TY - JOUR
T1 - 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
AU - Wieland, Theodor
AU - Götzendörfer, Christa
AU - Dabrowski, Janusz
AU - Lipscomb, William N.
AU - Shoham, Gil
PY - 1983
Y1 - 1983
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0020631114&partnerID=8YFLogxK
U2 - 10.1021/bi00274a043
DO - 10.1021/bi00274a043
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 6838852
AN - SCOPUS:0020631114
SN - 0006-2960
VL - 22
SP - 1264
EP - 1271
JO - Biochemistry
JF - Biochemistry
IS - 5
ER -