Dipeptidyl-peptidase IV
Catalyses the release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline. An integral protein of the plasma membrane of lymphocytes and other mammalian cells, in peptidase family S9 (prolyl oligopeptidase family). The reaction is similar to that of the unrelated Xaa-Pro dipeptidyl-peptidase of lactococci.
Reference Protein and Structure
- Sequence
-
P27487
(3.4.14.5)
(Sequence Homologues)
(PDB Homologues)
- Biological species
-
Homo sapiens (Human)
- PDB
-
1pfq
- crystal structure of human apo dipeptidyl peptidase IV / CD26
(1.9 Å)
- Catalytic CATH Domains
-
3.40.50.1820
(see all for 1pfq)
Enzyme Reaction (EC:3.4.14.5)
+
→
+
Alternative enzyme names: DPP IV/CD26, Gly-Pro naphthylamidase, T cell triggering molecule Tp103, X-PDAP, X-prolyl dipeptidyl aminopeptidase, Xaa-Pro-dipeptidyl-aminopeptidase, Amino acyl-prolyl dipeptidyl aminopeptidase, Dipeptidyl aminopeptidase IV, Dipeptidyl peptidase IV, Dipeptidyl-aminopeptidase IV, Dipeptidyl-peptide hydrolase, Glycoprotein GP110, Glycylproline aminopeptidase, Glycylprolyl aminopeptidase, Glycylprolyl dipeptidylaminopeptidase, Leukocyte antigen CD26, Lymphocyte antigen CD26, Pep X, Postproline dipeptidyl aminopeptidase IV, Xaa-Pro-dipeptidylaminopeptidase, Post-proline dipeptidyl aminopeptidase IV, DPP IV,
Enzyme Mechanism
Introduction
The serine nuelcophile is activated by the Ser-His-Asp triad and attacks the carbonyl carbon of the peptide bond in a nucleophilic addition. The oxyanion initiates an elimination reaction that cleaves the peptide bond, releasing the new N-terminus of the protein, which protonates from the His of the catalytic triad. His740 deprotonates water, which attacks the carbonyl carbon bound to the catalytic Ser in a nucleophilic addition. The serine is then eliminated by the collapse of the oxyanion in a classical Ser-His-Asp type reaction.
Catalytic Residues Roles
| UniProt | PDB* (1pfq) | ||
| Tyr631 (main-N), Tyr547 | Tyr631(596)A (main-N), Tyr547(512)A | Forms the oxyanion hole that stabilises the negatively charged intermediates and transition states formed during the course of the reaction. | hydrogen bond donor, electrostatic stabiliser |
| Ser630 | Ser630(595)A | Part of the catalytic Ser-His-Asp triad. Acts as a nucleophile during the course of the reaction, forming a covalent linkage between the enzyme and the protein substrate. | covalently attached, hydrogen bond acceptor, hydrogen bond donor, nucleophile, proton acceptor, proton donor, nucleofuge |
| Asp708 | Asp708(673)A | Part of the catalytic Ser-His-Asp triad. Activates the histidine to act as a general acid/base. | activator, hydrogen bond acceptor, electrostatic stabiliser |
| His740 | His740(705)A | Part of the catalytic Ser-His-Asp catalytic triad. Acts as a general acid/base, activating the catalytic serine and water. | hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor, electrostatic stabiliser |
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file;
y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain;
C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.
Chemical Components
proton transfer, bimolecular nucleophilic addition, overall reactant used, enzyme-substrate complex formation, intermediate formation, unimolecular elimination by the conjugate base, enzyme-substrate complex cleavage, intermediate collapse, overall product formed, intermediate terminated, native state of enzyme regeneratedReferences
- Bjelke JR et al. (2004), J Biol Chem, 279, 34691-34697. Tyrosine 547 Constitutes an Essential Part of the Catalytic Mechanism of Dipeptidyl Peptidase IV. DOI:10.1074/jbc.m405400200. PMID:15175333.
- Metzler WJ et al. (2008), Protein Sci, 17, 240-250. Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. DOI:10.1110/ps.073253208. PMID:18227430.
- Oefner C et al. (2003), Acta Crystallogr D Biol Crystallogr, 59, 1206-1212. High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl]amino)-acetyl]-2-cyano-(S)-pyrrolidine. DOI:10.1107/s0907444903010059. PMID:12832764.
- David F et al. (1993), J Biol Chem, 268, 17247-17252. Identification of serine 624, aspartic acid 702, and histidine 734 as the catalytic triad residues of mouse dipeptidyl-peptidase IV (CD26). A member of a novel family of nonclassical serine hydrolases. PMID:8102366.
Catalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp708(673)A | hydrogen bond acceptor, activator |
| His740(705)A | hydrogen bond acceptor, hydrogen bond donor |
| Ser630(595)A | hydrogen bond donor |
| Tyr631(596)A (main-N) | hydrogen bond donor |
| Tyr547(512)A | hydrogen bond donor |
| Ser630(595)A | proton donor |
| His740(705)A | proton acceptor |
Chemical Components
proton transfer
Step 2. Ser730 attacks the carbonyl carbon of the peptide bond in a nucleophilic addition.
Download: Image, Marvin FileCatalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp708(673)A | hydrogen bond acceptor, electrostatic stabiliser |
| His740(705)A | hydrogen bond donor, electrostatic stabiliser |
| Ser630(595)A | hydrogen bond acceptor |
| Tyr631(596)A (main-N) | hydrogen bond donor, electrostatic stabiliser |
| Tyr547(512)A | hydrogen bond donor, electrostatic stabiliser |
| Ser630(595)A | nucleophile |
Chemical Components
ingold: bimolecular nucleophilic addition, overall reactant used, enzyme-substrate complex formation, intermediate formation
Step 3. The oxyanion initiates an elimination reaction that cleaves the peptide bond, releasing the new N-terminus of the protein, which protonates from His740.
Download: Image, Marvin FileCatalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp708(673)A | hydrogen bond acceptor, electrostatic stabiliser |
| His740(705)A | hydrogen bond donor |
| Ser630(595)A | covalently attached, hydrogen bond acceptor |
| Tyr631(596)A (main-N) | hydrogen bond donor, electrostatic stabiliser |
| Tyr547(512)A | hydrogen bond donor, electrostatic stabiliser |
| His740(705)A | proton donor |
Chemical Components
proton transfer, ingold: unimolecular elimination by the conjugate base, enzyme-substrate complex cleavage, intermediate collapse, intermediate formation, overall product formed
Step 4. His740 deprotonates water, which attacks the carbonyl carbon bound to Ser630 in a nucleophilic addition.
Download: Image, Marvin FileCatalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp708(673)A | hydrogen bond acceptor |
| His740(705)A | hydrogen bond acceptor, hydrogen bond donor |
| Ser630(595)A | covalently attached, hydrogen bond acceptor |
| Tyr631(596)A (main-N) | hydrogen bond donor, electrostatic stabiliser |
| Tyr547(512)A | hydrogen bond donor, electrostatic stabiliser |
| His740(705)A | proton acceptor |
Chemical Components
proton transfer, ingold: bimolecular nucleophilic addition, overall reactant used, enzyme-substrate complex formation, intermediate formation
Step 5. The oxyanion initiates an elimination that cleaves the acyl bond to Ser630, releasing the L-aminoacyl-Lproline product. Ser630 then deprotonates His740, regenerating the active site.
Download: Image, Marvin FileCatalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp708(673)A | hydrogen bond acceptor, electrostatic stabiliser |
| His740(705)A | hydrogen bond donor |
| Ser630(595)A | hydrogen bond acceptor |
| Tyr631(596)A (main-N) | hydrogen bond donor, electrostatic stabiliser |
| Tyr547(512)A | hydrogen bond donor, electrostatic stabiliser |
| Ser630(595)A | proton acceptor |
| His740(705)A | proton donor |
| Ser630(595)A | nucleofuge |
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