Wieland T, Götzendörfer C, Dabrowski J, Lipscomb W N, Shoham G
Biochemistry. 1983 Mar 1;22(5):1264-71. doi: 10.1021/bi00274a043.
The three-dimensional structures of the slightly toxic diastereomeric (S)-sulfoxide of 6'-O-methyl-alpha-amanitin [6'-O-Me-alpha-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-alpha-amanitin [O-Me-alpha-ama (R)-sulfoxide, 3] and the corresponding thioether (O-Me-alpha-ama sulfide, 6] have been investigated in dimethyl sulfoxide solutions by 360-MHz 1H NMR spectroscopy including nuclear Overhauser effects (NOE). In addition alpha-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 beta-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 alpha-amanitin derivatives investigated here almost corresponds to that of beta-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.
通过X射线衍射分析确定了微毒的6'-O-甲基-α-鹅膏蕈碱的非对映体（S）-亚砜[6'-O-Me-α-ama（S）-亚砜，4]和相应的剧毒砜5的三维结构。在二甲亚砜溶液中，通过360兆赫的1H核磁共振光谱，包括核Overhauser效应（NOE），对相同的衍生物以及6'-O-甲基-α-鹅膏蕈碱[O-Me-α-ama（R）-亚砜，3]和相应的硫醚（O-Me-α-ama硫化物，6]进行了研究。此外，通过这种高分辨率方法对α-鹅膏蕈碱（2）进行了重新研究，包括鉴定色氨酸、半胱氨酸和天冬酰胺的ABMX系统以及区分甘氨酸残基。将化合物2-6的结构与先前通过X射线结构分析解析的β-鹅膏蕈碱的结构进行了比较。结果是：（1）（S）-亚砜4和砜5在晶体状态下的结构实际上是相同 的；（2）在二甲亚砜溶液中，化合物4和5的结构彼此相同，并且与（R）-亚砜3和硫醚6的结构相同。此处研究的α-鹅膏蕈碱衍生物的肽主链的总体结构几乎与β-鹅膏蕈碱（1）的结构相对应，主要区别在于天冬酰胺和半胱氨酸残基之间肽键的旋转平面。为了解释（S）-亚砜4中缺乏高毒性的原因，我们初步提出蛋白质供体的替代氢键，或者将R氧置换为氢键供体的S氧。这种替代键合或置换可能不会在亚砜4中发生。其他解释，包括抑制剂中的局部构象变化或SO和SO2局部偶极之间的差异，也是可能的。
