Dataset Information

Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria.

ABSTRACT: Hoiamide A, a novel bioactive cyclic depsipeptide, was isolated from an environmental assemblage of the marine cyanobacteria Lyngbya majuscula and Phormidium gracile collected in Papua New Guinea. This stereochemically complex metabolite possesses a highly unusual structure, which likely derives from a mixed peptide-polyketide biogenetic origin, and includes a peptidic section featuring an acetate extended and S-adenosyl methionine modified isoleucine moiety, a triheterocyclic fragment bearing two alpha-methylated thiazolines and one thiazole, and a highly oxygenated and methylated C15-polyketide substructure. Pure hoiamide A potently inhibited [(3)H]batrachotoxin binding to voltage-gated sodium channels (IC(50) = 92.8 nM), activated sodium influx (EC(50) = 2.31 microM) in mouse neocortical neurons, and exhibited modest cytotoxicity to cancer cells. Further investigation revealed that hoiamide A is a partial agonist of site 2 on the voltage-gated sodium channel.

SUBMITTER: Pereira A

PROVIDER: S-EPMC2763540 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria.

Pereira Alban A Cao Zhengyu Z Murray Thomas F TF Gerwick William H WH

Chemistry & biology 20090801 8

Hoiamide A, a novel bioactive cyclic depsipeptide, was isolated from an environmental assemblage of the marine cyanobacteria Lyngbya majuscula and Phormidium gracile collected in Papua New Guinea. This stereochemically complex metabolite possesses a highly unusual structure, which likely derives from a mixed peptide-polyketide biogenetic origin, and includes a peptidic section featuring an acetate extended and S-adenosyl methionine modified isoleucine moiety, a triheterocyclic fragment bearing t ...[more]

PMID: 19716479

Similar Datasets

Project description:The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations. We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine, which are potent blockers of the influenza M2 channel and licensed drugs against influenza infections. The adamantane derivatives have been used in HCV clinical trials, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.

Project description:BACKGROUND: In-frame deletion mutation (Del-L955) in NaV1.7 sodium channel from a kindred with erythromelalgia hyperpolarizes activation. RESULTS: Del-L955 twists the S6 helix, displacing the Phe960 activation gate. Replacement of Phe960 at the correct helical position depolarizes activation. CONCLUSION: Radial tuning of the activation gate is critical to the activation of NaV1.7 channel. SIGNIFICANCE: Structural modeling guided electrophysiology reveals the functional importance of radial tuning of the S6 segment. Voltage-gated sodium (NaV) channels are membrane proteins that consist of 24 transmembrane segments organized into four homologous domains and are essential for action potential generation and propagation. Although the S6 helices of NaV channels line the ion-conducting pore and participate in channel activation, their functional architecture is incompletely understood. Our recent studies show that a naturally occurring in-frame deletion mutation (Del-L955) of NaV1.7 channel, identified in individuals with a severe inherited pain syndrome (inherited erythromelalgia) causes a substantial hyperpolarizing shift of channel activation. Here we took advantage of this deletion mutation to understand the role of the S6 helix in the channel activation. Based on the recently published structure of a bacterial NaV channel (NaVAb), we modeled the WT and Del-L955 channel. Our structural model showed that Del-L955 twists the DII/S6 helix, shifting location and radial orientation of the activation gate residue (Phe(960)). Hypothesizing that these structural changes produce the shift of channel activation of Del-L955 channels, we restored a phenylalanine in wild-type orientation by mutating Ser(961) (Del-L955/S961F), correcting activation by ?10 mV. Correction of the displaced Phe(960) (F960S) together with introduction of the rescuing activation gate residue (S961F) produced an additional ?6-mV restoration of activation of the mutant channel. A simple point mutation in the absence of a twist (L955A) did not produce a radial shift and did not hyperpolarize activation. Our results demonstrate the functional importance of radial tuning of the sodium channel S6 helix for the channel activation.

Project description:BackgroundSince 2004, the Global Fund-supported National Malaria Control Programme of Papua New Guinea (PNG) has been implementing country-wide free long-lasting insecticidal net (LLIN) distribution campaigns. In 2009, after the first distribution, only 32.5% of the population used a LLIN, mainly due to an insufficient number of nets available. This study investigated changes in mosquito net ownership and use following the continued free distribution of LLINs across PNG.MethodsFive villages from each province and 30 households from each village were randomly sampled in a country-wide household survey in 2010/11. A structured questionnaire administered to household heads recorded information on mosquito net ownership and use alongside household characteristics. Revised ownership and access indicators were applied in the analysis to reveal coverage gaps.ResultsThe survey covered 1,996 households in 77 villages. Ownership of at least one LLIN was reported by 81.8% of households, compared to 64.6% in 2009 (P?=?0.002). Sufficient LLINs to cover all household members (one net per two people) were found in 41.3% of the households (21.4% in 2009, P?<?0.001). Of all household members, 61.4% had access to a LLIN within their household (44.3% in 2009 P?=?0.002), and 48.3% slept under a LLIN (32.5% in 2009, P?=?0.001). LLIN use in children under five years amounted to 58.2%, compared to 39.5% in 2009 (P?<?0.001). Significant regional differences in coverage and changes over time were observed. A recent LLIN distribution was a key determinant of LLIN ownership (adj. OR?=?3.46) while families in high quality houses would frequently not own a LLIN (adj. OR?=?0.09). Residents were more likely to use LLINs than household guests (OR?=?2.04).ConclusionsRepeated LLIN distribution has led to significant increases in mosquito net ownership and use with few regional exceptions. Additional nets are required in areas where access is low, while major efforts are required to encourage the use of existing nets in region where access is high but use remains low. Complementary vector control approaches should also be considered in such settings.

Dataset Information

Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria.

Publications

Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets