Biosynthesis of peptide

Synthesis and biosynthesis of peptides and proteins reqnires the combination of amino acids via amide bonds. We have seen eariier that the chemicai reaction of amines and acids to prodnce a simpie amide is severeiy hindered by initiai sait formation, and that... 

In marked contrast to the ribosomal biosynthesis of peptides and proteins where a biological production line interprets the genetic code of mRNA, many natural peptides are known to be synthesized by a... 

The biosynthesis of peptide hormones and proteohormones, as well as their secretion, is controlled by higher-order regulatory systems (see p. 372). Calcium ions are among the substances involved in this regulation as second messengers an increase in calcium ions stimulates synthesis and secretion. 

A strong influence on the biosynthesis of peptide metabolites exerted by exogenously supplied amino-acid precursors has been observed earlier both in prokaryotes and eukaryotes [26]. In several cases, enhanced yields of a desired metabolite can be obtained and a replacement of certain constitutional building elements by other amino acids may occur [27, 28]. 

Rajendran N and Marahiel MA (1999) Multifunctional peptide synthetases required for nonribosomal biosynthesis of peptide antibiotics. Comprehensive Natural Products Chemistry, Vol 4. Elsevier, Amsterdam, pp 195-200. 

H Kleinkauf, H von Dohren. Nonribosomal biosynthesis of peptide antibiotics. Eur J Biochem 192 1-15, 1990. 

PB Loder, EP Abraham. Biosynthesis of peptides containing alpha-aminoadipic acid and cysteine in extracts of a Cephalosporium sp. Biochem J 123 477-482, 1971. 

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. 

T, Peters C, Bogyo M. Cathepsin L and Arg/Lys aminopepti-dase a distinct prohormone processing pathway for the biosynthesis of peptide neurotransmitters and hormones. Biol. Chem. 2004 385 473-480. 

Proteins are linear polymers formed by linking the a -carboxyl group of one amino acid to the a -amino group of another amino acid with a peptide bond (also called an amide bond). The formation of a dipeptide from two amino acids is accompanied by the loss of a water molecule (Figure 3.18). The equilibrium of this reaction lies on the side of hydrolysis rather than synthesis. Hence, the biosynthesis of peptide bonds requires an input of free energy. Nonetheless, peptide bonds are quite stable kinetically the lifetime of a peptide bond in aqueous solution in the absence of a catalyst approaches 1000 years. 

Peptidyl-gly cine monooxygenase Amidate carboxyl end of peptide Biosynthesis of peptide... 

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]. 

Even in the case it should be possible to separate ribozyme activity from the ribosome or to isolate an in vitro selected ribozyme that can catalyze the same type of peptide bond formation as a ribosome, however such a biocatalyst seem does not to be suitable for simple practical use rather than using a chemical coupling reagent. In principle, this conclusion is also valid for the nonribosomal poly- or multienzymes which are involved in the biosynthesis of peptide antibiotics[7Z. Up to now, they have only found application in the synthesis field of cyclosporin, gramicidin S, special P-lactam antibiotics and analogs. 

In non-i ibosomal biosynthesis of peptide antibiotics by multimodular synthetases, amino acid monomers ai e activated by the adenylation domains of the synthetase and loaded onto the adjacent canier protein domains as thioesters, then the formation of peptide bonds and translocation of the growing chain are effected by the synthetase s condensation domains. Whether the condensation domains have any editing function has been unknown. Synthesis of aminoacyl-CoA molecules and direct enzymatic transfer of aminoacyl-phospho-pantetheine to the caiiier domains allow the adenylation domain editing function to be bypassed. This method was used to demonstrate that the first condensation domain of tyroci-dine synthetase shows low selectivity at the donor residue (D-phenyManine) and higher selectivity at the acceptor residue (L-proline) in the formation of the chain-initiating D-Phe-L-Pro dipeptidyl-enzyme intermediate. 

The biosynthesis of peptide antibiotics is complicate. Their mechanisms of formation have been the subject of detailed investigations during the last years (Ref. 21,... 

Kurahashi K. Biosynthesis of peptide antibiotics. Corcoran JW. ed. Antibiotics, Vol. 4. Biosynthesis. Berlin Springer. 1981 325-352. 

Simon RD. The biosynthesis of rnuiti-L-arginyi-polytL-aspartic acid) in the 6lamentous bacterium Aruihami cyi ndrtrn. Biochim Btophys Acta 1976 422 407-418. von Dohren H, Kleinkauf H. Research on nonribosomal systems Biosynthesis of peptide antihiotics. Kleinkauf H, von Dohren H, Jaenicke L. eds. The Roots of Modern Biochemistry Frit Lipmann s Squiggle and Its Consequences. Berlin Walter He Griiyter 1988 355-367. 

Kleinkauf H, von Dohren H. A survey of enzymatic biosynthesis of peptide antibiotics. Trends in Antibiotic Research. Japan Antibiotics Res. Ass. 1982 220-232. 

Kleinkauf H, von Dohren H. Cell-free biosynthesis of peptide antibiocics. Vezina C, Singh K, eds. Advances in Biotechnology, Vol. 3. Oxfotd Pergamon Press, 1981 83-88. 

Kurahashi K. Biosynthesis of small peptides. Annu Rev Biochem 1974 43 445-459. Kleinkauf H, von Dohren H. Biosynthesis of peptide antibiotics. Annu Rev Microbiol 1990 41 59-289. 

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