Amino acid pathway metabolites derived from

It is usual to classify alkaloids (basic nitrogenous metabolites) according to the amino acids (or their derivatives) from which they arise. Thus, the most important classes are derived from the amino acids ornithine, lysine, phenylalanine, tyrosine and tryptophan, and the skeletons of these amino acids are retained largely intact in the alkaloids derived from them. However, this type of classification is often criticized because it fails to include those alkaloids that are derived from a mixed biogenetic pathway (e.g. polyketide or terpenoid) with incorporation of a nitrogen atom, ultimately from ammonia. The alkaloids that are the subject of this review are excellent examples of such compounds and they are often known as pseudoalkaloids. 

The accumulation of biosynthetic intermediates, or of metabolites derived from these intermediates, has proven to be valuable in the analysis of biosynthetic pathways in microorganisms. It was found that these accumulations occurred only after the required amino acid had been consumed and growth had stopped. How might you account for this observation ... 

The chemistry of the subclass Zoantharia also shows significant deviation from the Octocorallia. Of 151 zoantharian metabolites reported, 88 (58%) are derived from the amino acid pathway. Zoanthids (order Zoanthidea) contain a high proportion of amino acid derivatives (46, 75%), the... 

Figure 1.3 Several pathways of secondary metabolites derive from precursors in the shikimate pathway. Abbreviation NPAAs, non-protein amino acids PAL, phenylalanine ammonia lyase TDC, tryptophan decarboxylase STS, strictosidine synthase CHS, chalcone synthase. (See Plate 2 in colour plate section.)...

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.

Despite the thousands of secondary metabolites made by microorganisms, they are synthesized from only a few key precursors in pathways that comprise a relatively small number of reactions and which branch off from primary metabolism at a limited number of points. Acetyl-CoA and propionyl-CoA are the most important precursors in secondary metabolism, leading to polyketides, terpenes, steroids, and metabolites derived from fatty acids. Other secondary metabolites are derived from intermediates of the shikimic acid pathway, the tricarboxylic acid cycle, and from amino acids. The regulation of the biosynthesis of secondary metabolites is similar to that of the primary processes, involving induction, feedback regulation, and catabolite repression [6]. 

Metabolites Derived from the Polyketide and Amino Acid Pathways... 

Metabolites Derived from the Amino Acid Pathway... 

The metabolic pathway responsible for biosynthesis of aromatic amino acids and for vitamin-like derivatives such as folic acid and ubiquinones is a major enzyme network in nature. In higher plants this pathway plays an even larger role since it is the source of precursors for numerous phenylpropanoid compounds, lignins, auxins, tannins, cyano-genic glycosides and an enormous variety of other secondary metabolites. Such secondary metabolites may originate from the amino acid end products or from intermediates in the pathway (Fig. 1). The aromatic pathway interfaces with carbohydrate metabolism at the reaction catalyzed by 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase, the condensation of erythrose-4-phosphate and PEP to form... 

A compound of unsuspected importance was isolated in 1885 from the fruit of Illicium religiosum. To this compound was given the name shikimic acid, a name derived from shikimi-no-ki which is the Japanese name for the plant. Shikimic acid (5.7), it transpired from the very elegant studies of much later investigators, is a key intermediate in the biosynthesis of the aromatic amino acids, L-phenylalanine, L-tyrosine and L-tryptophan, in plants and micro-organisms (animals cannot carry out de novo synthesis using this pathway). These three aromatic amino acids are individually important precursors for numerous secondary metabolites, and so to some extent are earlier biosynthetic intermediates related to shikimic acid, as the ensuing discussion in this chapter and in Chapters 6 and 7 will show. 

Structure and Function of Peptidyl Carrier Protein Domains Structure and Function of Adenylation Domains Structure and Function of Condensation Domains Structure and Function of Thioesterase Domains Multidomain NRPS Structural Information PCP-C didomain structure PCP-TE didomain structure Structure of a C-A-PCP-TE termination module Pathways to Nonproteinogenic Amino Acids Incorporated into NRP Natural Nonproteinogenic Amino Acids Present as Cellular Metabolites Modification of Proteinogenic Amino Acids Nonproteinogenic Amino Acids Derived from Multistep Pathways Tailoring Enzymology in NRP Natural Products Chemical Approaches Toward Mechanistic Probes and Inhibitors of NRPS... 

Vertebrates cannot convert fatty acids, or the acetate derived from them, to carbohydrates. Conversion of phosphoenolpyruvate to pyruvate (p. 532) and of pyruvate to acetyl-CoA (Fig. 16-2) are so exergonic as to be essentially irreversible. If a cell cannot convert acetate into phosphoenolpyruvate, acetate cannot serve as the starting material for the gluconeogenic pathway, which leads from phosphoenolpyruvate to glucose (see Fig. 15-15). Without this capacity, then, a cell or organism is unable to convert fuels or metabolites that are degraded to acetate (fatty acids and certain amino acids) into carbohydrates. 

All amino acids are derived from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway (Fig. 22-9). Nitrogen enters these pathways by way of glutamate and glutamine. Some pathways are simple, others are not. Ten of the amino acids are just one or several steps removed from the common metabolite from which they are derived. The biosynthetic pathways for others, such as the aromatic amino acids, are more complex. 

Aromatic compounds arise in several ways. The major mute utilized by autotrophic organisms for synthesis of the aromatic amino acids, quinones, and tocopherols is the shikimate pathway. As outlined here, it starts with the glycolysis intermediate phosphoenolpyruvate (PEP) and erythrose 4-phosphate, a metabolite from the pentose phosphate pathway. Phenylalanine, tyrosine, and tryptophan are not only used for protein synthesis but are converted into a broad range of hormones, chromophores, alkaloids, and structural materials. In plants phenylalanine is deaminated to cinnamate which yields hundreds of secondary products. In another pathway ribose 5-phosphate is converted to pyrimidine and purine nucleotides and also to flavins, folates, molybdopterin, and many other pterin derivatives. 

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. 

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. 

All of the Amathia brominated amides are presumably biosynthesised from amino acids by similar pathways in the related bryozoans. The amathamides are amides derived formally by reaction of 2-(2,4-dlbromo-5-methoxyphenyl)ethanamlne, 68, with proline followed variously by introduction of a double bond, or methyl, methoxy or bromine substituents. The A. convoluta metabolites 70-74, and 75 from A. alternata are all also derived formally from 2-(2,4-dibromo-5-methoxy-phenyDethanamlne, 68—either by direct amide formation with tyrosine, or by having an additional aminopropyl group which is then... 

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