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Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula. Structural isomerism of coordination compounds can be divided into two subcategories, the linkage isomers and coordination-sphere isomers.
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Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
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Body tissues, comprising approximately 40% of the body weight, are crucial in drug distribution and localization. These tissues can serve as drug storage sites, competing with plasma binding sites for drug molecules.
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When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and...
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Mycolactone A vs. B: Does localization or association explain isomer-specific toxicity?

John D M Nguyen1, Gabriel C A da Hora1, Jessica M J Swanson1

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Mycolactone B, a toxin causing Buruli ulcer, is more cytotoxic than A due to stronger ER membrane binding and Sec61 translocon interactions. This explains its unique toxicity and suggests therapeutic targets.

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Area of Science:

  • Molecular biology
  • Toxicology
  • Biophysics

Background:

  • Mycolactone, an exotoxin from Mycobacterium ulcerans, causes Buruli ulcer by inhibiting the Sec61 translocon in the endoplasmic reticulum (ER).
  • Two dominant mycolactone isoforms exist, but only one exhibits significant cytotoxicity, necessitating an investigation into the molecular basis of this difference.

Approach:

  • Utilized extensive molecular dynamics (MD) simulations with enhanced free energy sampling.
  • Investigated the association trends of mycolactone isoforms with the ER membrane and the Sec61 translocon.

Key Points:

  • Mycolactone B, the cytotoxic isoform, demonstrates stronger association with the ER membrane compared to mycolactone A.
  • Enhanced localization to the ER membrane may increase the proximity of mycolactone B to the Sec61 translocon.
  • Mycolactone B interacts more closely with the Sec61 translocon gates, inducing a closed conformation that blocks protein translocation.

Conclusions:

  • The distinct cytotoxicity of mycolactone B stems from its increased ER membrane localization and a channel-locking interaction with the Sec61 translocon.
  • These findings offer potential targets for developing Buruli ulcer diagnostics and Sec61-translocon-targeted therapeutics.