Metabolites from amino acid pathway

There are some classes of compounds present in seawater which have known biological activity but have received little attention. Compounds involved in chemical communication, especially halogenated compounds, will be discussed in other chapters. Other compounds of interest are those involved in the citric acid cycle, the major pathway of metabolism in almost all cells. Citric acid cycle intermediates and reactions are involved in the biosynthesis of most of the major metabolites, from amino acids and carbohydrates to long-chain fatty acids and porphyrins (Mahler and Cordes, 1971). The intermediates, such as succinic, fumaric, malic, oxaloacetic, citric, gly-oxylic, and oxoglutaric acids are present in almost all organisms and are certainly being produced in the sea. 

It is difficult to reconcile the unique chemical structure of tetrodotoxin with that of an animal product. Its structure is not related to that of other animal products by any readily recognized biosynthetic scheme. It is not a terpenoid, not obviously formed from amino acid or carbohydrate units, and apparently not constructed from acetate or propionate units. Nor does it resemble any of the various plant alkaloid patterns. It thus appears to be a very unlikely animal product to result from known biogenetic pathways. In this connection the metabolic incorporation of radioactive precursors using torosa and ]C. granulosa salamanders was studied by Shimizu et al. (47). They observed significant isotopic incorporation into amino acids and steroid metabolites, but they found no such incorporation associated with tetrodotoxin. 

Some inborn errors of metabolism can be characterized by excessive urinary excretion of aromatic acid metabolites. These acids are distinct from the vanillyl acids discussed in a previous section. Phenylketonuria, alkaptonuria, and tyrosinosis can be diagnosed by determination of the aromatic acid metabolites. Aromatic acid profiles are characteristic of specific metabolic defects, and can be used to confirm diagnoses obtained from amino acid and other studies. Quantification of the individual aromatic acid gives information as to the fate of ingested amino acid in diseases such as phenylketonuria, where there is a block in the metabolic pathway involving the particular amino acid. 

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. 

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... 

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... 

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... 

Secondary metabolites are produced by plants in response to biotic or abiotic interactions with their environment and confer protection through a variety of antimicrobial, pesticidal, and pharmacological properties. Alkaloids are a class of plant secondary metabolites that traditionally have been classified as basic compounds derived firom amino acids that contain one or more heterocyclic nitrogen atom. About 20 % of plant species accumulate alkaloids, which are mostly derived from amino acids, e.g., phenylalanine, tyrosine, tryptophan, and lysine. The alkaloids are popular for their medicinal importance. The pharmaceutically important representatives of secondary metabolites are mostly alkaloids derived from tyrosine. In this chapter, we summarized the prior information, basic knowledge about the alkaloids, origin, physicochemical properties, uses, classification, biosynthetic reactions, and distribution of tyrosine-derived alkaloids especially opium alkaloids and their biosynthetic pathways in plants. We have also reviewed different web resources related to alkaloids and secondary metabolic pathway databases such as KEGG. 

It is interesting to note that secondary metabolites are biosynthesised essentially from a handful of primary metabolites a-amino acids, acetyl-coenzyme A, mevalonic acid, and intermediates of the shikimic acid pathway. It is these starting points for the elaboration of secondary metabolites which allow their classification, and also their discussion as discrete groups (Chapters 3 to 7). In the remainder of this chapter various aspects of biosynthesis of general importance to the discussion in Chapter 3 and succeeding chapters is reviewed. The first examples of primary and secondary metabolite biosynthesis will be found in Sections 1.1.2 and 1.1.3. Chapter 2 is devoted to a brief discourse on the various techniques used in studying the biosynthesis of secondary metabolites. 

Another major nitrogenous constituent in trees is chlorophyll, but this is essentially absent from woody tissues. The traces of nitrogen-containing compounds in woody tissues often represent intermediary metabolites and translocated forms (Sect. 5.1), and compounds more typical of end-products of metabolism such as the alkaloids (Sect. 5.2). Alkaloids originate from acetate-malonate pathway, the mevalonate pathway, and various amino acid pathways. 

A rather limited collection of simple precursor molecules is sufficient to provide for the biosynthesis of virtually any cellular constituent, be it protein, nucleic acid, lipid, or polysaccharide. All of these substances are constructed from appropriate building blocks via the pathways of anabolism. In turn, the building blocks (amino acids, nucleotides, sugars, and fatty acids) can be generated from metabolites in the cell. For example, amino acids can be formed by amination of the corresponding a-keto acid carbon skeletons, and pyruvate can be converted to hexoses for polysaccharide biosynthesis. 

The citric acid cycle is not only a pathway for oxidation of two-carbon units—it is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids. It also provides the substtates for amino acid synthesis by transamination, as well as for gluconeogenesis and fatty acid synthesis. Because it fimctions in both oxidative and synthetic processes, it is amphibolic (Figure 16—4). 

The series of molecular events responsible for the uptake process constitutes the endocytic pathway, which enables cells to internalize macromolecules from the cell exterior, forming an endosome. The endosome is an intermediate organelle that serves as an essential component for many receptor-mediated signaling pathways and as a transport vector for eventual delivery to a specialized organelle known as the lysosome. Once in the lysosomal lumen, digestive enzymes provide essential metabolites from these macromolecules (i.e. free amino acids and lipids) directly to the cytosol for their use. 

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... 

Two additional types of methyltransferase domains have been identified in NRPSs. Yersiniabactin synthetase contains a carbon-MT domain within a Cy-MT-PCP-TE module. This domain methylates at the a-carbon of an intermediate thiazoline ring. The melithiazol synthetase utilizes an MT domain in trans to form a methyl ester at the C-terminus of the natural product. Recent in silica analysis of MT domains from secondary metabolite biosynthetic pathways has revealed the boundaries of these domains and suggests that they are typically approximately 200 amino acids in length, much shorter than previously thought. The results of this study by Mohanty and coworkers allow for the accurate prediction of N-, C-, or 0-MT activity through sequence analysis. " ... 

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