Natural products pathways

The term "structural genomics" is used to describe how the primary sequence of amino acids in a protein relates to the function of that protein. Currently, the core of structural genomics is protein structure determination, primarily by X-ray crystallography, and the design of computer programs to predict protein fold structures for new proteins based on their amino acid sequences and structural principles derived from those proteins whose 3-dimensional structures have been determined. Plant natural product pathways are a unique source of information for the structural biologist in view of the almost endless catalytic diversity encountered in the various pathway enzymes, but based on a finite number of reaction types. Plants are combinatorial chemists par excellence, and understanding the principles that relate enzyme structure to function will open up unlimited possibilities for the... 

Understanding the molecular genetics of plant natural product pathways facilitates the engineering of these pathways for plant improvement and human benefit (see Chapter by Halkier et al). This chapter focuses attention on the need to start applying genomics technology to exotic species for development of biotech crops with novel natural products and with improved pest resistance and increased nutritional value. 

Dixon RA (2005a) Engineering of plant natural product pathways. Curr Opin Plant Biol... 

As another example, from the Schmidt and Schultz laboratories, in a route amenable to smaller macrocyclic molecules with less peptidic character, the ribosomal peptide natural product pathway for cyanobactins was manipulated in a manner that permitted the incorporation of multiple non-proteinogenic amino acids. This produced structures, 307 (Figure 11.28) as a representative example, with rings as small as 18-membered and possessing more drug-like features. 

Phenolic compounds are commonplace natural products Figure 24 2 presents a sampling of some naturally occurring phenols Phenolic natural products can arise by a number of different biosynthetic pathways In animals aromatic rings are hydroxylated by way of arene oxide intermediates formed by the enzyme catalyzed reaction between an aromatic ring and molecular oxygen... 

Application of NMR spectroscopy to heterocyclic chemistry has developed very rapidly during the past 15 years, and the technique is now used almost as routinely as H NMR spectroscopy. There are four main areas of application of interest to the heterocyclic chemist (i) elucidation of structure, where the method can be particularly valuable for complex natural products such as alkaloids and carbohydrate antibiotics (ii) stereochemical studies, especially conformational analysis of saturated heterocyclic systems (iii) the correlation of various theoretical aspects of structure and electronic distribution with chemical shifts, coupling constants and other NMR derived parameters and (iv) the unravelling of biosynthetic pathways to natural products, where, in contrast to related studies with " C-labelled precursors, stepwise degradation of the secondary metabolite is usually unnecessary. 

The underlying assumption driving marine natural products chemistry research is that secondary metabolites produced by marine plants, animals, and microorganisms will be substantially different from those found in traditional terrestrial sources simply because marine life forms are very different from terrestrial life forms and the habitats which they occupy present very different physiological and ecological challenges. The expectation is that marine organisms will utilize completely unique biosynthetic pathways or exploit unique variations on well established pathways. The marine natural products chemistry research conducted to date has provided many examples that support these expectations. 

The stereochemical outcome of the reaction is determined by the geometry of the transition state for the Claisen rearrangement a chairlike conformation is preferred,and it proceeds strictly by an intramolecular pathway. It is therefore possible to predict the stereochemical course of the reaction, and thus the configuration of the stereogenic centers to be generated. This potential can be used for the planning of stereoselective syntheses e.g the synthesis of natural products. 

Natural product synthesis poses the challenge to consider and develop new pathways of structural transformation. Natural products as targets for synthetic research possess a special fertility in this regard, because the structural channels of biosynthesis are not necessarily the conduits of organic synthesis. A. Eschenmoser19... 

Hirsutene (1) and A9(,2,-capnellcnc (2), the parent members of the hirsutane and capnellane families of triquinane natural products, respectively, are isomeric molecules that possess four contiguous stereogenic centers, one of which is quaternary. The linearly fused tricyclopentanoid frameworks of compounds 1 and 2 are obviously very similar, differing only with respect to the positions of the three methyl groups. An asset of Curran s tandem radical cyclization strategy is that it provides a unified entry into a wide variety of linear condensed cyclopentanoid natural products. As a result, it is possible to devise nearly identical retrosynthetic pathways for these structurally related molecules. 

Scheme 10.14 Partial biosynthetic pathway leading to sterol natural products.

Sulphones occur relatively rarely as natural products. Thus there is no reported specific enzymatic system for the formation of sulphones. However, there are several well-understood pathways for the oxidation of sulphides to sulphoxides and these do lead to sulphones in some cases. 

KONG A N, YU R, CHEN c, MANDLEKAR s and PRIMIANO T (2000) Signal transduction events elicited by natural products role of M APK and caspase pathways in homeostatic response and induction of apoptosis . Arch Pharm Res, 23 1-16. 

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