Park S B, Howald W N, Cashman J R
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Chem Res Toxicol. 1994 Mar-Apr;7(2):191-8. doi: 10.1021/tx00038a012.
Posttranslational modification of proteins with a farnesyl or geranylgeranyl group appears to be crucial in the signal transduction of eukaryotic cells. For example, farnesylation of ras-encoded proteins is a key process that apparently leads to membrane association of proteins that perform a function in cell growth-promoting activity. Although it has been suggested that prenylation of proteins may be an important regulatory mechanism, little is known about the mechanism whereby prenylated proteins are removed from the membrane. In our previous report [(1992) Chem. Res. Toxicol. 5, 193-201], we showed that S-alkenylated cysteines and mercapturates of xenobiotics were S-oxygenated by the flavin-containing monooxygenase. The S-oxides were not indefinitely stable and rearranged or underwent elimination reactions that cleaved the C-S(O) bond. As a model for farnesylated proteins and peptides, the biotransformation of farnesylcysteine methyl ester was examined in the presence of pig liver microsomes. Two prominent products were formed: farnesyl methyl ester sulfoxide and farnesylcysteine, arising from the action of the flavin-containing monooxygenase and esterase of pig liver, respectively. Formation of farnesylcysteine methyl ester sulfoxide by the flavin-containing monooxygenase was stereoselective (i.e., 71.5%:28.5%, major to minor diastereomer) in good agreement with previously reported stereoselectivity studies of other related S-alkylcysteine-containing compounds. That the stereoselectivity observed was due to S-oxygenation of the sulfur atom was verified in parallel chemical oxidation studies by using micellar electrokinetic capillary chromatography. Farnesylcysteine methyl ester was an excellent substrate for the flavin-containing monooxygenase, and the S-oxide product was confirmed by HPLC electrospray mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)
蛋白质经法尼基或香叶基香叶基修饰在真核细胞信号转导中似乎至关重要。例如，ras编码蛋白的法尼基化是一个关键过程，显然会导致在细胞生长促进活性中发挥作用的蛋白与膜结合。尽管有人提出蛋白质的异戊二烯化可能是一种重要的调节机制，但对于异戊二烯化蛋白从膜上移除的机制却知之甚少。在我们之前的报告中[（1992年）《化学研究毒理学》5，193 - 201]，我们表明含黄素单加氧酶可将外源性物质的S - 烯基化半胱氨酸和硫醚氨酸进行S - 氧化。S - 氧化物并非无限稳定，会重排或发生消除反应，从而断裂C - S（O）键。作为法尼基化蛋白和肽的模型，在猪肝微粒体存在的情况下研究了法尼基半胱氨酸甲酯的生物转化。形成了两种主要产物：法尼基甲酯亚砜和法尼基半胱氨酸，分别由猪肝的含黄素单加氧酶和酯酶作用产生。含黄素单加氧酶形成法尼基半胱氨酸甲酯亚砜具有立体选择性（即71.5%:28.5%，主要非对映体对次要非对映体），这与之前报道的其他相关含S - 烷基半胱氨酸化合物的立体选择性研究结果高度一致。通过胶束电动毛细管色谱法进行的平行化学氧化研究证实，观察到的立体选择性是由于硫原子的S - 氧化所致。法尼基半胱氨酸甲酯是含黄素单加氧酶的优良底物，S - 氧化物产物通过高效液相色谱电喷雾质谱法得到了确认。（摘要截短至250字）
