C-terminal tetrapeptide

H-Tyr-D-Ala-Pile-Asp-Val-Val-Gly-NH2 (D-Ala -deltorpliiu I) and H-Tyr-D-Ala-Plie-Glu-Val-Val-Gly-NH2 (D-Ala -deltorpliiu II) display greater 5-selectivity than DPDPE owiag to their higher 5-receptor affinity (96). These compounds both contain the same N-terminal tripeptide sequence as the. -selective dermorphins, which underscores the importance of the C-terminal tetrapeptide sequence in conferring 5-selectivity. 

Other putative flp genes were identified using search strings comprising C-terminal tetrapeptides of known FaRPs plus a C-terminal G (amide donor) residue in searches of the C. elegans BLAST server, wormpep 17. 

PDI contains a C-terminal tetrapeptide sequence known as the endoplasmic retention signal, KDEL. This anchor mediates the interaction between plasma membrane and membranes of the Golgi apparatus via a KDEL receptor. The PDI KDEL receptor complex is recycled back into the endoplasmic reticulum (Xiao et al., 1999). It is thought that a saturation of the retention mechanism results in the secretion of PDI which is deposited on the cell membrane and stabilized by electrostatic interactions (Terada et al, 1995). The secreted PDI is termed cell surface PDI (csPDI)... 

The mechanisms of ER protein sorting are relatively well known (Teas-dale and Jackson, 1996). Most, if not all, soluble ER proteins have a well-conserved C-terminal tetrapeptide, KDEL ( HDEL for yeasts) in addition to a cleavable N-terminal signal peptide. A small set of membrane proteins also has this signal at the C terminus. This signal... 

Prenylated proteins have characteristic C-terminal sequences. For example, the three allelic Ras proteins (H-Ras, K-Ras, and N-Ras) expressed in mammalian tissues contain a C-terminal tetrapeptide which begins with cysteine, and ends with either methionine or serine. This part of the molecule is referred to as the CaaX box where C = cysteine, a = an aliphatic amino acid, and X = a prenylation specificity residue. The first step in the posttranslational processing of Ras proteins utilizes FTase and farnesyl diphosphate (FPP) to covalently attach a farnesyl group to the cysteine thiol of the CaaX box. While subsequent processing events involve proteolytic removal of the aaX tripeptide and methylation of the resulting C-termi-nal carboxylate group, only the farnesyl modification is required for mutant Ras proteins to associate with the cell membrane and transform a cell.2-6... 

The high delta-selectivity of D-Ala-deltorphins can be attributed to their C-terminal tetrapeptide sequence in which the anionic residue plays an important role. Elimination of the charge at the fourth position normally results in opiates that have similar delta and mu affinity and generally lack selectivity. Substitution of Gly in the fourth position would permit D-Ala-... 

On the other hand, pseudopeptide analogs of the C-terminal tetrapeptide of gastrin U7b), such as (tert.butyloxycarbonyl)-L-tryptophyl-4 (CH2—NH)-L-leucyl-L-aspartyl-L-phenylalaninamide 51b, in which the amide linkage is replaced by the isosteric modification CH2—NH, are potent agonists of acid secretion. 

In a reversed approach, N -Ras lipidated peptides were synthesized in solution via an Sjv2 displacement of bromoalanine containing hexapeptides with thiopalmitic acid and farnesylmer-captane as nucleophiles (26). The synthetic route started with the dipeptides and tetrapeptides A(Br)M and GLPA(Br), both incorporating bromoalanine. After farnesylation of the C-terminal tetrapeptide, it was coupled to the N -Alloc protected dipeptide. This farnesylated hexapeptide was then treated with thiopalmitic acid for flnal pahnitoylation. 

With respect to the advantage of using a protein rather than a synthetic polypeptide as a carrier, we can refer to Jaffe et who showed that an active fragment of gastrin, its C-terminal tetrapeptide amide, was antigenic when covalently attached to serum protein carriers but not when linked to poly(L-lysine) or to poly(L-glutamic acid). Walker et al. in 1973 made similar comparisons with steroid conjugates and obtained the same result, i.e., bovine serum albumin was a better carrier than poly(L-lysine). (But also see below. 

Prominent peaks corresponding to the N-terminal sequences 1-5 and 5-9 (irrespective of what their masses may indicate) show that Ser or Thr is likely to be present somewhere central in the sequence, since these are sites of easiest hydrolysis (Figure 4.11). Five pairs of peaks that added up to [M + FI]+ were found Arg FI+ and [2-9] (1-2) and [3-9] (1-3) and [4-9] (1-4) and [5-9] and (1-5) and [6-9], (Flere (X - Y) represents a positive ion formed by cleavage of a peptide bond, in such a way that the positive charge is on the A-terminal side of the cleavage point (C in Scheme 4.2) [X - Y] represents a C-terminal-side positive ion formed by fragmentation made y in Scheme 4.4). Therefore Arg—Pro—Pro—Gly—Phe—... is indicated from the mass differences. Matching the differences between [6-9] and [7-9] and [7-9] and [8-9] indicated that the C-terminal tetrapeptide sequence is —Ser—Pro—[8-9],... 

Fig. 1. The C-terminal structure of members of the gastrin family. The members are characterized by the same active site, i.e., the C-terminal tetrapeptide amide (shown in the internal box). Another characteristic is an O-sulfated tyrosyl residue close to the active site. In gastrin peptides the sulfated tyrosyl residue is located in position six (as counted from the C-terminus) in cholecystokinins it is position seven. The frog skin peptide caerulein therefore acts as cholecystokinin in mammals. Cionin is a neuropeptide from the protochordate, Ciona intestinalis. Cionin is unique in having O-sulfated tyrosyl residues in both positions six and seven. The cionin structure is therefore likely to correspond to that of the common ancestor of gastrin and cholecystokinin.

M4. Morley, J. S., Tracy, H. J., and Gregory, R. A., Function relationships in the active C-terminal tetrapeptide sequence of gastrin. Nature (London) 207, 1356-1359 (1965). 

Modified peptides containing reduced amide bonds, i. e. compounds L-731,735 and L-731,734, were designed by the Merck groups [7] (Fig. 1), and have shown to be potent inhibitors of partially purified FPTase, the homoserine compound being the more active inhibitor in vitro. Subsequent inhibitors include L-739,749 and L-739,750 [8] and even trancated versions of the C-terminal tetrapeptide CAAX motif were prepared which do not have a C-terminal carboxyl... 

Aspartame (APM), H-Asp-Phe-OMe, a nonnutritive high-intensity sweetener. APM is about 200 times sweeter than sucrose. It was first approved by the FDA in 1981 as a table-top sweetener and an additive, for example, in dry-based beverages, dry cereals, chewing gum, gelatins, puddings, instant coffee, and tea. APM was discovered accidentally during the recrystaUization of an intermediate of the synthesis of the C-terminal tetrapeptide of gastrin at Searle Co. For commercial synthesis, various... 

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