Fluorescence, circular dichroism, NMR, and docking studies of the interaction of the alkaloid malbrancheamide with calmodulin

Figueroa, Mario; González-Andrade, Martín; Sosa‐Peinado, Alejandro; Madariaga-Mazón, Abraham; Rı́o-Portilla, Federico del; González, Marı́a del Carmen; Mata, Rachel

doi:10.3109/14756366.2010.518964

Cited by 26 publications

(33 citation statements)

References 26 publications

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“…Malbrancheamides are rare indole‐monoterpenoid alkaloids with a diazaoctane core obtained from the fungus Malbranchea aurantiaca . The potent anti‐calmodulin activity of the three alkaloids has been thoroughly described in previous works [17]. Calmodulin is one of the major cellular Ca 2+ ‐binding proteins involved in the regulation of a series of CaM‐dependent enzymes, such as NO synthases, phosphodiesterases, ion channels and kinases, among others.…”

Section: Discussionmentioning

confidence: 90%

“…Fermentation, extraction and purification of malbrancheamide (1), malbrancheamide B (2) and isomalbrancheamide B (3) (structures shown in Figure 1) were undertaken as previously described. [17] Briefly, 25 l of potato dextrose broth (PDB; Difco, Franklin Lakes, NJ, USA) were inoculated with 1 cm 2 agar plugs taken from a stock culture of M. aurantiaca on potato dextrose agar (PDA; Difco). After incubation (30 days), the combined organic extracts of mycelia and culture were obtained (12.0 g).…”

Section: Extraction and Isolation Of Malbrancheamidesmentioning

confidence: 99%

“…[9][10][11][12][13] Malbrancheamides are unusual indole-monoterpenoids alkaloids isolated from the coprophilous fungus Malbranchea aurantiaca; [14,15] these compounds have been fully characterized as CaM ligands by NMR, fluorescence, circular dichroism, computational and enzymatic functional methods. [16,17] The need for new therapeutic agents capable of influencing NO generation, and the fact that a few CaM inhibitors display smooth muscle relaxant activity, prompted us to determine the potential of malbrancheamides (1-3) as vasorelaxant agents. For this endeavour, we employed classical pharmacological assays and in-silico studies.…”

Section: Introductionmentioning

confidence: 99%

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Insights on the vasorelaxant mode of action of malbrancheamide

Madariaga-Mazón

Hernández-Abreu

Estrada-Soto

et al. 2015

Journal of Pharmacy and Pharmacology

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Experimental evidence revealed that malbrancheamides induced both endothelium-independent and endothelium-dependent relaxant effects. According to theoretical studies, it is feasible that the endothelium-independent relaxation exerted by malbrancheamide could be mediated by its calmodulin inhibitory properties throughout an interference with myosin light chain phosphorylation and a positive modulation of eNOS.

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Section: Discussionmentioning

confidence: 90%

Section: Extraction and Isolation Of Malbrancheamidesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insights on the vasorelaxant mode of action of malbrancheamide

Madariaga-Mazón

Hernández-Abreu

Estrada-Soto

et al. 2015

Journal of Pharmacy and Pharmacology

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“…25 We had previously proposed that there is a site-selective chlorination of the C9 position prior to functionalization of C8 for production of malbrancheamide ( 1 ). 25 However, the isolation of both C8 (isomalbrancheamide B ( 4 )) and C9 (malbrancheamide B ( 3 )) monohalogenated metabolites from M. aurantiaca 20 and from M. graminicola 19 conflicted with the proposed C9 selectivity hypothesis, providing further motivation to investigate the malbrancheamide halogenation process.…”

Section: Introductionmentioning

confidence: 99%

Function and Structure of MalA/MalA′, Iterative Halogenases for Late-Stage C–H Functionalization of Indole Alkaloids

Fraley

Garcia‐Borràs

Tripathi³

et al. 2017

J. Am. Chem. Soc.

105

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Malbrancheamide is a dichlorinated fungal indole alkaloid isolated from both Malbranchea aurantiaca and Malbranchea graminicola that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core. The introduction of chlorine atoms on the indole ring of malbrancheamide differentiates it from other members of this family and contributes significantly to its biological activity. In this study, we characterized the two flavin-dependent halogenases involved in the late-stage halogenation of malbrancheamide in two different fungal strains. MalA and MalA’ catalyze the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogs were generated through MalA-mediated chemoenzymatic synthesis. Structural analysis and computational studies of MalA’ in complex with three substrates revealed that the enzyme represents a new class of zinc-binding flavin-dependent halogenases, and provides new insights into a potentially unique reaction mechanism.

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“…A mutant of CaM coupled to three different environment-sensitive fluorophores (MDCC, acrylodan, and IANBD ester) was detected the CaM interaction with phenothiazines and related tryclic antidepressants (Douglass, Salins et al 2002). Recently Gonález-Andrade and col, has been designed a alternative biosensing assay for CaM inhibitors by chemical modification of bromobimane at position 124 (Gonzalez-Andrade, et al 2009;Figueroa, et al 2010), that allowed to determine the IC 50 …”

Section: A B Cmentioning

confidence: 99%