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MX Jar - Eastman Eastman GFY Jar Assy. Jar HSM Open navigation menu. Close suggestions Search Search. User Settings. Skip carousel. Carousel Previous. We have conducted an initial examination of holomycin reactivity with the most abundant cellular thiol, glutathione, as a prototypic marker of redox behavior.
We first incubated the disulfide-containing holomycin with the reduced form of glutathione GSH and monitored for reduction of holomycin by gain of UV absorbance at nm.
No changes were detected over a wide range of GSH concentrations and molar excess over 1. When we assayed in the opposite direction, for the ability of 2 to reduce oxidized glutathione GS-SG , a rapid decrease in UV absorbance at nm was observed, corresponding to the oxidation of 2 by GS-SG.
Subsequent studies will be necessary to determine redox equilibria and ultimately reduction potentials of holomycin under conditions where competing oxidation by molecular O 2 is suppressed. It is clear that red -holomycin is kinetically and thermodynamically competent to reduce the intermolecular disulfide in oxidized glutathione. Thus, the reduced form of holomycin and presumably holothin perhaps even more so may be strong thiol reductants in both microbial producers and target cells.
The combination of oxidation by HlmI and acetylation by HlmA may ensure accumulation of the natural product in the oxidized and acetylated state with low adventitious redox reactivity. Future studies will involve the examination of the formation of any mixed disulfides between holomycin and intracellular proteins as part of the antibacterial effect of holomycin and related dithiolopyrrolone scaffolds.
An alternative mode of reactivity is also possible involving conjugated addition of cellular nucleophiles to the dienone chromophore for holomycin. Alignment of HlmI with a number of bacterial and fungal proteins that are likely to catalyze dithiol-disulfide redox chemistry revealed four distinctive phylogeny groups: the thioredoxin oxidoreductase TrxB group, and three small molecule oxidoreductase groups Figure 7 and S8.
The TrxB group catalyzes the reduction of disulfides in thioredoxins, which are small proteins involved in a wide range of cellular processes such as redox-sensitive signal transduction, stress response, and detoxification This group includes both bacterial and fungal thioredoxin oxidoreductases.
The GliT group consists of fungal proteins from gene clusters for biosyntheses of molecules closely related to gliotoxin, and is likely differentiated from the HlmI and DepH groups because of its fungal origin. The DepH group contains a number of bacterial putative oxidoreductases including TdpH encoded in a FK homologous gene cluster from Burkholderia thailandensis E The products of this gene cluster have recently been identified as burkholdac A and B, which are new HDAC inhibitors containing an intramolecular disulfide Many hypothetical proteins in the HlmI group are predicted dithiol-disulfide oxidoreductases, and they may be involved in similar cellular processes such as small molecule biosynthesis or detoxification.
Further interrogation of the genome context of these hypothetical proteins may lead to the discovery of novel natural product biosynthetic gene clusters. This dendrogram is generated by RAxML and bootstrap support values and the distance scale are displayed. HlmI joins GliT as a member of FAD-dependent dithiol oxidases, using O 2 as cosubstrate to accelerate the formation of intramolecular disulfide bridges in the late steps of small molecule biosynthesis.
Both HlmI and GliT were shown to play a role in protecting the producer organisms from the action of their own natural products. HlmI and related proteins constitute a new phylogenetic group of oxidoreductases that catalyze disulfide formation in small molecules and are different from the GliT and DepH dithiol oxidase groups.
These small molecule dithiol oxidases are phylogenetically separated from the peptide oxidoreductases, suggesting they have evolved for specific and efficient catalysis of small molecule substrates. We thank Dr. Carl Balibar for the generous gift of purified GliT, Dr.
Kapil Tahlan for providing S. Emily Balskus and Dr. Rebecca Case for assistance in constructing the phylogeny tree, and Dr. Albert Bowers for suggestions regarding the manuscript. Carl Balibar, a previous graduate student in the Walsh group. Supporting information includes Figures S1—8 and Table S1.
Read article at publisher's site DOI : Nat Commun , 12 1 , 28 Sep Appl Environ Microbiol , 87 11 , 11 May Chem Sci , 12 11 , 08 Feb J Nat Prod , 83 2 , 12 Feb Nat Prod Rep , 36 8 , 01 Aug Cited by: 6 articles PMID: This data has been text mined from the article, or deposited into data resources.
This data has been provided by curated databases and other sources that have cited the article. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. Chembiochem , 13 17 , 24 Oct Liras P. Appl Microbiol Biotechnol , 98 3 , 10 Dec Cited by: 10 articles PMID: Li B , Walsh CT. Cited by: 13 articles PMID: Nat Prod Rep , 31 7 , 01 Jul Review Free to read.
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Affiliations 1 author 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Holomycin and related dithiolopyrrolone antibiotics display broad-spectrum antimicrobial activities and contain a unique 5,5-bicyclic ring structure with an N-acylated aminopyrrolone fused to a cyclic ene-disulfide.
As a dithiol oxidase, HlmI is functionally homologous to GliT and DepH, which perform a similar dithiol to disulfide oxidation in the biosynthesis of fungal natural product gliotoxin and epigenetic regulator compound FK, respectively.
Free full text. Author manuscript; available in PMC May PMID: Bo Li and Christopher T. Author information Copyright and License information Disclaimer.
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