On the activation of trypsinogen. A study of peptide models related to the N-terminal sequence of the zymogen

Delaage, M; Desnuelle, P.; Lazdunski, Michel; Bricas, E.; Šavrda, J.

doi:10.1016/0006-291x(67)90593-1

Cited by 31 publications

(18 citation statements)

References 9 publications

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“…When analyzed using model peptides or recombinant trypsinogens, all three activation peptide mutations significantly increased autoactivation of cationic trypsinogen; particularly the D22G and K23R mutations, which lie closer to the trypsinogen activation site Lys23-Ile24 [Teich et al, 2000b;Chen et al, 2003a]. These data are consistent with earlier peptide studies showing that neutralization of any of the four aspartate residues in the activation peptide increases autoactivation of trypsinogen [Delaage et al, 1967;Abita et al, 1969;Radhakrishnan et al, 1969]. This notion was also confirmed recently by Alascanning mutagenesis of the tetra-Asp motif in human cationic trypsinogen .…”

Section: Mutations Of the Trypsinogen Activation Peptidesupporting

confidence: 80%

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

et al. 2006

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Section: Mutations Of the Trypsinogen Activation Peptidesupporting

confidence: 80%

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

et al. 2006

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“…Ca2+ has a negative effect on trypsinogen activation by aspergillopeptidase A. At (Table 3) have been published previously [15]. They are compared in Table 3 with the data concerning the nonapeptide Val-(Asp),-Lys-Ile-Val-Gly.…”

Section: The Activation Of Trypsinogenmentioning

confidence: 98%

“…They are compared in Table 3 with the data concerning the nonapeptide Val-(Asp),-Lys-Ile-Val-Gly. For all peptides K , are true equilibrium constants [15]. The dissociat,ion constant of trypsin-substrate complexes formed with peptides 1, 2, 3, and 4 which contain between 0 and 2 aspartyl residues, is largely independent of the number of these amino-acids.…”

Section: The Activation Of Trypsinogenmentioning

confidence: 99%

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The Mechanism of Activation of Trypsinogen. The Role of the Four N-Terminal Aspartyl Residues

et al. 1969

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1-This paper examines in detail the activation of bovine and porcine trypsinogens and of bovine chymotrypsinogens A and B by trypsin and aspergillopeptidase A. Kinetic data have also been obtained ( K , and kcat) for the hydrolysis catalyzed by these proteases of several model peptides with sequences related to the N-terminal sequence of bovine trypsinogen.2. The N-terminal sequence of (aspartyl), residues is not necessary for the recognition of the strategic Lys-Ile bond of trypsinogen.3. We have shown previously that there are two binding sites for Ca2 i-on trypsinogen. One of these sites is constituted by the 2 aspartyl residues which are the nearest neighbours of the important Lys-Ile bond. The saturation of the site by Ca2+ improves the formation of the trypsinogen-trypsin complex; Ca2+ has no effcct on the rate of decomposition of t,his complex. I n the activations by aspergillopeptidase A, trypsinogen is a much better substrate than chymotrypsinogen. The implications of this exceptionally slow hydrolysis of the Lys-Ile bond are discussed. The problem of the formation of inert proteins in particular appears to be closely related to the very poor quality of this bond as a substrate for trypsin. A mechanism is given for the formation of inert proteins ; a similar mechanism also explains the degradative autolysis of trypsin. 4.The sequence of trypsinogen has been elucidated recently [l, 21 and the covalent changes occurring in the course of the activation of the zymogen have been known for several years [3]. However, there are still two main problems related to the mechanism of the transformation into trypsin. The first one concerns the nature of the morphological changes occurring in the course of the activation which result in the correct positioning of the different elements of the active center. This problem has been studied and is still being studied in this laboratory using both physicochemical and chemical approaches [4-71. The second problem, which is the subject of this paper, is related Unusual Abbreviations. BzArgOEt, a-N-benzoyl-xuginine ethyl ester; AcTyrOEt, N-acetyl-L-tyrosine ethyl ester, to the effect of the unusual sequence Asp-Asp-AspAsp, just preceding the Lys-Ile bond which is hydrolyzed as the first step in the activation process.This sequence has been found in bovine [S, 91, porcine [lo] and ovine [ll] trypsinogens. The peptide sequences liberated in the course of the activation are Val-(Asp),-Lys [S, 9,111 and Phe-Pro-Thr-(Asp),-Lys [10,11]. The kinetic data which relate the effect of a sequence of four aspartyl residues on the rate of hydrolysis of an adjacent trypsin sensitive bond in model peptides, to the mode of activation of bovine and porcine trypsinogens, and of bovine chymotrypsinogens A and B, constitute as far as we are aware, tfhe first detailed study of the proteolytic action of trypsin (and also of aspergillopeptidase A) on a specific bond in large peptides and proteins. Up

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“…Subsequently, tryptic digestion of synthetic model peptides indicated that Asp residues are not favored in the P2-P5 positions (11,12). More recently, biochemical characterization of pancreatitis-associated activation peptide mutations in human cationic trypsinogen confirmed the importance of Asp residues in the activation peptide in autoactivation control.…”

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confidence: 99%

The Tetra-aspartate Motif in the Activation Peptide of Human Cationic Trypsinogen Is Essential for Autoactivation Control but Not for Enteropeptidase Recognition

Nemoda

Sahin–Tóth

2005

Journal of Biological Chemistry

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The activation peptide of vertebrate trypsinogens contains a highly conserved tetra-aspartate sequence (Asp 19 -22 in humans) preceding the Lys-Ile scissile bond. A large body of research has defined the primary role of this acidic motif as a specific recognition site for enteropeptidase, the physiological activator of trypsinogen. In addition, the acidic stretch was shown to contribute to the suppression of autoactivation. In the present study, we determined the relative importance of these two activation peptide functions in human cationic trypsinogen. Individual Ala replacements of Asp 19 -22 had minimal or no effect on trypsinogen activation catalyzed by human enteropeptidase. Strikingly, a tetra-Ala 19 -22 trypsinogen mutant devoid of acidic residues in the activation peptide was still a highly specific substrate for human, but not for bovine, enteropeptidase. In contrast, an intact Asp

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On the activation of trypsinogen. A study of peptide models related to the N-terminal sequence of the zymogen

Cited by 31 publications

References 9 publications

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

The Mechanism of Activation of Trypsinogen. The Role of the Four N-Terminal Aspartyl Residues

The Tetra-aspartate Motif in the Activation Peptide of Human Cationic Trypsinogen Is Essential for Autoactivation Control but Not for Enteropeptidase Recognition

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