Substrate specificities of tissue kallikrein and T-kininogenase: their possible role in kininogen processing.
Abstract: The present studies demonstrate the importance of subsite interactions in determining the cleavage specificities of kallikrein gene family proteinases. The effect of substrate amino acid residues in positions P3-P'3 on the catalytic efficiency of tissue kallikreins (rat, pig, and horse) and T-kininogenase was studied using peptidyl-pNA and intramolecularly quenched fluorogenic peptides as substrates. Kinetic analyses show the different effects of D-amino acid residues at P3, Pro at P'2, and Arg at either P'1 or P'3 on the hydrolysis of substrates by tissue kallikreins from rat and from horse or pig. T-Kininogenase was shown to differ from tissue kallikrein in its interactions at subsites S2, S'1, and S'2. As a result of these differences, Abz-FRSR-EDDnp with Arg at P'2 is a good substrate for tissue kallikreins from horse, pig, and rat but not for T-kininogenase. Abz-FRRP-EDDnp and Abz-FRAPR-EDDnp with Pro at P'2 (rat high molecular weight kininogen sequence) are susceptible to rat tissue kallikrein but not to tissue kallikreins from horse and pig. Arg at P'3 increased the susceptibility of the Arg-Ala bond to rat tissue kallikrein. These data explain the release of bradykinin by rat tissue kallikrein and of kallidin by tissue kallikreins from other animal species. Abz-FRLV-EDDnp and Abz-FRLVR-EDDnp (T-kininogen sequence) are good substrates for T-kininogenase but not for tissue kallikrein. Arg at the leaving group (at either P'1, P'2, or P'3) lowers the Km values of T-kininogenase while Val at P'2 increases its kcat values.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Date: 1992-06-02 PubMed ID: 1599922DOI: 10.1021/bi00136a008Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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The research article focuses on exploring the distinct functionalities and substrate specificities of kallikrein gene family proteinases, namely tissue kallikreins from different animals, and T-kininogenase, which are crucial in the kininogen processing, a biological function relevant to blood pressure regulation and inflammation response.
Key Specificities and Functions
- The research primarily studied the impact of substrate amino acid residues located at positions P3-P’3 on the catalytic efficiency of tissue kallikreins that originate from rat, pig, and horse, alongside T-kininogenase.
- The researchers utilized peptidyl-pNA and intramolecularly quenched fluorogenic peptides as the substrates for this study.
- The kinetic analyses demonstrated variant impacts of D-amino acid residues at the P3 position, Proline (Pro) at the P’2 position, and Arginine (Arg) at either the P’1 or P’3 position on substrate hydrolysis by tissue kallikreins from different animals.
T-Kininogenase versus Tissue Kallikrein
- The study also showcased fundamental differences between T-kininogenase and tissue kallikrein in terms of their interactions at subsites S’2, S2, and S’1, highlighting distinct cleavage specificities.
- For instance, the peptide Abz-FRSR-EDDnp with Arg at the P’2 position proves to be a favorable substrate for tissue kallikrien from horse, pig, and rat but not for T-kininogenase.
- In contrast, peptides Abz-FRLV-EDDnp and Abz-FRLVR-EDDnp, affiliated with T-kininogen sequence, were excellent substrates for T-kininogenase instead of tissue kallikrein.
Implications for Kininogen Processing
- Data derived from the study explain how tissue kallikreins and T-kininogenase contribute differently to the release of bradykinin and kallidin, both of which are bioactive peptides produced during the kininogen processing and play significant roles in biological activities like blood pressure regulation and inflammatory responses.
- The presence of Arginine at the leaving group (either at P’1, P’2, or P’3) decreases the Km values of T-kininogenase, indicating increased enzyme-substrate affinity, whereas Valine at P’2 positions amplifies its kcat values, thus enhancing enzyme turnover rate.
Cite This Article
APA
Chagas JR, Hirata IY, Juliano MA, Xiong W, Wang C, Chao J, Juliano L, Prado ES.
(1992).
Substrate specificities of tissue kallikrein and T-kininogenase: their possible role in kininogen processing.
Biochemistry, 31(21), 4969-4974.
https://doi.org/10.1021/bi00136a008 Publication
Researcher Affiliations
- Department of Biophysics, Escola Paulista de Medicina, Sao Paulo, Brazil.
MeSH Terms
- Amino Acid Sequence
- Animals
- Horses
- Humans
- Hydrolysis
- Kallikreins / metabolism
- Kinetics
- Kininogens / metabolism
- Protein Processing, Post-Translational
- Rats
- Substrate Specificity
- Swine
- Tissue Kallikreins
Grant Funding
- HL29397 / NHLBI NIH HHS
Citations
This article has been cited 11 times.- Gao L, Chao L, Chao J. A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: activation of proteinase-activated receptor 1 and epidermal growth factor receptor. Exp Cell Res 2010 Feb 1;316(3):376-89.
- Chao J, Yin H, Gao L, Hagiwara M, Shen B, Yang ZR, Chao L. Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation. Hypertension 2008 Oct;52(4):715-20.
- Fogaça SE, Melo RL, Pimenta DC, Hosoi K, Juliano L, Juliano MA. Differences in substrate and inhibitor sequence specificity of human, mouse and rat tissue kallikreins. Biochem J 2004 Jun 15;380(Pt 3):775-81.
- Souza DG, Pinho V, Pesquero JL, Lomez ES, Poole S, Juliano L, Correa A Jr, de A Castro MS, Teixeira MM. Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury. Br J Pharmacol 2003 May;139(1):129-39.
- Pimenta DC, Chao J, Chao L, Juliano MA, Juliano L. Specificity of human tissue kallikrein towards substrates containing Phe-Phe pair of amino acids. Biochem J 1999 Apr 15;339 ( Pt 2)(Pt 2):473-9.
- Katz BA, Liu B, Barnes M, Springman EB. Crystal structure of recombinant human tissue kallikrein at 2.0 A resolution. Protein Sci 1998 Apr;7(4):875-85.
- Pimenta DC, Juliano MA, Juliano L. Hydrolysis of somatostatin by human tissue kallikrein after the amino acid pair phe-Phe. Biochem J 1997 Oct 1;327 ( Pt 1)(Pt 1):27-30.
- Portaro FC, Cezari MH, Juliano MA, Juliano L, Walmsley AR, Prado ES. Design of kallidin-releasing tissue kallikrein inhibitors based on the specificities of the enzyme's binding subsites. Biochem J 1997 Apr 1;323 ( Pt 1)(Pt 1):167-71.
- Ma JX, Chao L, Zhou G, Chao J. Expression and characterization of rat kallikrein-binding protein in Escherichia coli. Biochem J 1993 Jun 15;292 ( Pt 3)(Pt 3):825-32.
- Chagas JR, Portaro FC, Hirata IY, Almeida PC, Juliano MA, Juliano L, Prado ES. Determinants of the unusual cleavage specificity of lysyl-bradykinin-releasing kallikreins. Biochem J 1995 Feb 15;306 ( Pt 1)(Pt 1):63-9.
- Del Nery E, Chagas JR, Juliano MA, Prado ES, Juliano L. Evaluation of the extent of the binding site in human tissue kallikrein by synthetic substrates with sequences of human kininogen fragments. Biochem J 1995 Nov 15;312 ( Pt 1)(Pt 1):233-8.
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