C-terminal amidation

The group of peptides known as tachykinins include substance P, substance K or neurokinin A, and neuromedin K, ie, neurokinin B, as well as a number of nonmammalian peptides. All members of this family contain the conserved carboxy-terrninal sequence Phe-X-Gly-Leu-Met-NH2, where X is an aromatic, ie, Phe or Tyr, or branched aliphatic, eg, Val or lie, amino acid. In general, this C-terminal sequence is cmcial for tachykinin activity (33) in fact, both the methionineamide and the C-terminal amide are cmcial for activity. The nature of the X residue in this sequence determines pharmacological identity (34,35) thus the substance P group contains an aromatic residue in this position, while the substance K group contains an aliphatic residue (33). 

Galanin is a biologically active neuropeptide containing 30 amino acids and an unamidated C-terminus in human galanin from other species contains 29 amino acids and C-terminal amidation. 

Functionalized supports with amino groups such as benzhydrylamine (BHA) 26 [32] and 4-methylbenzhydrylamine (MBHA) 3 [3] provided C-terminal amides upon HF cleavage (Fig. 2). Polyalkoxyaminobenzyl and alkoxydiphenylamino resins such as PAL (5-(4-aminomethyl-3,5-dime-... 

Ajayaghosh A, Pillai YNR. Solid-phase synthesis and C-terminal amidation of peptides using a photolabile o-nitrobenzhydrylaminopolystyrene support. Tetrahedron Lett 1995 36 777-780. 

Johnson, T. W. Kostic, N. M. Steric effect on the rate of hydrolysis by Pd(II) complexes of the C-terminal amide bond in a series of dipeptides Ac-Met-AA, American Chemical Society, Washington, D. C. In Book of Abstracts, 212th ACS National Meeting, Orlando, FL, August 25-29, 1996. 

Fig. 6 Sequence alignment of the deduced amino acid sequence from the identified cDNA encoding PBAN and related peptides from Helicoverpa zea and Bombyx mori. The putatively expressed peptides are shown in boxes. The conserved amino acids are underlined in the B. mori sequence. Putative proteolytic posttranslational processing sites are shown in bold with glycine contributing the C-terminal amide. Sequences of PBAN-like peptides are also shown in Table 1. GenBank accession numbers H. zea - PI 1159 and B. mori - BAA05971...

Bernatowicz MS, Daniels SB, Koster H (1989) A comparison of acid-labile linkage agents for the synthesis of peptide C-terminal amides. Tetrahedron Lett 30 4645-4648... 

Two approaches for solid-phase chemical ligation have been described. Canne et al. have developed an elegant system that utilizes an oxime forming ligation to attach the first peptide to the resin, a selectively cleavable ester link to remove the peptide from the resin as a C-terminal carboxylic acid, and the Acm group to protect the N-terminal cysteine residue)311 A complementary approach has been developed by Brik et al. that utilizes native chemical ligation to attach the first peptide to the solid support, a safety-catch acid labile linker to remove the final polypeptide from the support as a C-terminal amide and either Acm or Msc group for N-terminal cysteine protection)32 ... 

Adrenomedullin (AM) was first discovered in human adrenal medullary pheochromocytoma tissue. It is a 52-amino acid peptide with a six-amino-acid ring and a C-terminal amidation sequence. Like CGRP, AM is a member of the calcitonin family of peptides. 

Addition of the lithium acetylide of tetrahydropyranyl-protected but-3-yn-l-ol 156 provided the racemic alcohol 157 (Scheme 34). The nitrogen was introduced through a Mitsunobu reaction, followed by oxidation of the primary alcohol to the carboxylic acid and a change of the phthaloyl protecting group to Boc protection. The latter reaction was necessary because hydrazinolysis of the C-terminal amide analogue of 159 did result in deeply red-colored mixtures, indicating that phthaloyl removal by this method should occur prior to peptide synthesis. 131 ... 

Peptide-resin assembly was performed by Fmoc solid-phase methodology. All peptide-amphiphiles were synthesized as C-terminal amides to prevent piperazine-2,5-dione formation. 62 Peptide-resins were characterized by Edman degradation sequence analysis as described previously for embedded (non-covalent) sequencing. 67 Peptide-resins were then lipidated with the appropriate (Cn)2-Glu-C2-OH tail to give the dialkyl peptide-amphiphile-resin. 

Method B Peptide Bond Formation in Solution Peptide-peptoid chains containing Gly-Pro-(iBu)Gly repeats were assembled by solid-phase methods, cleaved from the resin as N-terminal free amine and C-terminal amidated forms, and purified by RP-HPLC. The template KTA-(Gly-OH)3 (32) and free-amine peptide-peptoid chains were then coupled in soln using EDC and HOBt as the coupling reagents. The final products were separated by RP-HPLC yields 6-80%. Structures containing 1, 6, or 9 Gly-Pro-(iBu)Gly repeats were synthesized using this approach. 

The alkaline hydrolysis of the compounds (118)-(123) in 70% (v/v) dioxane-water at various temperatures has been investigated.101 Intramolecular catalysis by the neighbouring carbonyl group occurs in the alkaline hydrolysis of (118)-(121) and the alkaline hydrolysis of (122) and (123) is rapid owing to their lactone structures. The hydrolyses of C-terminal amides of a-amino acids was dealt with earlier.56 Also, the acid-catalysed cleavage of A-(2-aminophcnyI)phthalamic acid (82) was discussed earlier.72... 

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