Synthesis and evaluation of simplified functionalized bongkrekic acid analogs

Fujita, Satoshi; Suyama, Masaki; Matsumoto, Kenji; Yamamoto, Atsushi; Yamamoto, Toshiharu; Hiroshima, Yuka; Iwata, Tomonori; Kano, Arihiro; Shinohara, Yasuo; Shindo, Mitsuru

doi:10.1016/j.tet.2018.01.018

Cited by 8 publications

(5 citation statements)

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“…[4][5][6] BA can efficiently inhibit the mitochondrial adenine nucleotide translocator, leading to human death. [4][5][6] Outbreaks of BA food poisoning have been reported in Indonesia, Mozambique, and certain regions of China, with mortality rates reaching 40-60%. [7][8][9][10] The most recent lethal food poisoning case was reported in Heilongjiang Province, China, in October 2020, resulting in nine deaths, with a fatality rate of 100%.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 B. cocovenenans is pervasive in the natural environment and can cause fatal food poisoning by producing a heatstable mitochondrial toxin called bongkrekic acid (BA), which has an acute toxicity of 1.41 mg kg −1 (LD50 by intravenous injection in mice). [4][5][6] BA can efficiently inhibit the mitochondrial adenine nucleotide translocator, leading to human death. [4][5][6] Outbreaks of BA food poisoning have been reported in Indonesia, Mozambique, and certain regions of China, with mortality rates reaching 40-60%.…”

Section: Introductionmentioning

confidence: 99%

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A DNAzymes-in-droplets assay for Burkholderia gladioli pathovar cocovenenans with single-bacterium sensitivity

Li,

Chang,

et al. 2024

Chem. Sci.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A DNAzymes-in-droplets assay for Burkholderia gladioli pathovar cocovenenans with single-bacterium sensitivity

Li,

Chang,

et al. 2024

Chem. Sci.

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“…These inhibitors specifically block the ADP/ATP carrier from either the cytosolic side or the matrix side, respectively. To understand how the ADP/ATP carrier interacts with its inhibitors or substrates, several strategies have been used: (i) purification and crystallization of the carrier complexed with its transport substrates or with its inhibitors, followed by X‐ray crystallography and structural characterization (Nury et al, 2005; Pebay‐Peyroula et al, 2003; Ruprecht et al, 2014, 2019); (ii) analyses of the structure and function of the ADP/ATP carrier using mutants or revertants (Babot et al, 2012; Zeman et al, 2003); and (iii) analyses of the structure and function of the ADP/ATP carrier using a chemically modified transport substrate or inhibitor (Fujita et al, 2018, 2021; Jaiquel et al, 2021; Todisco et al, 2016; Yamamoto et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

KH‐17, a simplified derivative of bongkrekic acid, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane

et al. 2023

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Two natural products, bongkrekic acid and carboxyatractyloside, are known to specifically inhibit the mitochondrial ADP/ATP carrier from its matrix side and cytosolic side, respectively, in concentration ranges of 10−6 M. In the present study, we investigated the manner of action of a synthetic bongkrekic acid derivative, KH‐17, lacking three methyl groups, one methoxy group, and five internal double bonds, on the mitochondrial ADP/ATP carrier. At slightly acidic pH, KH‐17 inhibited mitochondrial [3H]ADP uptake, but its inhibitory action was about 10 times weaker than that of its parental compound, bongkrekic acid. The main site of action of KH‐17 was confirmed as the matrix side of the ADP/ATP carrier by experiments using submitochondrial particles, which have an inside‐out orientation of the inner mitochondrial membrane. However, when we added KH‐17 to mitochondria at neutral pH, it had a weak inhibitory effect on [3H]ADP uptake, and its inhibitory strength was similar to that of bongkrekic acid. These results indicated that KH‐17 weakly inhibits the ADP/ATP carrier not only from the matrix side but also from the cytosolic side. To ascertain whether this interpretation was correct, we examined the effects of KH‐17 and carboxyatractyloside on mitochondrial [3H]ADP uptake at two [3H]ADP concentrations. We found that both KH‐17 and carboxyatractyloside showed a stronger inhibitory effect at the lower [3H]ADP concentration. Therefore, we concluded that the bongkrekic acid derivative, KH‐17, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane. These results suggested that the elimination of three methyl groups, one methoxy group, and five internal double bonds present in bongkrekic acid altered its manner of action towards the mitochondrial ADP/ATP carrier. Our data will help to improve our understanding of the interaction between bongkrekic acid and the mitochondrial ADP/ATP carrier.

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“…BA is also called a respiratory toxin since this toxin can prevent the respiratory chain phosphorylation (Rohm et al, 2010). BA causes food poisoning with an acute toxicity of 1.41 mg/kg (LD 50 by intravenous injection on mice) (Fujita et al, 2018). In epidemiological investigations, B. cocovenenans and BA were detected simultaneously in coconut-and corn-based products responsible for food-borne outbreaks in Indonesia, China, and Mozambique (Anwar et al, 2017;Gudo et al, 2018;Li J. et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies on B. cocovenenans and BA have mostly focused on clinical case reports (Falconer et al, 2017;Shi et al, 2019), BA synthesis (Rohm et al, 2010;Moebius et al, 2012;Matsumoto et al, 2015;Fujita et al, 2018), and apoptosis inhibition (Matsumoto et al, 2015;Takeda et al, 2016;Kano et al, 2017Kano et al, , 2019. However, the origin and evolution of BA biosynthesis gene cluster, bon, in B. cocovenenans remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Comparative Genomic Analysis of the Foodborne Pathogen Burkholderia gladioli pv. cocovenenans Harboring a Bongkrekic Acid Biosynthesis Gene Cluster

Peng

Dottorini

et al. 2021

Front. Microbiol.

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The environmental bacterium Burkholderia gladioli pv. cocovenenans (B. cocovenenans) has been linked to fatal food poisoning cases in Asia and Africa. Bongkrekic acid (BA), a mitochondrial toxin produced by B. cocovenenans, is thought to be responsible for these outbreaks. While there are over 80 species in the Burkholderia genus, B. cocovenenans is the only pathovar capable of producing BA and causing human death. However, the genomic features of B. gladioli and the evolution of the BA biosynthesis gene cluster, bon, in B. cocovenenans remain elusive. In this study, 239 whole genome sequences (WGSs) of B. gladioli, isolated from 12 countries collected over 100 years, were used to analyze the intra-species genomic diversity and phylogenetic relationships of B. gladioli and to explore the origin and evolution of the bon gene cluster. Our results showed that the genome-wide average nucleotide identity (ANI) values were above 97.29% for pairs of B. gladioli genomes. Thirty-six of the 239 (15.06%) B. gladioli genomes, isolated from corn, rice, fruits, soil, and patients from Asia, Europe, North America, and South America, contained the bon gene cluster and formed three clades within the phylogenetic tree. Pan- and core-genome analysis suggested that the BA biosynthesis genes were recently acquired. Comparative genome analysis of the bon gene cluster showed that complex recombination events contributed to this toxin biosynthesis gene cluster’s evolution and formation. This study suggests that a better understanding of the genomic diversity and evolution of this lethal foodborne pathovar will potentially contribute to B. cocovenenans food poisoning outbreak prevention.

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Synthesis and evaluation of simplified functionalized bongkrekic acid analogs

Cited by 8 publications

References 24 publications

A DNAzymes-in-droplets assay for Burkholderia gladioli pathovar cocovenenans with single-bacterium sensitivity

A DNAzymes-in-droplets assay for Burkholderia gladioli pathovar cocovenenans with single-bacterium sensitivity

KH‐17, a simplified derivative of bongkrekic acid, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane

Comparative Genomic Analysis of the Foodborne Pathogen Burkholderia gladioli pv. cocovenenans Harboring a Bongkrekic Acid Biosynthesis Gene Cluster

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