Dipeptidyl peptidase 4
| Dipeptidyl peptidase 4 | ||
|---|---|---|
|
||
| Belt model according to PDB 1PFQ | ||
| Properties of human protein | ||
| Mass / length primary structure | 766/728 amino acids | |
| Secondary to quaternary structure | soluble / single pass type 2 membrane protein; Homodimer; Heterodimer | |
| Identifier | ||
| Gene names | DPP4 ; ADABP; ADCP2; CD26; DPPIV; TP103 | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 3.4.14.5 , serine protease | |
| MEROPS | S09.003 | |
| Response type | Hydrolysis, splits dipeptides from the N-terminal end of a peptide | |
| Substrate | Oligopeptides and also polypeptides (preferably peptides with proline residues in the P1 position) | |
| Products | shorter peptides + dipeptides | |
| Occurrence | ||
| Homology family | Dipeptidyl peptidase 4 | |
| Parent taxon | Creature | |
| Orthologue | ||
| human | House mouse | |
| Entrez | 1803 | 13482 |
| Ensemble | ENSG00000197635 | ENSMUSG00000035000 |
| UniProt | P27487 | P28843 |
| Refseq (mRNA) | NM_001935 | NM_001159543 |
| Refseq (protein) | NP_001926 | NP_001153015 |
| Gene locus | Chr 2: 161.99 - 162.07 Mb | Chr 2: 62.33 - 62.41 Mb |
| PubMed search | 1803 |
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The proteolytic enzyme dipeptidyl peptidase 4 (short forms: DPP 4 , also DPP IV , DP IV ) is assigned to the exopeptidases . It is a surface protein and splits off dipeptides at the N-terminus of a peptide . DPP4 is the receptor for MERS-CoV .
history
The enzyme was first described in 1966 by Hopsu-Havu and Glenner and named dipeptide naphthylamidase. Independently of this, the enzyme was rediscovered in 1974 by Schulz and Alfred Barth and named dipeptidyl peptidase IV [DP IV] as a result of various chemism studies.
Effects
The dipeptides are preferably split off if there is a proline or alanine residue in the second position in the amino acid sequence . However, if the third position of the amino acid sequence is a proline residue, the peptide is not attacked. Jaron (Israel) presented a number of biologically active peptides that can act as potential substrates for DP IV. They all have the N -terminal sequence AS-Pro-…. Some of these substances were tested experimentally and they could be confirmed as substrates of dipeptidyl peptidase 4. It turned out that their catalytic hydrolysis (cleavage) abolishes, diminishes or intensifies their biological effect or that a biological effect develops from an inactive precursor or that no cleavage by DP IV takes place. Here are a few examples:
GLP-1
The intestinal peptide hormone GLP-1 (7-39) is inactivated by DP IV. The breakdown product GLP-1 (9-39) acts as a functional GLP-1 receptor antagonist.
PYY
In contrast to GLP-1, PYY is activated by DP IV. The bioactive PYY is only created through hydrolytic splitting of a dipeptide from the prohormone.
Casomorphins
The casomorphins are short-chain peptides that were first obtained from the β-casein of cow's milk (Henschen, Brantl and Teschemacher, Max Planck Institute Martinsried and Munich). They are contained in the sequence of the protein and can be isolated from it. The bovine casomorphins are a heptapeptide and a pentapeptide. Both compounds have an opioid activity physiologically (about 4% that of morphine). The pentapeptide arises from the heptapeptide by C-terminal sequence shortening means of carboxypeptidase Y . β-Casomorphine-5 is further broken down gradually by dipeptidyl peptidase 4 and is inactivated in the process:
- β-Casomorphine-5: Tyr-Pro - Phe-Pro -Gly
Some derivatives of β-casomorphin-5 show a higher opioid activity compared to morphine (icv-applied). The des-Tyr derivatives of these compounds no longer have an opioid activity, but a neuroleptic activity comes to the fore in their place.
Substance P
The physiologically active substance P is hydrolyzed in a limiting manner by DP IV. This leads to a measurable increase in activity.
- Substance P: Arg-Pro - Lys-Pro -Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2
Melittin
The work of the group around Kreil from Salzburg on honey bee venom is very interesting . The bee venom melittin is released from a precursor peptide (Promelittin) by dipeptidyl peptidase 4 by cleaving 10 dipeptides of the sequence AS-Pro and AS-Ala step by step:
- Promelittin: Ala-Pro - Glu-Pro - Glu-Pro - Ala-Pro - Glu-Pro - Glu-Ala - Glu-Ala - Asp-Ala - Glu-Ala - Asp-Pro - Glu-Ala -Melittin
Bradykinin
Bradykinin cannot be hydrolyzed by DP IV despite the N-terminal Arg-Pro sequence, since there is a Pro in AS 3 position.
- Bradykinin: Arg-Pro-Pro -Gly-Phe-Ser-Pro-Phe-Arg
Inhibitors
By inhibiting the catalytic activity of dipeptidyl peptidase 4, it is possible to switch off the action of this enzyme. This leads to the demand for the development of effective and specific inhibitors of dipeptidyl peptidase 4 . In principle, the cleavage products of the enzyme action are potential enzyme inhibitors, especially the AS-Pro compounds. The decarboxylated derivatives, i.e. the AA pyrrolidides, are more effective. Recently, the β-aminoacylamides have become interesting. Sitagliptin , in particular , was approved in the USA as an active ingredient against type II diabetes in October 2006 and sold as a medicinal substance under the trade name Januvia . The hormone glucagon-like peptide 1 (GLP-1) stimulates the release of insulin. It also blocks the release of the hormone glucagon, which in the glucose metabolism leads to an increase in the glucose level in the blood. Dipeptidyl peptidase 4 degrades GLP-1. DP IV inhibitors prevent this degradation and thus indirectly promote the release of insulin, as does the reduced formation of glucose on the path of gluconeogenesis. Since this mechanism takes place in the intestine, oral administration is possible.
Studies have shown that the substance εZ (4-NO 2 ) -Lys-Pro has an effect that promotes wound healing, combined with a stimulation of the formation of granulation tissue. The compound εZ (4-NO 2 ) -Lys-Pro is a dipeptidyl peptidase-4 inhibitor. A causal relationship between wound healing-promoting effectiveness and DP IV inhibition leads to the conclusion: The different curative effects are triggered by identical receptors (DP IV), but they are a consequence of different application sites (in the case of DP IV inhibitors as drugs against diabetes Type 2 is oral application in tablet form via the intestine. In contrast to this, the application site in wound healing is determined by the wound to be treated.).
Research published in 2010 showed that CD26 (DP IV protein) is not necessarily directly linked to HIV infection, but it is involved in reducing the immune response in AIDS disease. In 2012 it was reported that the CD26 / DP4 in the mouse model has a high probability of having a protective function against airway inflammation (e.g. allergic asthma).
PETIR ( Peptidase Target Immune Regulation ) is a research platform for the development of therapeutics for the treatment of chronic inflammation, allergies and autoimmune diseases. PETIR therapeutics are structures that combine the properties of inhibiting the two target enzymes dipeptidyl peptidase IV and aminopeptidase N in a single low molecular weight chemical compound. By inhibiting the target enzymes, a highly effective reduction in the general inflammatory reaction is initiated, which is based on the simultaneous lowering of the activation state of chronically activated immune cells and the parallel reactivation of the immunosuppressive regulatory T cells. Appropriate therapeutic agents are being developed for the local therapy of moderate and severe forms of acne vulgaris. The preparation IP10.C8 influences the growth and differentiation of sebocytes as well as keratinocytes and is a very potent inhibitor of the local inflammatory reaction. In addition, the substance has a bacteriostatic effect on Propionibacterium acnes and, through the parallel attack of these main pathogenicity factors, represents an alternative to the current treatment options for acne.
Studies show that diseases such as Alzheimer's, arteriosclerosis, and multiple sclerosis have key enzymes in the metabolism, namely glutaminyl cyclase (QC) and iso-glutaminyl cyclase (isoQC), which prevent the catalyzed cleavage of the N- through a pyroglutamate ring closure. terminal glutamic acid by aminopeptidases or the elimination of the dipeptide Glu-Pro from the substrates by dipeptidyl peptidase IV.
Essential roles of the DP IV
- DP IV inhibitors are drugs against type 2 diabetes
- DP IV inhibitors promote wound healing
- The DP IV is involved in the immune deficiency in AIDS
- Bifunctional inhibitors are anti-inflammatory drugs and drugs against acne
- DP IV is involved in the mechanism of Alzheimer's disease, arteriosclerosis, and multiple sclerosis
- The DP IV has a protective function against airway inflammation (allergic asthma)
Literature (selection)
- Küllertz G, Fischer G, Barth A: [Catalytic mechanism of dipeptidyl-peptidase IV] . In: .. Acta Biol Med Ger. . 37, No. 4, 1978, pp. 559-67. PMID 735626 .
- Barth, A., Neubert, K., Schwarz, G., Fischer, G., Dove, S., Franke, R: Enzymatic Hydrolyses of Alanyl-alanine-anilides by Dipeptidyl Peptidase IV . In: Seydel, JK (Ed.): QSAR and Strategies in the Design of Bioactive Compounds . Proceedings of the 5th European Symposium on QSAR. Verlag Chemie, Weinheim 1985, ISBN 3-527-26306-3 , pp. 318-21 .
- Brandt W, Lehmann T, Thondorf I, et al. : A model of the active site of dipeptidyl peptidase IV predicted by comparative molecular field analysis and molecular modeling simulations . In: Int. J. Pept. Protein Res . 46, No. 6, December 1995, pp. 494-507. PMID 8748710 .
- Tulinsky A, Blevins RA: Structure of a tetrahedral transition state complex of alpha-chymotrypsin dimer at 1.8-A resolution . In: J. Biol. Chem. . 262, No. 16, June 1987, pp. 7737-43. PMID 3584139 .
- Mace JE, Agard DA: Kinetic and structural characterization of mutations of glycine 216 in alpha-lytic protease: a new target for engineering substrate specificity . In: J. Mol. Biol. . 254, No. 4, December 1995, pp. 720-36. doi : 10.1006 / jmbi.1995.0650 . PMID 7500345 .
- Stoll VS, Eger BT, Hynes RC, Martichonok V, Jones JB, Pai EF: Differences in binding modes of enantiomers of 1-acetamido boronic acid based protease inhibitors: crystal structures of gamma-chymotrypsin and subtilisin Carlsberg complexes . In: Biochemistry . 37, No. 2, January 1998, pp. 451-62. doi : 10.1021 / bi971166o . PMID 9425066 .
- Brandt W, Lehmann T, Hofmann T, Schowen RL, Barth A: The probable conformation of substrates recognized by dipeptidyl-peptidase IV and some aspects of the catalytic mechanism derived from theoretical investigations . In: J. Comput. Aided Mol. Des. . 6, No. 2, April 1992, pp. 159-74. PMID 1352539 .
- Ludwig K, Yan S, Fan H, Reutter W, Böttcher C: The 3D structure of rat DPPIV / CD26 as obtained by cryo-TEM and single particle analysis . In: Biochem. Biophys. Res. Commun. . 304, No. 1, April 2003, pp. 73-7. PMID 12705886 .
Individual evidence
- ↑ E. Prompetchara, C. Ketloy, T. Palaga: Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. In: Asian Pacific journal of allergy and immunology. [Electronic publication before printing] 02 2020, doi : 10.12932 / AP-200220-0772 , PMID 32105090 .
- ↑ Hopsu-Havu VK, Glenner GG: A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide . In: Histochemistry . 7, No. 3, 1966, pp. 197-201. PMID 5959122 .
- ^ Alfred Barth, Horst Schulz, Pharmazie 29, 195, 1974.
- ↑ Jaron: Biopolymers 26, 215, 1987.
- ↑ Hartrodt B, Neubert K, Fischer G, Schulz H, Barth A: Synthesis and enzymatic degradation of β-casomorphin-5 . In: Pharmacy . 37, No. 3, March 1982, pp. 165-9. PMID 7100234 .
- ↑ Heymann E, Mentlein R: Liver dipeptidyl aminopeptidase IV hydrolyzes substance P . In: FEBS Lett . . 91, No. 2, July 1978, pp. 360-4. PMID 680144 .
- ↑ Kreil G, Haiml L, Suchanek G: Stepwise cleavage of the pro part of promelittin by dipeptidylpeptidase IV. Evidence for a new type of precursor - product conversion . In: Eur. J. Biochem. . 111, No. 1, October 1980, pp. 49-58. PMID 7002560 .
- ↑ Kato T, Nagatsu T, Fukasawa K, Harada M, Nagatsu I, Sakakibara S: Successive cleavage of N-terminal Arg1 - Pro2 and Lys3-Pro4 from substance P but no release of Arg1-Pro2 from bradykinin, by X-Pro dipeptidyl aminopeptidase . In: Biochim. Biophys. Acta . 525, No. 2, August 1978, pp. 417-22. PMID 687639 .
- ↑ Patent DD248961 : Process for manufacturing preparations promoting wound healing, and such preparations .. Applied on May 22, 1984 , published on August 26, 1987 , Applicant: Jentzsch, KD, Buntrock, P., Oehme, P., Kuhl, A ., Neubert, K., inventor: Academy of Sciences of the GDR.
- ↑ Tansi FL, Blanchard V, Berger M, Tauber R, Reutter W, Fan H: Interaction of human dipeptidyl peptidase IV and human immunodeficiency virus type-1 transcription transactivator in Sf9 cells . (PDF) In: Virol. J. . 7, 2010, p. 267. doi : 10.1186 / 1743-422X-7-267 . PMID 20942971 . PMC 2967539 (free full text).
- ↑ S. Yan, R. Gessner et al. a .: Enhanced ovalbumin-induced airway inflammation in CD26 - / - mice. In: European Journal of Immunology. Volume 42, number 2, February 2012, pp. 533-540, doi: 10.1002 / eji.201041038 . PMID 22101691 .
- ↑ Anorge et al.: IMTM, novel active principle, various publications on the effects of bifunctional inhibitors on acne and as anti-inflammatory agents.
- ↑ H. Cynis, T. Hoffmann u. a .: The isoenzymes of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. In: EMBO molecular medicine. Volume 3, number 9, September 2011, pp. 545–558, doi: 10.1002 / emmm.201100158 . PMID 21774078 . PMC 3377097 (free full text).