Document Type

Senior Honors Project

Publication Date



Geranylgeranyl transferase (GGTase) is an enzyme involved in the prenylation of many proteins, including Ras proteins. Prenylation is the addition of a hydrophobic hydrocarbon chain to a molecule. This addition is responsible for the activation of signaling pathways connected to cell growth and development. A malfunction of prenylated Ras proteins can lead to uncontrollable cell growth and proliferation which can lead to many types of diseases, including cancer. This study focuses on the synthesis of a probe that is identical to the GGTase natural substrate, geranylgeranyldiphosphate (GGPP), with the only difference being the addition of a norbornene motif. This non-natural GGTase substrate will trick the enzyme into binding with the non-natural substrate rather than its natural substrate geranylgeranyldiphosphate. The non-natural substrate can then be used in conjugation with a modified tetrazine molecule for the selective inhibition of GGTase. Norbornenes have shown promise in bioconjugation reactions with modified tetrazines. Bioconjugation reactions are reactions which contain desirable features to occur in biological settings using reactants that are biologically inert. Future directions include in vitro and in vivo tests of the synthesized probe on the inhibition of GGTase.