Structural Biochemistry of CaaX Protein Prenyltransferases

Protein prenylation is a posttranslational lipid modification required for proper function by over 100 proteins in the eukaryotic cell. A family of structurally related protein prenyltransferase enzymes carry out this reaction: protein farnesyltransferase (FTase), protein geranylgeranyltransferase-I (GGTase-I), and Rab geranylgeranyltransferase (GGTase-II or Rab GGTase). This chapter concerns the structural biology of Ca 1 a 2 X protein prenyltransferases (FTase and GGTase-I). These enzymes recognize a well-defined C-terminal motif on substrate proteins: cysteine (C), followed by two generally aliphatic amino acids (aa) and a variable (X) residue. FTase and GGTase-I catalyze the addition of a 15-carbon or 20-carbon isoprenoid lipid, respectively. FTase and GGTase-I have been shown to be important targets for the development of cancer chemotherapeutics because prenylated signal transduction proteins play significant roles in oncogenesis. More recently, it has been demonstrated that protein prenyltransferases also show promise as drug targets for treating a variety of infectious diseases caused by fungi and protozoans. We review the structural features of the enzymatic reaction cycle, and how these relate to the mechanisms of inhibition by small molecules. We also review recent structural studies of human pathogen protein prenyltransferases, and how this information can be used for developing species-specific prenyltransferase inhibitors to treat infectious diseases. © 2011 Elsevier Inc.

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Author Lorena Sue Beese Biochemistry