Metabolites from isoprenoid pathway

More than half of the reported secondary metabolites from macroalgae are isoprenoids. Terpenes, steroids, carotenoids, prenylated quinines, and hydroqui-nones make up the isoprenoid class, which is understood to derive from either the classical mevalonate pathway, or the mevalonate-independent pathway (Stratmann et al. 1992). Melavonic acid (MVA) (Fig. 1.2) is the first committed metabolite of the terpene pathway. Dimethylallyl (dl meth al lal) pyrophosphate (DMAPP) (Fig. 1.3) and its isomer isopentenyl pyrophosphate (IPP, Fig. 1.3) are intermediates of the MVA pathway and exist in nearly all life forms (Humphrey and Beale 2006). Geranyl (ja ran al) (C10) and famesyl (C15) units are generated by head-to-tail (Fig. 1.3) condensation of two (for C10) or three (for C15) 5-carbon DMA-like isoprene units, identifiable in final products by the characteristic fish-tail repeating units, as traced over the structure of a sesquiterpene in Fig. 1.3 (Humphrey and Beale 2006). Additional IPP condensation with famesyl pyrophosphate (FPP)... 

Metabolites of the phylum Porifera account for almost 50% of the natural products reported from marine invertebrates. Of the 2609 poriferan metabolites, 98% are derived from amino acid, acetogenin, or isoprenoid pathways. Isoprenoids account for 50% of all sponge metabolites, while amino acid and polyketide pathways account for 26% and 22%, respectively. A significant number of sponge metabolites appear to be derived from mixed biosynthetic pathways. Most structures reported containing carbohydrate moieties were glycosides. 

Metabolites Derived from the Isoprenoid Pathway Sesquiterpenes... 

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

As presented in Table 1.2, over half of reported marine natural products are derived from the isoprenoid biosynthetic pathway (56%), with the remainder split mainly between amino acid (19%) and acetogenin (20%) pathways. Secondary metabolites falling into the categories of nucleic acids and carbohydrates comprise only 1%. Such low levels are somewhat surprising given the fundamental importance of such classes of compounds as primary metabolites. 

Figure 1 The retrobiosynthetic principle. Labeling patterns of central metabolic intermediates (shown in yellow boxes) are reconstructed from the labeling patterns of sink metabolites, such as protein-derived amino acids, storage metabolites (starch and lipids), cellulose, isoprenoids, or RNA-derived nucleosides. The reconstruction is symbolized by retro arrows following the principles of retrosynthesis in synthetic organic chemistry. The figure is based on known biosynthetic pathways of amino acids, starch, cellulose, nucleosides, and isoprenoids in plants. The profiles of the central metabolites can then be used for predictions of the labeling patterns of secondary metabolites. In comparison with the observed labeling patterns of the target compounds, hypothetical pathways can be falsified on this basis.

A far more complex situation arises in higher plants that use both the pathways in parallel.53 With hindsight, it is even obvious that the belated discovery of the deoxyxylulose pathway can be traced to a significant extent to the very occurrence of both the pathways in plants. More specifically, due to metabolite exchange between the two pathways that is the subject of this chapter, it appears likely that labeled mevalonate can contribute at least some label to most if not all plant isoprenoids hence, it was easy to jump to the conclusion — fallacious as we now know — that all plant isoprenoids are invariably biosynthesized from mevalonate. 

Marine macroalgae produce a wide variety of intriguing and diverse isoprenoid structures derived from C5 isoprene units, and many reports have been published on the ecological roles of these metabolites. Marine terpenoids are frequently found with halogenated functionalities and one or more rings, which can have important implications for their biological activities. Isoprenoid metabolites are derived via the classical mevalonate pathway or the more recently discovered deoxyxylulose phosphate pathway. Isoprenoids are... 

Two compounds common in plant metabolism are believed to be precursors of isoprenoid cytokinins in plants adenosine-5 -monophosphate (AMP) and A -isopentenylpyrophos-phate (iPP). As a final product of the mevalonate pathway, the latter substance serves also as a precursor for a wide spectrum of metabolites including some other plant hormones, as abscisic acid, gibberellins and brassinosteroids. The hypothetical scheme of reactions resulting in the formation of iPA, Z and DHZ is given in Fig. 2. The enzyme of entry into isoprenoid cytokinin formation is A -isopentenylpyrophosphate 5 -AMP-A -iso-pentenyltransferase (EC 2.5.1.8, trivially named cytokinin synthetase ). This enzyme activity was first detected in a cell-free preparation from the slime mould Dictyostelium discoideum [7,8]. Later the enzyme from higher plants (cytokinin-independent tobacco callus [9,10] and immature Zea mays kernels [11]) was described and the data were recently summarised in [12], The enzyme is very specific as far as the substrate is concerned [13,14] only the nucleotide AMP can be converted and only iPP (with a double bond in A position) may function as a side chain donor. 

Plant secondary metabolites are biosynthesized from rather simple building blocks supplied by primary metabolism. Two important metabolic routes in this are the shikimate pathway and the isoprenoid biosynthesis. The shikimate pathway leads to the synthesis of phenolic compounds and the aromatic amino acids phenylalanine, tyrosine and tryptophan. The isoprenoid biosjmthesis is a heavily branched pathway leading to a broad spectrum of compounds (fig. 1). From plants and microorganisms more than 37,000 isoprenoid compounds have been isolated so far [1]. 

From chorismic acid, four major pathways lead to essential metabolites tryptophan, phenylalanine and tyrosine, p-aminobenzoic acid and the folate group of coenzymes, and the isoprenoid quinones (Fig. 7.2). Numerous secondary compounds in plants and other organisms are formed from products and intermediates of these pathways. 

It should be noted that isoprenoid biosynthesis requires acetyl-CoA, ATP, and NADPH. The physiological source of these compounds is presumably sugar phosphate metabolism, via glycolysis and the pentose phosphate pathway. We show sucrose as the starting material in Fig. 1, since it is the principal transport sugar in plants. Free acetate is not an important metabolite in plants acetyl-CoA is normally derived from pyruvate formed in glycolysis. Biosynthesis of terpenes implies that acetyl-CoA is diverted from the Krebs cycle and that the energy available from the Krebs cycle and oxidative phos-... 

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