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PDBsum entry 5ahj
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Contents |
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250 a.a.
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244 a.a.
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241 a.a.
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236 a.a.
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231 a.a.
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244 a.a.
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242 a.a.
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222 a.a.
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204 a.a.
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195 a.a.
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212 a.a.
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222 a.a.
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233 a.a.
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196 a.a.
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References listed in PDB file
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Key reference
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Title
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Macyranones: structure, Biosynthesis, And binding mode of an unprecedented epoxyketone that targets the 20s proteasome.
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Authors
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L.Keller,
A.Plaza,
C.Dubiella,
M.Groll,
M.Kaiser,
R.Müller.
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Ref.
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J Am Chem Soc, 2015,
137,
8121-8130.
[DOI no: ]
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PubMed id
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Abstract
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In our screening efforts to identify unique scaffolds from myxobacteria for the
drug discovery process, we used LC-SPE-NMR-MS techniques to isolate six linear
peptides, termed macyranone A-F, from Cystobacter fuscus MCy9118. The
macyranones are characterized by a rare 2-methylmalonamide moiety and an
α-amino ketone fragment including an α',β'-epoxyketone in macyranone A. Gene
disruption experiments confirmed the biosynthetic gene cluster of the
macyranones as PKS/NRPS hybrid. Detailed in silico and phylogenetic analysis
unraveled that the biosynthesis involves two conspicuous amide bond formations
accomplished by an amidotransferase and a unique condensation domain. The gene
cluster provides further insights into the formation of the powerful epoxyketone
residue involving an acyl-CoA dehydrogenase and an unconventional free-standing
thioesterase. Macyranone A was found to inhibit the chymotrypsin-like activity
of the yeast 20S proteasome with an IC50 of 5.9 nM and the human constitutive
proteasome and immunoproteasome with IC50 values of 21 and 15 nM, respectively.
The β5 subunit of the 20S proteasome was characterized as target by X-ray
crystallography revealing an irreversible binding mode similar to the natural
product epoxomicin. The presence of the methylmalonamide residue facilitates the
stabilization of macyranone A with the active β5 subunit of the proteasome.
Macyranone A exhibits a potent inhibitory effect against the parasites
Trypanosoma brucei rhodesiense and Leishmania donovani with IC50 values of 1.55
and 0.22 μM, respectively.
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