Prenylation, of proteins

Prenylation of proteins (a posttranslational modification) that need to be held in the cell membrane by a lipid tail. An example is the p21 G protein in the insulin and growth factor pathways. 

HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35-3) that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. 

The effect of FTIs on retinal function also needs to be carefully examined. Several proteins involved in retinal signal transduction are farnesylated in vivo, presumably by FTase. These include rod cell cGMP phosphodiesterase a-subunit,108,109 rod cell transducin y-subunit,110,111 and rhodopsin kinase.112 Since the retina consists of terminally differentiated, nondividing cells, the anti-proliferative properties of FTIs should be inconsequential. Visual function could possibly be affected by alterations in the prenylation of proteins involved in retinal signal transduction, although any changes of this sort should be reversible. 

Prenylation of proteins by 15- and 20-carbon-chain prenyl groups presented in partial formulation in Figure 2-5... 

Magee, T., Seabra, M.C. 2005. Fatty acylation and prenylation of proteins what s hot in fat. Curr. Opin. Cell Biol. 17 190-196. 

Squalene synthase is an enzyme catalyzing the formation of squalene from farnesyl diphosphate which is a committed step in the cholesterol biosynthetic pathway. Therefore, squalene synthase is considered a better target than HMG-CoA reductase because farnesyl pyrophosphate, a downstream product of HMG-CoA reductase, is needed for prenylation of proteins and for the biosyntheses of ubiquinone and dolichol (Fig. 2). Before squalestatins and zaragozic acids were discovered, a number of squalene synthase inhibitors were synthesized that showed respectable inhibitory potencies in vitro, but none were successful in animal testing [41]. It was the discovery of squalestatins and zaragozic acids that renewed interest in this biological target, and at picomolar potencies they were the most active inhibitors of squalene synthase. 

Prenylation of proteins with polyisoprenoids is an important post-translational modification that participates in proliferation of both normal and cancerous cells. These modifications were first discovered on fungal mating factor peptides [55-57] where it was observed that the isoprene group was covalently linked to the cysteine residue of the protein substrate via a thioether bond. Although, the functional significance of this modification was not well understood it was found to be stable and an important component of active mating factor. 

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