GGTase-Iα Inhibitors

Chemical inhibitors of GGTase-Iα function primarily by disrupting the enzyme's ability to facilitate the attachment of geranylgeranyl groups to its substrate proteins. GGTI-298, GGTI-DU40, GGTI-2133, and GGTI-2418 exemplify this approach by binding to the catalytic site of GGTase-Iα, preventing the enzyme from catalyzing the transfer of these lipid groups. Specifically, GGTI-298 selectively inhibits the enzyme's action, while GGTI-DU40 acts by blocking the active site. GGTI-2133 and GGTI-2418 function as competitive inhibitors, obstructing the enzyme's ability to interact with its protein substrates. This blockage is critical as the geranylgeranylation process is essential for the proper localization and function of various proteins within the cell.

Other chemicals interfere with GGTase-Iα indirectly by targeting pathways and processes that provide the necessary substrates or conditions for the enzyme's activity. For example, Decylubiquinone disrupts the mitochondrial electron transport chain, which can lead to reduced ATP levels, affecting GGTase-Iα's ATP-dependent functioning. Perillyl alcohol intervenes in the mevalonate pathway, potentially reducing the availability of geranylgeranyl pyrophosphate for the enzyme. Similarly, Lovastatin and Zaragozic acid A inhibit earlier steps of the same pathway, leading to a decrease in the substrate necessary for GGTase-Iα activity. Manumycin A and L-778123, while also targeting farnesyltransferase, block the enzyme-substrate complex formation in GGTase-Iα as well. Quercetin modulates protein kinase pathways, which can alter the phosphorylation status of proteins related to GGTase-Iα, impacting its function. Lastly, Tipifarnib competes for the binding sites on GGTase-Iα, impeding the enzyme's geranylgeranyl group transfer to protein substrates.