuo; Oki, Taikan

doi:10.7164/antibiotics.46.149

Cited by 51 publications

(26 citation statements)

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“…Aside from avoiding some of the disadvantages of proteinbased CBAs, such as cost and lower stability, the main advantage of non-proteinageneous CBAs is their low molecular weight, which is beneficial in scale-up, purification, and production. [15][16][17][18] This model correlates with the finding that when the carboxylic acid is methylated, PRM-A loses its biological activity. The molecular architecture of pradimicins is proposed to be crucial, with the aglycon core, the amino acid, and the disaccharide all involved in the binding mechanism.…”

Section: Introductionsupporting

confidence: 77%

“…As low-molecular-weight natural products, the ability of pradimicins to bind to carbohydrates is very rare, proving them to be unique and with great potential for antifungal and antiviral applications. [15][16][17][18] According to a study conducted by Oki and co-workers, a calcium ion coordinates to two molecules of pradimicin A (PRM-A) through the carboxylic acid groups, and the other two moieties are involved in binding to the target oligomannan. [14] The pradimicins show specificity towards high-mannosetype glycans.…”

Section: Introductionmentioning

confidence: 99%

“…[14] The pradimicins show specificity towards high-mannosetype glycans. [15][16][17][18] It is unclear whether the function of calcium is solely to bridge two PRM-A units or whether it plays a role in coordinating mannose to the antibiotic. [15][16][17][18] According to a study conducted by Oki and co-workers, a calcium ion coordinates to two molecules of pradimicin A (PRM-A) through the carboxylic acid groups, and the other two moieties are involved in binding to the target oligomannan.…”

Section: Introductionmentioning

confidence: 99%

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Synthetic Studies Towards the Core Tricyclic Ring System of Pradimicin A

Zilke¹,

Hall²

2012

Eur J Org Chem

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Pradimicins are structurally intriguing natural products that possess potent biological activity as antifungal and antiviral agents through a unique mode of action as carbohydrate binding agents. A preliminary synthetic approach towards pradimicin A has focused on a model study of the core tricyclic ring system. The route features an alkoxyallylboration/cycloisomerization/Diels–Alder cycloaddition sequence as the key steps. The alkoxyallylboration was critical for differentiating the hydroxy groups in the central cyclohexadienediol unit of pradimycins, which will ensure a regiocontrolled glycosylation. For the cycloisomerization reaction, various substrates and conditions were tested for a ring‐closing enyne metathesis reaction. With enyne substrate 23, dimerization‐prone bicyclic diene 24 was isolated as the major product under the conditions of both ruthenium‐catalyzed metathesis and palladium‐catalyzed cycloisomerization. In the end, the optimal route found for the synthesis of the model functionalized tricyclic ring system 31 features a one‐pot sequential palladium‐catalyzed cycloisomerization, Diels–Alder reaction, and oxidative aromatization.

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Section: Introductionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthetic Studies Towards the Core Tricyclic Ring System of Pradimicin A

Zilke¹,

Hall²

2012

Eur J Org Chem

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“…4) This binding is essential for pradimicin to exert its fungicidal action, because the antifungal activity is antagonized by mannan, D-mannoside, or a calciumchelator, EGTA. 5) In yeast cells, pradimicin causes nuclear DNA fragmentation and intracellular accumulation of reactive oxygen species, both of which are described as apoptotic markers in metazoans. 4) Despite these observations, the molecular basis for the fungicidal action of pradimicin remains to be determined.…”

mentioning

confidence: 99%

Pradimicin Resistance of Yeast Is Caused by a Mutation of the PutativeN-Glycosylation Sites of Osmosensor Protein Sln1

Hiramoto

Nomura

Furumai

et al. 2005

Bioscience, Biotechnology, and Biochemistry

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“…1), an artificial PRM derivative with improved water solubility, 8 revealed that PRMs and Ca 2+ ion form the binary [PRM/Ca 2+ ] complexes, which bind D-Man but not L-mannose, 2-, 3-, and 4-epimers of D-Man (D-glucose, D-altrose, and D-talose, respectively), D-mannosamine, and N-acetyl-D-mannosamine. 9,10 This sugar-binding profile led to the assumption that PRMs recognize the 2-, 3-, and 4-hydroxyl groups of D-Man.…”

Section: Introductionmentioning

confidence: 99%

Pradimicin A, a d-mannose-binding antibiotic, binds pyranosides of l-fucose and l-galactose in a calcium-sensitive manner

Nakagawa

Watanabe

Igarashi

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Pradimicin A (PRM-A) is a unique antibiotic with a lectin-like ability to bind D-mannose (D-Man) in the presence of Ca(2+) ion. Although accumulated evidences suggest that PRM-A recognizes the 2-, 3-, and 4-hydroxyl groups of D-Man, BMY-28864, an artificial PRM-A derivative, was shown not to bind L-fucose (L-Fuc) and L-galactose (lLGal), both of which share the characteristic array of the three hydroxyl groups with D-Man. To obtain a plausible explanation for this inconsistency, we performed co-precipitation experiments of PRM-A with L-Fuc, L-Gal, and their methyl pyranosides (L-Fuc-OMe, L-Gal-OMe) by taking advantage of aggregate-forming propensity of the binary [PRM-A/Ca(2+)] complex. While L-Fuc and L-Gal were hardly incorporated into the aggregate, L-Fuc-OMe and L-Gal-OMe were found to exhibit significant binding to PRM-A. However, increased Ca(2+) concentration abolished this binding, raising the possibility that poor binding of L-Fuc and L-Gal to PRM-A is attributed to their chelation with Ca(2+) ion. This possibility was partly supported by (1)H NMR analysis that detected interaction of L-Fuc and L-Gal with Ca(2+) ion in aqueous solution. These results collectively indicate that PRM-A binds pyranosides of L-Fuc and L-Gal when Ca(2+) concentration is not excessive to trap these sugars by chelation but sufficient to form the [PRM-A/Ca(2+)] complex.

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Studies on the mode of antifungal action of pradimicin antibiotics. I.Lectin-mimic binding of BMY-28864 to yeast mannan in the presence of calcium.

Cited by 51 publications

References 1 publication

Synthetic Studies Towards the Core Tricyclic Ring System of Pradimicin A

Synthetic Studies Towards the Core Tricyclic Ring System of Pradimicin A

Pradimicin Resistance of Yeast Is Caused by a Mutation of the PutativeN-Glycosylation Sites of Osmosensor Protein Sln1

Pradimicin A, a d-mannose-binding antibiotic, binds pyranosides of l-fucose and l-galactose in a calcium-sensitive manner

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