Unique molecular conformation of aureobasidin A, a highly amide N-methylated cyclic depsipeptide with potent antifungal activity: X-ray crystal structure and molecular modeling studies.
A structural feature of aureobasidins, cyclic depsipeptide antibiotics produced by Aureobasidium pullulans R106, is the N-methylation of four out of seven amide bonds. In order to investigate possible relationship between the molecular conformation and the amide N-methylation, aureobasidin A (AbA), which exhibits the potent antifungal activity, was subjected to X-ray crystal analysis. The crystal, recrystallized from ether (orthorhombic, space group P2(1)2(1)2(1), a = 21.643 (3) A, b = 49.865(10) A, c = 12.427 (1) A, z= 8), contained two independent conformers per asymmetric unit and they took on a similar arrowhead-like conformation. The conformation consisted of three secondary structures of antiparallel beta-sheet, and beta- and gamma-turns, and was stabilized by three intramolecular and transannular N-H O=C hydrogen bonds. The beta-hydroxy-N-methyl-l-valine residue, which is indispensable for its bioactivity, was located at the tip of the corner. Since a nearly identical conformation has been observed for aureobasidin E, a related cyclic depsipeptide, this arrowhead-like conformation may be energetically stable and important for biological activity. The contribution of the amide N-methylation to the conformation was investigated by model building and energy calculations. The energy-minimizations of AbA analogs, in which some (one to four) of four N-methylated amide bonds were replaced with usual amide bond, led to some conformers which are fairly different from the arrowhead form of AbA, although they are stabilized by three intramolecular N-H...O=C hydrogen bonds. This result explains the reason why four out of the seven amide bonds have to be methylated to manifest biological activity, i.e. the high N-methylation of aureobasidin is necessary to form only one well-defined conformation.
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Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
Ishida
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Takesako
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D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D002087:Butyrates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D047630:Depsipeptides; D005449:Fluorenes / Q000737:chemistry*; D006860:Hydrogen Bonding; D007536:Isomerism; D008745:Methylation; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011113:Polymyxins / Q000031:analogs & derivatives*; D011487:Protein Conformation
D000935:Antifungal Agents; D002087:Butyrates; D047630:Depsipeptides; D005449:Fluorenes; C121747:N(alpha)--fluorenylmethyloxycarbonylamino-4N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)butyric acid; D010456:Peptides, Cyclic; D011113:Polymyxins; C071398:aureobasidin A; C121746:polymyxin B(1); D011112:Polymyxin B