a Department of Medicine , McGill University , Montreal , Canada.
b Department of Chemistry , McGill University , Montreal , Canada.
Crit Rev Biochem Mol Biol. 2019 Feb;54(1):41-60. doi: 10.1080/10409238.2019.1568964. Epub 2019 Feb 18.
Dysregulation of isoprenoid biosynthesis is implicated in numerous biochemical disorders that play a role in the onset and/or progression of age-related diseases, such as hypercholesterolemia, osteoporosis, various cancers, and neurodegeneration. The mevalonate metabolic pathway is responsible for the biosynthesis of the two key isoprenoid metabolites, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational prenylation of various proteins, including the small GTP-binding proteins (GTPases), with either FPP or GGPP is vital for proper localization and activation of these proteins. Prenylated GTPases play a critical role in cell signaling, proliferation, cellular plasticity, oncogenesis, and cancer metastasis. Pre-clinical and clinical studies strongly suggest that inhibition of protein prenylation can be an effective treatment for non-skeletal cancers. In this review, we summarize the most recent drug discovery efforts focusing on blocking protein farnesylation and/or geranylgeranylation and the biochemical and structural data available in guiding the current on-going studies in drug discovery. Furthermore, we provide a summary on the biochemical association between disruption of protein prenylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR) signaling, and cancer.
异戊烯基生物合成的失调与许多生化紊乱有关，这些紊乱在与年龄相关的疾病（如高胆固醇血症、骨质疏松症、各种癌症和神经退行性疾病）的发生和/或进展中发挥作用。甲羟戊酸代谢途径负责两种关键异戊烯基代谢物——法呢基焦磷酸（FPP）和香叶基焦磷酸（GGPP）的生物合成。各种蛋白质的翻译后异戊烯基化，包括小 GTP 结合蛋白（GTPases），用 FPP 或 GGPP 进行异戊烯基化对于这些蛋白质的正确定位和激活至关重要。异戊烯化 GTPases 在细胞信号转导、增殖、细胞可塑性、致癌和癌症转移中发挥着关键作用。临床前和临床研究强烈表明，抑制蛋白质异戊烯化可能是治疗非骨骼癌症的有效方法。在这篇综述中，我们总结了最近在阻断蛋白质法尼基化和/或香叶基化方面的药物发现努力，以及在指导当前药物发现研究的生化和结构数据。此外，我们还总结了蛋白质异戊烯化、内质网（ER）应激、未折叠蛋白反应（UPR）信号与癌症之间的生化关联。
