Lange A B, Wang Z, Orchard I, Starratt A N
Department of Zoology, University of Toronto, Ontario, Canada.
Peptides. 1996;17(3):375-80. doi: 10.1016/0196-9781(96)00008-3.
The FMRFamide-related peptide PDVDHVFLRFamide (SchistoFLRFamide) is involved in the neural control of locust oviducts, where it acts as a potent inhibitor of spontaneous and induced contractions. Previous studies have shown that the His residue in the truncated analogue HVFLRFamide is critical for the retention of inhibitory biological activity, whereas VFLRFamide, in which inhibitory biological activity is lost, is the minimum sequence for binding of comparable affinity to the parent compound. In the present study we have used binding and bioassay to further investigate the properties of the His residue in determining the inhibitory biological activity of HVFLRFamide. Substitution of His by the D-isomer or Phe produced analogues with stimulatory rather than inhibitory activity, confirming the importance of the His moiety. In addition, inhibitory activity was retained when the His moiety was methylated at the N-3 position of the imidazole ring, but methylation of N-1 yielded a peptide that stimulated contractions. Inhibitory activity was further retained when Nn-methyl-L-His and D,L-1',2',4'-triazole-3-Ala were substituted for His. These results, along with binding studies, suggest that transfer of an imidazole proton is not responsible for inhibitory activity and further suggest that hydrogen bonding to the N-1 of the imidazole ring of histidine may be required to evoke the inhibitory response.
与FMRF酰胺相关的肽PDVDHVFLRF酰胺（血吸虫FLRF酰胺）参与蝗虫输卵管的神经控制，在那里它作为自发和诱导收缩的有效抑制剂起作用。先前的研究表明，截短类似物HVFLRF酰胺中的His残基对于保留抑制性生物活性至关重要，而失去抑制性生物活性的VFLRF酰胺是与母体化合物具有相当亲和力结合的最小序列。在本研究中，我们使用结合和生物测定法进一步研究His残基在确定HVFLRF酰胺抑制性生物活性中的特性。用D-异构体或Phe取代His产生具有刺激而非抑制活性的类似物，证实了His部分的重要性。此外，当His部分在咪唑环的N-3位置甲基化时，抑制活性得以保留，但N-1甲基化产生一种刺激收缩的肽。当用Nn-甲基-L-组氨酸和D,L-1',2',4'-三唑-3-丙氨酸取代His时，抑制活性进一步保留。这些结果以及结合研究表明，咪唑质子的转移与抑制活性无关，进一步表明可能需要与组氨酸咪唑环的N-1形成氢键来引发抑制反应。
