Caged protein prenyltransferase substrates: tools for understanding protein prenylation.
Caged protein prenyltransferase substrates: tools for understanding protein prenylation.
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DOI：
10.1111/j.1747-0285.2008.00698.x
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发表时间：
2008-09
影响因子：
3
通讯作者：
Distefano MD
中科院分区：
文献类型：
--
作者：
DeGraw AJ;Hast MA;Xu J;Mullen D;Beese LS;Barany G;Distefano MD
最初设计用于阻断致癌Ras的异戊烯化，目前在临床前和临床试验中的蛋白法尼基转移酶抑制剂在具有正常Ras的癌症中显示出功效。阻断蛋白质异戊烯化也在治疗疟疾、恰加斯病和早老综合症方面显示出希望。需要更好地理解蛋白质异戊二烯化的机制、靶点和体内后果，以阐明当前PFT酶抑制剂的作用模式，并创造更有效和选择性的化合物。笼状酶底物是了解酶的作用机制和生物学功能的有用工具。本文报道了PFTase笼状底物的合成和表征。笼状类异戊二烯二磷酸盐在光解之前是不良底物。笼状CAAX肽是PFT酶的真正催化笼状底物，因为它不是底物，但能够结合酶，如通过抑制研究和X射线晶体学所确定的。用350 nm光照射笼状分子容易释放其同源底物，并且其光解产物是良性的。这些性质突出了这些类似物对各种体外和体内应用的效用。
Originally designed to block the prenylation of oncogenic Ras, inhibitors of protein farnesyltransferase currently in pre-clinical and clinical trials are showing efficacy in cancers with normal Ras. Blocking protein prenylation has also shown promise in the treatment of malaria, Chagas disease, and progeria syndrome. A better understanding of the mechanism, targets and in vivo consequences of protein prenylation are needed to elucidate the mode of action of current PFTase inhibitors and to create more potent and selective compounds. Caged enzyme substrates are useful tools for understanding enzyme mechanism and biological function. Reported here is the synthesis and characterization of caged substrates of PFTase. The caged isoprenoid diphosphates are poor substrates prior to photolysis. The caged CAAX peptide is a true catalytically caged substrate of PFTase in that it is to not a substrate, yet is able to bind to the enzyme as established by inhibition studies and x-ray crystallography. Irradiation of the caged molecules with 350 nm light readily releases their cognate substrate, and their photolysis products are benign. These properties highlight the utility of those analogues towards a variety of in vitro and in vivo applications.
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影响因子：
3.6
作者：
Han, YX;Albericio, F;Barany, G
通讯作者：
Barany, G
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16.6
作者：
Cambridge, SB;Geissler, D;Cürten, B
通讯作者：
Cürten, B
影响因子：
4.8
作者：
Fu, HW;Moomaw, JF;Casey, PJ
通讯作者：
Casey, PJ
影响因子：
3.6
作者：
Gaon, I;Turek, TC;Distefano, MD
通讯作者：
Distefano, MD