Peptide natural product

Introduction Peptide-Based Natural Products Nonribosomal Peptide Natural Products The Canonical Enzymology of NRPS Modules Classes of Nonribosomal Peptide Synthetases... 

Multidomain synthetases can include specialized domains to modify the amino acids of peptide intermediates during chain elongation. The chemistry carried out by these domains introduces specific structural motifs, which are often important for biological activity, into the peptide natural product. A summary of additional NRPS enzyme chemistry is described below and illustrated in Figure 9. 

Frequently, after assembly of the peptide natural product by the NRPS, enzyme-catalyzed reactions impart additional functionality and structural elements. The reactions are very diverse and a thorough survey of the known enzymology is beyond the scope of this chapter, however, several recent review articles describe the various chemistries that are known. °... 

Lautru S, Deeth RJ, Bailey LM, Challis GL (2005) Discovery of a New Peptide Natural Product by Streptomyces coelicolor Genome Mining. Nature Chem Biol 1 65... 

Cyclic hexapeptides can be considered as the classical and the most prominent representatives among cyclic peptides. Natural products are numerous and widespread (see Scheme 11), e.g. segetalin A,[278] bouvardin/279280 RA-IIlJ281-283 or pneumocandin B0,[284 286] and this type of ring structure has frequently been used to stabilize conformational preferences of bioactive portions of larger peptides or even proteins. 

This volume focuses on extensions of peptide chemistry into the novel areas of template-conjugated peptides, helical arrays of polypeptides, dendrimers, and C-terminally modified peptides. The volume concludes with an overview of the classic syntheses of representative peptide natural products. 

Further aliphatic a-methyl-/ -amino acids, for example Amha 69, Admpa 70, and Amoa 73, have been found in peptidic natural products from marine animals and from cyanobacteria. Although dolastatin D 82 and dolastatin 17 83 have so far been obtained from sea hare isolates only, these peptides should now be considered to be of cyanobacterial origin, as indicated by their p-amino acid substructures, i.e. Amba 67 and Aoya 72. 

CsA as well as FK506 (18), a completely unrelated non-peptide natural product with similar activity to CsA, have resisted many efforts to improve them as drugs. However, the X-ray structures of the ternary complex may help to stimulate the design of superior immunosuppressants. 

Both FASs and PKSs are structurally and mechanistically related to another class of multifunctional enzymes called nonribosomal peptide synthetases. These enzymes activate amino acids as aminoacyl thioesters, which subsequently undergo condensation via formation of amide bonds, leading to biosynthesis of peptide natural products. Enzyme-bound phosphopantetheinyl groups also play a central role in the peptide assembly process. For comparison, the genetics and biochemistry of peptide synthetases are also briefly reviewed here. 

Lautra S, Deeth RJ, Bailey LM, ChalUs GL. Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nat. Chem. Biol. 2005 1 265-269. 

The total synthesis of peptide natural products, especially hormones and neurotransmitters, is a highly developed area of organic synthesis. Although peptides with numerous 3-substituted amino acids, highly constrained peptides, highly hydrophobic... 

The realization that a non-peptide natural product was mimickingthe action of a natural peptide effector led Farmer to postulate that other non-peptide structures might be found that would mimic other peptide effectors (7). His concept of peptide mimetic," which later was called "peptidomimetic," proposed that... 

For some years (1987-1992), thermospray LC-MS was the most widely apphed LC-MS interface. It has demonstrated its potential in qualitative as well as quantitative analysis in mat r application areas, such as drugs and metabolites, conjugates, nucleosides, peptides, natural products, pesticides. A few examples are given below. 

An enzyme has been isolated from the FK520 producer which is believed to be the key one responsible for inserting pipecolic acid into the macrocycle [114]. It is reported to be dimeric and activates pipecohc acid and several structural analogues in an ATP-dependent reaction to give an enzyme-bound amino-acyl adenylate. There is evidence that this then reacts to form a thioester linkage to the enzyme. This mechanism of activation is the same as that found in the non-ribosomal biosynthesis of peptide natural products such as gramicidin [112]. 

Figure 9 Novel ribosomally biosynthesized peptide natural products discovered by genome mining.

Given the enormous library of peptidic natural products found in the venom of cone snails, the discovery of conopeptides is a task that will occupy researchers for decades to come. Only a small fraction of the existing Conus peptides library has been characterized nevertheless, new peptidic arrangements with novel bioactivities are constantly described in the literature. 

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