Inhibitors of protein: Geranylgeranyl transferases

被引:26
作者
El Oualid, Farid
Cohen, Louis H.
van der Marel, Gijs A.
Overhand, Mark
机构
[1] Leiden Univ, Gorlaeus Labs, Leiden Inst Chem, NL-2300 RA Leiden, Netherlands
[2] TNO Qual Life, Gaubius Lab, Dept Vasc & Metab Dis, Business Unit,Biomed Res, NL-2301 CE Leiden, Netherlands
[3] Univ Oxford, Dept Chem, Oxford OX1 3TA, England
关键词
protein; geranylgeranyl transferase-1 and-2; peptidomimetics; Ca(1)a(2)L box; small GTP binding proteins; signal transduction; aberrant cell proliferation; anti-cancer agents; functional proteomics;
D O I
10.2174/092986706777935078
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The enzyme protein: geranylgeranyl transferase-1 (PGGT-1 or GGTase-1) catalyzes the geranylgeranylation of cysteine residues near the C-termini of a variety of proteins, including most monomeric GTP binding precursor proteins belonging to the Rho, Rae and Rap subfamilies. These proteins are involved in signaling pathways controlling important processes such as cell differentiation and growth. In the framework of the development of therapeutics against disorders associated with aberrant cell proliferation, the interference with these signal transduction cascades has been a major focus of investigation. For instance inhibitors of PGGT-1 have shown promise in the treatment of cancer, smooth muscle hyperplasia as well as parasitic infections, such as malaria. In this review, structural and mechanistic aspects of the protein:geranylgeranyl transferases are discussed as well as their importance with respect to the terpene metabolism. An extensive summary of reported inhibitors of PGGT-1, classified as natural products, peptide substrate (Ca(1)a(2)L box), terpene substrate (geranylgeranyl pyrophosphate) and others, is presented. The few known inhibitors of the other geranylgeranylating enzyme, protein: geranylgeranyl transferase-2 (PGGT-2), are also included.
引用
收藏
页码:2385 / 2427
页数:43
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