Isoprenoid pathway metabolism

Figure 9.2. The inherent metabolic flexibility of the isoprenoid pathway leading to the synthesis of some carotenoid pigments. Genes coding for two enzymes capable of acting on carotenoid structures were introduced into Escherichia coli which had already been transformed to give it the capacity to make p,p-carotene. Both of the two introduced new enzymes (one shown with red arrows and the other with blue arrows) acted on multiple substrates because of their lack of specificity. The resulting matrix of transformations means that nine different products can be made by just two tailoring enzymes. (Adapted from Umeno et al. ° who used data from Misawa et al. °)...

Hanley, K.M., Voegeli, U. and ChappeU, J. (1992) A study of the isoprenoid pathway in elicitortreated tobacco cell suspension cultures, in Secondary-Metabolite Biosynthesis and Metabolism (eds R.J. Petroski and S.R McCormick). Plenum, New York,pp. 329-36. 

Producte of normal metabolism, particularly those of the fatty acid and isoprenoid pathways, were modified by a few pheromone gland-specific enzymes to produce the myriad of pheromone molecules. The elegant work of the Roelofs laboratory [21] demonstrated that many of the lepidopteran pheromones could be formed by the appropriate interplay of highly selective chain shortening of fatty acids and a unique delta-11 desaturase enzyme followed by modification of the carboxyl carbon (see Fig. 5). Chain shortening of fatty acids is also involved in producing the queen pheromone in honeybees [69, 70]. 

Mitochondrial and cytosolic biosynthesis and utilization of HMG-CoA in the liver. The molecules indicated by an asterisk are the ketone bodies. Acetoacetate and /i-hydroxybutyrate (after conversion to acetoacetate) are metabolized in extrahepatic tissues. Acetone is excreted in the lungs. Note the cytosolic multifunctional isoprenoid pathway for cholesterol biosynthesis. The double arrow indicates a multistep pathway. 

Fig. 1 is an overview of the metabolic and transport pathways that control cholesterol levels in mammalian cells (reviewed in Ref. [1]). Cholesterol is synthesized from acetyl-CoA via the isoprenoid pathway. At least 14 enzymes in the biosynthetic pathway are regulated by cellular cholesterol levels [2], of which the four key enzymes are shown. 

Shimada, H., Kondo, K., Fraser, P., Miura, Y, Saito, T., and Misawa, N. 1998. Increased carotenoid production by the food yeast Candida utilis through metabolic engineering of the isoprenoid pathway. Appl Environ Microbiol 64 2676-2680. 

Carotenoids are the dominant products of the isoprenoid pathway in mango. Phytochemicals in mango have been implicated in protection from cancer [38]. Mango impacts favorably on a number of metabolic functions such as the production of a low plasma glucose concentration relative to other tropical and subtropical fruits commonly consumed in Thailand [39], and also to an increase in plasma vitamin C [40],... 

A second pathway based upon small molecule diphosphates, isoprenoid biosynthesis, may rival the importance of nucleotide metabolism in the treatment of human disease [201]. Because isoprenoids have important roles in heart disease, bone disease, and cancer, various groups have investigated ways to elevate the concentration and target the delivery of isoprenoid pathway inhibitors using prodrug strategies. 

Goto T, Kim YI, Funakoshi K, Teraminami A, Uemura T, Hirai S, Lee JY, Makishrma M, Nakata R, Inoue H, Senju H, Matsunaga M, Horio F, Takahashi N, Kawada T (2011) Am J Famesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARa-dependent and -independent pathways. Physiol Endocrinol Metab 301(5) E1022-E1032... 

Ajikumar PK, Xiao W-H, Tyo KEJ, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G (2010) Isoprenoid pathway optimization for taxol precursor overproduction m Escherichia coli. Science 330(6000) 70-74. doi 10.1126/science.l 191652 Albrecht M, Misawa N, Sandmann G (1999) Metabolic engineering of the terpenoid biosynthetic pathway of Escherichia coli for production of the carotenoids p-carotene and zeaxanthin. Biotechnol Lett 21(9) 791-795... 

Figure 5.10 represents an outline of the isoprenoid pathway in plants and highlights the importance of this pathway in providing molecules essential for the metabolism of plant cells. Many of the isoprenoids (terpenoids) derived from the pathway are unique to plants, and therefore their biosynthesis would be a good herbicide target. Indeed, this has already been seen in Chapter 4 with the inhibition of carotenoid biosynthesis from phytoene by several classes of successful herbicides. In this section, the evidence for herbicide inhibition of other sites within the isoprenoid pathway is reviewed. 

Rodriguez-Concepcion, M. and Boronat, A., Elncidation of the methylerythritol phosphate pathway for isoprenoid biosynthesis in hacteria and plastids a metabolic milestone achieved throngh genomics. Plant Physiol. 130, 1079, 2002. Rodriguez-Concepcion, M., Early steps in isoprenoid biosynthesis multilevel regulation of the supply of common precursors in plant cells, Phytochem. Rev. 5, 1, 2006. Eisenreich, W., Rohdich, F., and Bacher, A., Deoxyxylulose phosphate pathway to terpenoids, Trends Plant Sci. 6, 78, 2001. 

Pitera, D.J., Paddon, C.J., Newman, J.D. and Keasling, J.D. (2007) Balancing a heterologous mevalonate pathway for improved isoprenoid production in Escherichia coli. Metabolic Engineering, 9, 193-207. 

The activity of PK and NRPSs is often precluded and/or followed by actions upon the natural products by modifying enzymes. There exists a first level of diversity in which the monomers for respective synthases must be created. For instance, in the case of many NRPs, noncanonical amino acids must be biosynthesized by a series of enzymes found within the biosynthetic gene cluster in order for the peptides to be available for elongation by the NRPS. A second level of molecular diversity comes into play via post-synthase modification. Examples of these activities include macrocyclization, heterocyclization, aromatization, methylation, oxidation, reduction, halogenation, and glycosylation. Finally, a third level of diversity can occur in which molecules from disparate secondary metabolic pathways may interact, such as the modification of a natural product by an isoprenoid oligomer. Here, we will cover only a small subsection of... 

Abstract Pheromones are utilized by many insects in a complex chemical communication system. This review will look at the biosynthesis of sex and aggregation pheromones in the model insects, moths, flies, cockroaches, and beetles. The biosynthetic pathways involve altered pathways of normal metabolism of fatty acids and isoprenoids. Endocrine regulation of the biosynthetic pathways will also be reviewed for the model insects. A neuropeptide named pheromone biosynthesis activating neuropeptide regulates sex pheromone biosynthesis in moths. Juvenile hormone regulates pheromone production in the beetles and cockroaches, while 20-hydroxyecdysone regulates pheromone production in the flies. 

Poly(3HB) synthesis in various subcellular compartments could be used to study how plants adjust their metabolism and gene expression to accommodate the production of a new sink, and how carbon flux through one pathway can affect carbon flux through another. For example, one could study how modifying the flux of carbon to starch or lipid biosynthesis in the plastid affects the flux of carbon to acetyl-CoA and poly(3HB). Alternatively, one could study how plants adjust the activity of genes and proteins involved in isoprenoid and flavonoid biosynthesis to the creation of the poly(3HB) biosynthetic pathway in the cytoplasm, since these three pathways compete for the same building block, i. e., acetyl-CoA. 

In addition, it has been discovered that there are naturally occurring enzymes that facilitate Diels-Alder type reactions within certain metabolic pathways and that enzymes are also instrumental in forming polyketides, isoprenoids, phenylpropanoids, and alkaloids (de Araujo et al., 2006). Agresti et al. (2005) identified ribozymes from RNA oligo libraries that catalyzed multiple-turnover Diels-Alder cycloaddition reactions. 

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