Geranylgeranyl side chain

Biosynthesis.—Further evidence has been adduced for the formation of 5-ALA and magnesium protoporphyrin-IX from glutamate in greening plants,and the enzymic preparation of the monomethyl ester of magnesium protoporphyrin has been described." Intermediates in the last stages of chlorophyll biosynthesis in which the geranylgeranyl side-chain is converted into phytyl have been studied l- C-labelled acetate is incorporated into the expected alternate positions in the phytyl ester side-chain (as shown by C n.m.r. spectral studies), but only low incorporations of mevalonate were obtained, presumably because of poor transport into the cell. The biosynthesis of chlorophyll-f has also been studied." ... 

FIGURE 9.19 Proteins containing the C-terminal sequence CAAX can undergo prenylation reactions that place thioether-linked farnesyl or geranylgeranyl groups at the cysteine side chain. Prenylation is accompanied by removal of the AAX peptide and methylation of the carboxyl group of the cysteine residue, which has become the C-terminal residue. 

Fig. 2. Schematic representation of paclitaxel biosynthesis. Dimethylallyl-diphosphate and isopentenyl-diphosphate are condensed through geranylgeranyl diphosphate synthase activity to render geranylgeranyl-diphosphate (GGPP). GGPP is converted into taxa-4(5), 11 (12)-diene in a reaction catalyzed by the taxane synthase (TS). A series of reactions catalyzed by cytochrome P450 monoxygenases lead to the production of a taxane intermediate that is further converted to baccatin III through enzymes-driven oxidation and oxetane ring formation. The side chain moiety of paclitaxel is derived from L-phenylalanine. Three consecutive arrows mean multiple steps. Ac, acetyl Bz, benzoyl.

The presence of a nitrogen-containing side chain facilitates interaction with the catalytic site of FPPS, an enzyme in the metabolic pathway that is required for the production of the isoprenoid hpids farnesyl diphosphate and geranylgeranyl diphosphate, essential metabolites for posttranslational protein prenylation [5, 8]. Inhibiting the prenylation of guanosine triphosphate-binding proteins such as Ras, Rho, and Rac disrupts the normal cellular signal transduction that is required for osteoclast function and survival [5]. 

Geranylgeranylation Geranylgeranyl Transferase I (GGTase I) Side chain of Cys No Intracellular plasma membrane, Golgi, endosome, lyso-some, vesicle, other endomembranes Rho, Rab, Ras... 

Figure 6.5 Construction of prenylated Rab7 proteins with a fluorophore on the isoprenyl moiety and mono- and digeranylgeranylated Rab7 proteins with a fluorophore at the peptide side chain. The NBD-farnesyl group is a fluorescent analog of a geranylgeranyl group [15].

The cysteine side chain of CaaX is the nucleophile that reacts with farnesyl pyrophosphate or geranylgeranyl pyrophosphate, forming a thioether and eliminating pyrophosphate. Once the protein has been prenylated, the C—aaX amide bond is hydrolyzed, causing cysteine to become the C-terminal amino acid. Cysteine s carboxyl group is then esterified with a methyl group. 

It uses a series of enzyme-controlled reactions. The step responsible for the creation of the unusual core is a cyclization reaction which changes geranylgeranyl diphosphate into taxa-4,11-diene. This then undergoes a variety of processes involving oxidation, acylation, and addition of a side chain to form taxol. The structure of the enzyme responsible for this, taxadiene synthase, was reported injanuary 2011. 

Vitamin E, as well as vitamin K, plastoquinones and ubiquinones, is formed, in principle, from shikimic acid via 4-hydroxyphenylpyruvic and homogentisic acid. The terpenoid side chain k synthesised from isopentenyl diphosphate, or more precisely from geranylgeranyl diphosphate, which is gradually reduced to phytyl diphosphate. The primary product of biosynthesis is 5-tocopherol other tocopherok are products of its methylation. The biosynthesis of tocotrienok lies in the condensation of homogentisic acid with geranylgeranyl diphosphate. Vitamin E k only synthesised by plants and some cyanobacteria. 

Phylloquinone and menaquinone are derived from chorismic acid, which results from 3-phosphoenolpyruvic acid (a product of glycolysis) and D-erythrose 4-phosphate (a product of the pentose and Calvin cycles) as a starting compound for the biosynthesis of phenylalanine, tyrosine and tryptophan. It is transformed into iso-chorismic acid other carbon atoms are derived from 2-oxoglutaric acid. The side chain is provided by ph)4yl diphosphate or by polyprenyl diphosphates, which are formed from geranylgeranyl diphosphate. The final reaction is a methylation at C-2. 

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