Monatshefte f€ ur Chemie 137, 1241–1281 (2006) DOI 10.1007/s00706-006-0534-9 Invited Review Protein Prenylation: An (Almost) Comprehensive Overview on Discovery History, Enzymology, and Significance in Physiology and Disease Wolfgang Benetka  , Manfred Koranda, and Frank Eisenhaber  Research Institute of Molecular Pathology (IMP), Vienna, Austria Received May 17, 2006; accepted June 2, 2006 Published online September 25, 2006 # Springer-Verlag 2006 Summary. Since 1979, when prenylation has been first discovered as chemical oddity of a yeast mating factor, the two forms of this posttranslational modification of proteins (farnesylation and geranylgeranylation) have been found as wide spread among proteins from Eukarya and their viruses. This review attempts to summarize as comprehensively as possible the enzymological processes of prenylation and the various aspects of their biological significance. The substrate proteins of prenyltransferases are known to carry a sequence signal composed of a cysteine-containing 4–5 residue stretch at the utmost C-terminal end that is N-terminally preceded by a flexible and polar linker region of ca. 10 residues. Postprenylation processing of substrate proteins can involve C-terminal proteolysis, C-terminal carboxyl methylation, and other steps of maturation. The prenyl anchor functions as module for membrane attachment or for protein–protein interaction. Prenyl anchor carrying proteins fulfill a large array of functions in signaling and regulation of cellular processes. Therefore, they are involved in the pathogenesis of a variety of human diseases, the most prominent one being cancer. Farnesyltransferase inhibitors show surprisingly high efficiency in controlling tumor growth in model systems but, so far, clinical trials with human patients have re- mained without the desired success. Interference into prenylation pathways appears also a promising treatment principle in a variety of parasitic diseases. Keywords. Farnesyl; Geranylgeranyl; Prenyl; Farnesyltransferase inhibitor; Cancer; Parasitic disease. Introduction The key to the ability of proteins to perform all the functions necessary in cell life is provided by their amino acid sequence. Linear combinations of the 20 amino  Corresponding authors. E-mails: benetka@imp.univie.ac.at, Frank.Eisenhaber@imp.univie.ac.at