Unexpected Similarity of the Structures of the Weakly Toxic Amanitin (S)-Sulfoxide and the Highly Toxic (R)-Sulfoxide and Sulfone As Revealed by Proton Nuclear Magnetic Resonance and X-ray Analysis

Theodor Wieland*, Christa Götzendörfer, Janusz Dabrowski, William N. Lipscomb, Gil Shoham

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The three-dimensional structures of the slightly toxic diastereomeric (S)-sulfoxide of 6′-O-methyl-α-amanitin [6′-O-Me-α-ama (S)-sulfoxide, 4] and of the corresponding highly toxic sulfone 5 have been determined by X-ray diffraction analysis. The same derivatives along with 6′-O-methyl-α-amanitin [O-Me-α-ama (R)-sulfoxide, 3] and the corresponding thioether (O-Me-α-ama sulfide, 6) have been investigated in dimethyl sulfoxide solutions by 360-MHz 1H NMR spectroscopy including nuclear Overhauser effects (NOE). In addition α-amanitin (2) has been reinvestigated by this high-resolution method involving the identification of the ABMX systems of the tryptophan, cysteine, and asparagine and discrimination between the glycine residues. The structures of compounds 2–6 are compared with the structure of β-amanitin which was solved previously by X-ray structure analysis. The results are (1) the structures in the crystalline state of the (S)-sulfoxide 4 and sulfone 5 are practically identical and (2) in dimethyl sulfoxide solution the structures of compounds 4 and 5 are likewise identical with each other and with those of the (R)-sulfoxide 3 and the thioether 6. The general structure of the peptide backbone of the α-amanitin derivatives investigated here almost corresponds to that of α-amanitin (1), the main difference being a rotated plane of the peptide bond between the asparagine and cysteine residue. In order to explain the lack of high toxicity in the (S)-sulfoxide 4 we tentatively suggest alternative hydrogen bonding of a donor from the protein, or displacement of the R oxygen to the S oxygen of a hydrogen bond donor. This alternative bonding or displacement might not occur in the sulfoxide 4. Other explanations which include local conformational changes in the inhibitors or a difference between the SO and SO2 local dipoles are also possible.

Original languageAmerican English
Pages (from-to)1264-1271
Number of pages8
JournalBiochemistry
Volume22
Issue number5
DOIs
StatePublished - 1983
Externally publishedYes

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