|Jmol-3D images||Image 1|
|Molar mass||1,368.35 g mol−1|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
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The calicheamicins are a class of enediyne antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "calichi pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and in the year 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calichiamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.
Mechanism of toxicity
Calicheamicins target DNA and cause strand scission. Calicheamicins bind with DNA in the minor groove, wherein they then undergo a reaction analogous to the Bergman cyclization to generate a diradical species. This diradical, 1,4-didehydrobenzene, then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which ultimately leads to strand scission. The specificity of binding of calicheamicin to the minor groove of DNA was demonstrated by Crothers et al. (1999) to be due to the aryltetrasaccharide group of the molecule.
The core metabolic pathway for biosynthesis of this molecule resembles that of other characterized enediyne compounds and occurs via an iterative polyketide synthase (PKS) pathway. This type I PKS loads Acetyl-CoA and then repeatedly adds a total of seven Malonyl-CoAs. The growing polyketide is acted upon by the ketoreductase domain (KR) and dehydratase domain (DH) during each iteration to produce a 15 carbon polyene, which is then processed by accessory enzymes to yield the enediyne core of calicheamicin. This enediyne is further modified by additional enzymes to yield calicheamicinone, a precursor to the glycosylation pathway.
Glycosylation of calicheamicinone requires 4 glycosyltransferasses (CalG1-4) and one acyltransferase (CalO4) each recognizing a specific sugar or orsellinic acid substrate . The structures of all four glycosyltransferases have been elucidated revealing a conserved calicheamicin binding motif that coordinates the enediyne backbone thorough interactions with aromatic resides . The catalytic site of CalG1, CalG3 and CalG4 was shown to possess a highly conserved catalytic diyad of histadine and aspartate which promotes nucleophilic attack on the acceptor hydroxyl group of calicheamicin intermediates. Notably, this motif is absent from CalG2, suggesting a different catalytic mechanism in this enzyme.
It has been proposed that Alexander the Great was poisoned by drinking the water of the river Styx (Mavroneri) which is postulated to have been contaminated by this compound however toxicologist believe an extensive knowledge of biological chemistry would have been requisite for any application of this poison in antiquity.
- Monoclonal antibodies using calicheamicins as cytotoxic agents:
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- Total Synthesis and the Creative Process: An Interview with K.C. Nicolaou, Scripps Research Institute
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- Horsman, GP; Chen, Y; Thorson, JS; Shen, B (Jun 22, 2010). "Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes". Proc Natl Acad Sci U S A. 107 (25): 11331–5. doi:10.1073/pnas.1003442107. PMC 2895059. PMID 20534556.
- Ahlert, J.; Shepard, E.; Lomovskaya, N.; Zazopoulos, E.; Staffa, A. (2002), "The calicheamicin gene cluster and its iterative type I enediyne", Science 297 (5584): 1173–6, doi:10.1126/science.1072105, PMID 12183629, retrieved 2014-05-29
- Chang, A.; Singh, S.; Helmich, K. (2011), "Complete set of glycosyltransferase structures in the calicheamicin biosynthetic pathway reveals the origin of regiospecificity", Proceedings of the National Academy of Sciences 108 (43): 17649–54, doi:10.1073/pnas.1108484108, PMID 21987796, retrieved 2014-05-29
- Nick Squires (August 4, 2010). "Alexander the Great poisoned by the River Styx.html". Telegraph.
- Rossella Lorenzi (16 Jul 2010). "Alexander the Great killed by toxic bacteria?". Discovery News.