Isoprenoid biosynthetic pathway prenylation

Quinones represent a very large and heterogeneous class of biomolecules. Three major biosynthetic pathways contribute to the formations of various quinones. The aromatic skeletons of quinones can be synthesized by the polyketide pathway and by the shikimate pathway. The isoprenoid pathways are involved in the biosynthesis of the prenyl chain and in the formation of some benzoquinones and naphthoquinones. ... 

The biosynthetic pathway producing isoprenoid cytokinins has been identified, whereas that of aromatic cytokinins is poorly characterized.363 385 Two distinct pathways for isoprenoid cytokinin biosynthesis have been described, and each pathway employs a different type of isopentenyltransferase at the initial step. The major pathway in higher plants, which is catalyzed by IPT, is conjugation of adenine nucleotide and DMAPP or 4-hydroxy-3-methyl-2-( )-butenyl diphosphate (HMBDP) (Figure 14). In the less frequently used pathway, cytokinins are formed by degradation of prenylated tRNAs. The initial prenylation reaction of tRNA is catalyzed by tRNA-isopentenyltransferase (tRNA-IPT) (Figure 14). 

The MVA pathway was accepted as the unique biosynthetic pathway for the formation of aU isoprenoids in aU living organisms. Discrepancies with this general assertion appeared, however, as early as the 1950s (1, 2). For instance, -labeled MVA was not incorporated into chloroplast isoprenoids (e.g., carotenoids 25 and phytol 24 from chlorophylls Fig. 6), whereas it was well incorporated into phytosterols 27 synthesized in the cytoplasm. Unexpected labeling patterns were found in the prenyl chain of ubiquinone 22 in Escherichia coli at incorporation of C-labeled acetate. Finally, the labeling pattern in an isoprene unit from the sesquiterpenic pentalenene 21 series from a Streptomyces species at incorporation of uniformly... 

This study provides evidence that Rab prenylation is important to statin-induced muscle toxicity, and that it is possible to identify suppressive small molecules that should not inhibit the beneficial effects of statins on blood cholesterol levels. The use of small molecules to dissect biosynthetic pathways is certainly not new, but affords a precise and rapid understanding of the phenotypic consequences of cellular perturbations. For the future, modern chemical biology techniques, including affinity labeling of isoprenoids [11], provide an attractive opportunity to identify the specific Rabs responsible for statin-induced muscle toxicity. As a common laboratory tool compound, G66976 is unlikely to become a clinical candidate. 

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

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