Geranyl transferase

Seabra, M. C., Brown, M. S. and Goldstein, I. L. Retinal degeneration in choroideremia deficiency of rat geranyl-geranyl transferase. Science 259 377-381,1993. 

Proteins with an isoprenoid modification possess either a C15-famesyl residue or a C20-geranyl-geranyl residue. Both residues are bound via a thioester linkage to a cysteine residue. As with myristoylation, these are constitutive, stable modification performed by farnesyl or geranyl transferases. 

Overhand, M., et al. (1998). Inhibitors of protein farnesyltransferase and protein geranyl-geranyl transferase I Synthesis of homologous diphosphonate analogues of isoprenylated pyrophosphate. Bioorg Chem 26 269-282. 

These isomeric C5 units condense to form a Cjq compound isopentenyl pyrophosphate attacks an allylic carbonium ion formed from dimethylallyl pyrophosphate to yield geranylpyrophosphate (Figure 26.9). The same kind of reaction takes place again geranyl pyrophosphate is converted into an allylic carbonium ion, which is attacked by isopentenyl pyrophosphate. The resulting C15 compound is called farnesylpyrophosphate. The same enzyme, geranyl transferase, catalyzes each of these condensations. 

Prenylation also influences the balance between myocyte viability and apoptosis. Statin-induced apoptosis has been demonstrated in vitro, using myotubes [84], myoblasts [85], and differentiated primary human skeletal muscle cells [86], This effect can be reproduced by geranyl-geranyl-transferase inhibitors, and rescued by replacement of mevalonic acid [84], Compelling evidence suggests that statins cause apoptosis in skeletal muscle by disrupting the prenylation of small G proteins like Rho [85],... 

Figure 2. Tocopherol biosynthesis in plants. Enzyme abbreviation El - geranyl geranyl transferase E2-2-methyl-6-phytylplastoquinol methyltransferase E3-tocopherol cyclase E4-y-tocopherol methyltransferase (Adapted from Kamal-Eldin et al., 1997).

Prenyl transferase, which catalyses the addition of an allylic pyrophosphate to iso-pentenyl pyrophosphate, also catalyses the hydrolysis of geranyl pyrophosphate.104 Inorganic pyrophosphate stimulates this hydrolysis, and the C—O bond is broken in... 

This enzyme [EC 2.5.1.1] (also referred to as prenyl-transferase and geranyl-diphosphate synthase) catalyzes the reaction of dimethylallyl diphosphate and isopen-tenyl diphosphate to produce geranyl diphosphate and pyrophosphate (or, diphosphate). The enzyme will not accept larger prenyl diphosphates as substrates. 

The prenyl transferases are a class of enzymes that is involved in post-translational modification of membrane-associated proteins. These enzymes catalyze the transfer of a farnesyl (FTase, EC 2.5.1.58, for structural information see References 55-65) or geranyl-geranyl group (GGTase I, EC 2.5.1.59 GGTase n, EC 2.5.1.60, for structural information... 

Hemiterpenoids are produced from the isoprenyl diphosphate DMAPP. All other terpenoids are produced from DMAPP and IPP via longer-chain prenyl diphosphate intermediates formed by prenyl transferases. Prenyl transferases (20) catalyze the formation of geranyl diphosphate (GPP), famesyl diphosphate (FPP), and geranylgeranyl diphosphate (GGPP) from one molecule of DMAPP and one, two, or three molecules of IPP, respectively (Fig. 1). Isoprenyl diphosphates are the substrates for all TPS, which lead to the hemiterpenoids, monoterpenoids, sesquiterpenoids, and diterpenoids, which will be highlighted with selected examples in the following sections. 

With the preceding reviews of the enzymology of monoterpene cyclization and of model studies relevant to the cyclization process, it is possible to formulate a unified stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (Figure 4). The proposal which follows is consistent with the implications of parallel advances in related fields, most notably the contributions of Cane (8,16,24,25,52), Arigoni (67) and Coates (68,69) on the stereochemistry of sesquiterpene and diterpene cyclizations, and of Poulter and Rilling (29,70) on the stepwise, ionic mechanism of prenyl transferase, a reaction type of which several monoterpene, sesquiterpene and diterpene cyclizations are, in a sense, the intramolecular equivalents. 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

A problem in the use of dimethylallyl pyrophosphate (3) is its instability. In a study of this problem the half-life of this substance was examined over a range of pH values and temperatures. Both cis- and trans-prenyl pyrophosphates (4 n = 0, 1, or 2) occur in Pinus radiata. Their biosynthesis from [2- C,3R,4K- H]-mevalonic acid proceeded with retention of tritium whereas with [2- C,3K,4S- HJmevalonic acid tritium was lost [except in the case of isopentenyl pyrophosphate (4 n = 0)]. The authors suggest that since they could not detect an isomerase, there may be a cis- and a trans-prenyl transferase both of which eliminate the label derived from [4S- H]mevalonic acid. However, compart-mentalization may have resulted in the isomerase not being available to the administered monoterpenoids, although it may act on geranyl pyrophosphate formed in situ. The absence of 6-cis-famesol derivatives tends to support this idea. Further work on this system again produced no evidence for isomerization or metabolism of [l- H]nerol pyrophosphate to 2-rrans-6-c(s-farnesyl pyrophosphate. 

The early stages of carotenoid biosynthesis are common to the biosynthesis of all isoprenoids. The characteristic isoprenoid precursor, mevalonic acid (MVA) is converted into the C5 compound isopentenyl diphosphate (IDP), some of which is isomerized to dimethyallyl diphosphate (DMADP). The isoprenoid chain is then built from these precursors by means of prenyl transferase enzymes to give, successively, the Ciq geranyl... 

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