Farnesyl-diphosphate farnesyltransferase

This enzyme [EC 2.5.1.21], officially known as farnesyl-diphosphate farnesyltransferase (and also referred to as farnesyltransferase and presqualene-diphosphate synthase), catalyzes the conversion of two molecules of farnesyl diphosphate to yield presqualene diphosphate and pyrophosphate (or, diphosphate). In its polymeric form, the enzyme then catalyzes the NADPH-dependent reduction of presqualene diphosphate to form squalene. See also Farnesyl Diphosphate Farnesyltransferase... 

The molecular elements of that pathway were mapped with photoaffinity labeling by different investigators. Farnesyltransferase contains a and heterodimer subunits, and binds to both protein and farnesyl diphosphate. The main recognition elements for the protein is the C-terminal CAAX motif. Coleman et al. attached two benzophenones to the recognition sequence and the resulting photoprobe (38, Fig. 14) specifically labeled both subunits [125]. 

Long, S.B., Casey, P.J., and Beese, L.S. (1998). Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate. Biochemistry 37 9612-9618. 

Manne, V., et al. (1995). Ras farnesylation as a target for novel antitumor agents potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase. Drug Dev Res 34 121-137. 

This subsection is a continuation of the review of biological aspects of synthesized molecules, which have been mentioned in the previous subsections devoted to synthesis and reactions. Synthesis and biochemical evaluation of 3,7-disubstituted farnesyl diphosphate (FPP) analogues (67) have been described by Gibbs and co-workers as both potent inhibitors of protein-farnesyltransferase (FTase) and efficient, alternative substrates for the FTase. ... 

Roquefortine C was often accompanied by a structurally related mycotoxin isofumigaclavine A (12-98). P. roqueforti molds may occasionally produce patulin, citrinin (12-99), penicillic acid (12-100), the so-called PR-toxin (12-101) and certain other toxins that have been implicated in incidents of mycotoxicoses. However, PR toxin is not stable in cheese and breaks down to the less toxic PR imine (12-101). Other secondary metabolites ofP. roqueforti found in blue cheeses are andrastins A-D with skeletons of ent-5a,lA -androstane. In European blue cheeses, the content of andrastin A (12-102) ranged from 0.1 to 3.7 mg/kg and contents of andrastins B, C and D were on average five times lower. The most significant biological activity of adrastins is the ability to inhibit the enzyme farnesyltransferase, an enzyme that catalyses the transfer of farnesyl residue from farnesyl diphosphate to proteins. It is a part of the apparatus carrying post-translational modification of proteins in... 

Protein farnesylation, catalyzed by protein farnesyltransferase, plays important roles in the membrane association and protein-protein interaction of a number of eukaryotic proteins. The enzyme transfers a 15-carbon farnesyl moiety from famesyl diphosphate (FPP) to the sulfhydryl group of cysteine. The activity of the enzyme was measured by CE with LIE detection, which is a powerfiil alternative to classical methods involving radiolabeled FPP." LIE detection was performed with an argon ion laser (excitation, 488 nm/emission, 520 nm). A fluorescently labeled pentapeptide that was used as substrate was clearly separated from its farnesylated form under the four CE buffer conditions investigated (e.g., 25 mM borax, 25 mM SDS, pH 9.3, uncoated capillary). The method will be of great value in studies of inhibitors of protein farnesyltransferase in vitro. 

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