Schwartz T W
Laboratory of Molecular Endocrinology, University Department of Clinical Chemistry, Copenhagen, Denmark.
J Biol Chem. 1988 Aug 15;263(23):11504-10.
Amino acid analogs, which can be incorporated into nascent peptide chains were used in cultures of endocrine cells from canine pancreas to study the effect on processing of the metabolically labeled precursor for pancreatic polypeptide. Analogs for basic amino acids, canavanine, and aminoethylcysteine prevented the di-basic processing of the prohormone. The polar leucine analog, beta-hydroxyleucine, only partially perturbed the function and cleavage of the signal peptide but efficiently and unexpectedly blocked the dibasic cleavage of the prohormone. Other nonbasic amino acid analogs, beta-hydroxynorvaline and azetidine-2-carboxylic acid, which only could be incorporated into the prohormone at a distance from the processing site, also prevented dibasic cleavage of the prohormone. Although there are no phenylalanine residues in the prohormone, analogs for this amino acid, fluoro-phenylalanine and particularly phenylserine, could also block the processing of the prohormone at the dibasic site. This effect was prevented by addition of a small quantity of phenylalanine. It is concluded that amino acid analogs can interfere with precursor processing through altering both the primary and the secondary structure of the precursor but also through incorporation into cosynthesized protein(s) which are necessary for the precursor processing.
氨基酸类似物可掺入新生肽链中，将其用于犬胰腺内分泌细胞培养，以研究对胰腺多肽代谢标记前体加工过程的影响。碱性氨基酸类似物刀豆氨酸和氨基乙基半胱氨酸可阻止激素原的双碱性加工。极性亮氨酸类似物β-羟基亮氨酸仅部分干扰信号肽的功能和切割，但有效且出人意料地阻断了激素原的双碱性切割。其他非碱性氨基酸类似物β-羟基正缬氨酸和氮杂环丁烷-2-羧酸，只能在距加工位点一定距离处掺入激素原中，它们也能阻止激素原的双碱性切割。尽管激素原中没有苯丙氨酸残基，但该氨基酸的类似物氟苯丙氨酸，尤其是苯丝氨酸，也能在双碱性位点阻断激素原的加工。加入少量苯丙氨酸可阻止这种效应。结论是，氨基酸类似物可通过改变前体的一级和二级结构，也可通过掺入前体加工所必需的共合成蛋白质中，来干扰前体加工。
