DPP3

DPP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3FVY, 3T6B, 3T6J, 5E2Q, 5EHH, 5E33, 5E3C, 5E3A, 5EGY
Identifiers
Aliases	DPP3, DPPIII, dipeptidyl peptidase 3
External IDs	OMIM: 606818; MGI: 1922471; HomoloGene: 40210; GeneCards: DPP3; OMA:DPP3 - orthologs
Gene location (Human) Chr. Chromosome 11 (human) Band 11q13.2 Start 66,480,013 bp End 66,509,657 bp
Gene location (Mouse) Chr. Chromosome 19 (mouse) Band 19|19 A Start 4,957,257 bp End 4,978,315 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon oocyte rectum islet of Langerhans secondary oocyte granulocyte mucosa of pharynx mucosa of esophagus stromal cell of endometrium right adrenal gland Top expressed in yolk sac lip primitive streak epiblast esophagus neural tube lacrimal gland right kidney embryo ventricular zone More reference expression data BioGPS n/a
Gene ontology Molecular function zinc ion binding peptidase activity aminopeptidase activity protein binding hydrolase activity metallopeptidase activity dipeptidyl-peptidase activity metal ion binding Cellular component plasma membrane extracellular exosome cytoplasm nuclear speck cytosol Biological process proteolysis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10072 75221 Ensembl ENSG00000254986 ENSMUSG00000063904 UniProt Q9NY33 Q99KK7 RefSeq (mRNA) NM_130443 NM_001256670 NM_005700 NM_133803 NM_001360711 RefSeq (protein) NP_001243599 NP_005691 NP_569710 NP_598564 NP_001347640 Location (UCSC) Chr 11: 66.48 – 66.51 Mb Chr 19: 4.96 – 4.98 Mb PubMed search
Wikidata
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Dipeptidyl-peptidase 3 is an enzyme that in humans is encoded by the DPP3 gene.

This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. This cytoplasmic protein binds a single zinc ion with its zinc-binding motif (HELLGH) and has post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Increased activity of this protein is associated with endometrial and ovarian cancers. Alternate transcriptional splice variants have been characterized.

Dipeptidyl-peptidase 3 has been found to act as a myocardial depressant factor. Procizumab, a specific antibody for dipeptidyl-peptidase 3, was found to improve cardiac and renal function in a mouse model of heart failure. In human studies, higher levels of circulating DPP3 protein in cardiogenic shock patients indicated a more severe disease course, with a higher risk of refractory cardiogenic shock and death.

Tissue distribution

Outside cells, DPP3, referred to as circulating DPP3 (cDPP3), is detected in various extracellular fluids, including cerebrospinal fluid, seminal plasma, and retroplacental plasma in low levels. In healthy adults, cDPP3 is present in plasma at a median concentration of 10 ng/mL, with an upper normal range of 22 ng/mL (97.5th percentile). However, in populations resembling ICU patients (e.g., older individuals with comorbidities), median cDPP3 levels of 14 ng/mL, with an upper range of 30 ng/mL, as defined by the 95th percentile.

Function

DPP3 degrades a variety of bioactive peptides, including angiotensins and endogenous opioids like enkephalins and endomorphins Its best-characterized substrate is angiotensin II (Ang II), a key regulator of cardiovascular and renal function. Recent research demonstrates that DPP3 actively degrades Ang II in vivo, leading to reduced blood pressure in hypertensive mice. In addition, DPP3 i.v. administration significantly increases renal blood flow, while blood pressure was minimally affected. Conversely, procizumab, a DPP3 inhibitor, leads to significantly decreased renal blood flow. Angiotensin peptides measurement and an AT1R (angiotensin II receptor type 1) blockade experiment using valsartan demonstrated that the renovascular effect induced by DPP3 is due to reduced AT1R activation via decreased concentrations of circulating angiotensin II, III, and IV. Measurements of circulating catecholamines and an adrenergic receptor blockade by labetalol demonstrated a concomitant catecholamine release that explains blood pressure maintenance upon DPP3 administration. In conclusion, high circulating DPP3 increases renal blood flow due to reduced AT1R activation via decreased concentrations of circulating angiotensin peptides while blood pressure is maintained by concomitant endogenous catecholamines release.

DPP3 is a zinc-dependent enzyme that sequentially removes dipeptides from the N-terminus of bioactive substrates, typically ranging from 4 to 10 residues in length.

Oxidative stress

Within cells, DPP3 plays a critical role in activating the Keap1-Nrf2 antioxidant pathway, which helps combat oxidative stress. Studies have shown that DPP3 is overexpressed under conditions of oxidative stress, such as in severe heart failure models. Consequently, DPP3 knockout mice exhibit sustained oxidative stress, disrupted bone homeostasis, and dysregulation of the renin-angiotensin-aldosterone system (RAAS) peptides in the blood. DPP3 is highly conserved among higher animals, underscoring its biological importance.

Clinical significance

High cDPP3 levels (>40 ng/mL) in critically ill patients are strongly associated with myocardial depression, multi-organ dysfunction, disease severity, and poor outcomes. Retrospective studies and in vivo experiments support this link, showing that intravenous DPP3 administration in healthy rodents impairs cardiac and renal function. These findings suggest that DPP3 contributes to circulatory failure by degrading vasoactive peptides like Ang II. In summary, DPP3 is a multifunctional enzyme with significant roles in oxidative stress regulation, cardiovascular homeostasis, and disease progression. Its involvement in Ang II degradation and circulatory dysfunction highlights its potential as a therapeutic target in conditions like shock and heart failure

Role in shock and circulatory failure

During shock, Angiotensin II production increases to restore blood pressure. However, this compensatory mechanism is often impaired by factors such as myocardial infarction medications, endothelial dysfunction, and angiotensin-converting enzyme (ACE) dysfunction. Additionally, hypoperfusion and tissue death can elevate DPP3 levels in the blood, further compromising Ang II levels. This DPP3-dependent Ang II deficiency significantly exacerbate circulatory dysfunction in shock patients, perpetuating the shock spiral and ultimately leading to death.

As a drug target

DPP3 is the drug target of Procizumab, an anti-DPP3 antibody in clinical development by 4TEEN4 Pharmaceuticals (4TEEN4.de). Procizumab is a humanized monoclonal antibody for the treatment of adult patients suffering from cardiogenic shock. Procizumab is designed to block the enzymatic activity of cDPP3 in the bloodstream, thereby inhibiting DPP3-dependent Ang II degradation. This blockade is intended to rapidly stabilize cardiovascular and renal functions, and therefore hemodynamics, and reduce mortality in affected patients. Inhibition of excess cDPP3 in the blood via procizumab has shown beneficial hemodynamic effects (improvement of cardiac and renal function), reduction of myocardial oxidative stress and improved survival in rodent models Procizumab studies in a large animal model of cardiovascular dysfunction showed that Procizumab-treated animals required lower doses of vasopressors and fluids to maintain adequate tissue perfusion and target mean arterial pressure (MAP) at 65 mmHg. These effects were associated with an increase in circulating Ang II concentrations, a preserved Ang I/Ang II ratio, prevention of ATIR downregulation and higher alpha-1, beta-1, and beta-2 adrenergic receptor expression. Reduction in catecholamine exposure by procizumab led to reduced inflammation and myocardial injury, exerting a cardioprotective effect. This aligns with the findings in rodents, where Procizumab administration reduces myocardial oxidative stress. Finally, Procizumab treatment also resulted in improved PaO2/FiO2 ratio (respiratory function). This positive effect on hypoxemia could be a better regional blood flow and distribution due to improved vascular tone caused by the normalized Ang II levels.

Further reading

• Kar NC, Pearson CM (January 1978). "Dipeptidyl peptidases in human muscle disease". Clinica Chimica Acta; International Journal of Clinical Chemistry. 82 (1–2): 185–192. doi:10.1016/0009-8981(78)90042-6. PMID 618680.
• Grdisa M, Vitale L (1991). "Types and localization of aminopeptidases in different human blood cells". The International Journal of Biochemistry. 23 (3): 339–345. doi:10.1016/0020-711X(91)90116-5. PMID 2044841.
• Swanson AA, Davis RM, Meinhardt NC (January 1985). "Proteases in human lenses and their possible significance". Current Eye Research. 4 (1): 43–48. doi:10.3109/02713688508999965. PMID 2858361.
• Shimamori Y, Watanabe Y, Fujimoto Y (December 1988). "Human placental dipeptidyl aminopeptidase III: hydrolysis of enkephalins and its stimulation by cobaltous ion". Biochemical Medicine and Metabolic Biology. 40 (3): 305–310. doi:10.1016/0885-4505(88)90133-8. PMID 3233187.
• Abramić M, Zubanović M, Vitale L (January 1988). "Dipeptidyl peptidase III from human erythrocytes". Biological Chemistry Hoppe-Seyler. 369 (1): 29–38. doi:10.1515/bchm3.1988.369.1.29. PMID 3348886.
• Swanson AA, Davis RM, McDonald JK (February 1984). "Dipeptidyl peptidase III of human cataractous lenses. Partial purification". Current Eye Research. 3 (2): 287–291. doi:10.3109/02713688408997211. PMID 6368131.
• Jones TH, Kapralou A (January 1982). "A rapid assay for dipeptidyl aminopeptidase III in human erythrocytes". Analytical Biochemistry. 119 (2): 418–423. doi:10.1016/0003-2697(82)90607-8. PMID 7041700.
• Vitale L, Zubanović M, Abramić M (1982). "Properties and distribution of aminopeptidase and dipeptidyl aminopeptidase III of human erythrocytes". Acta Biologica et Medica Germanica. 40 (10–11): 1489–1495. PMID 7044004.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Fukasawa K, Fukasawa KM, Kanai M, Fujii S, Hirose J, Harada M (January 1998). "Dipeptidyl peptidase III is a zinc metallo-exopeptidase. Molecular cloning and expression". The Biochemical Journal. 329 ( Pt 2) (Pt 2): 275–282. doi:10.1042/bj3290275. PMC 1219041. PMID 9425109.
• Simaga S, Babić D, Osmak M, Ilić-Forko J, Vitale L, Milicić D, et al. (February 1998). "Dipeptidyl peptidase III in malignant and non-malignant gynaecological tissue". European Journal of Cancer. 34 (3): 399–405. doi:10.1016/S0959-8049(97)00401-2. PMID 9640230.
• Akiyama T, Harada S, Kojima F, Takahashi Y, Imada C, Okami Y, et al. (June 1998). "Fluostatins A and B, new inhibitors of dipeptidyl peptidase III, produced by Streptomyces sp. TA-3391. I. Taxonomy of producing strain, production, isolation, physico-chemical properties and biological properties". The Journal of Antibiotics. 51 (6): 553–559. doi:10.7164/antibiotics.51.553. PMID 9711218.
• Fukasawa K, Fukasawa KM, Iwamoto H, Hirose J, Harada M (June 1999). "The HELLGH motif of rat liver dipeptidyl peptidase III is involved in zinc coordination and the catalytic activity of the enzyme". Biochemistry. 38 (26): 8299–8303. doi:10.1021/bi9904959. PMID 10387075.
• Hashimoto J, Yamamoto Y, Kurosawa H, Nishimura K, Hazato T (July 2000). "Identification of dipeptidyl peptidase III in human neutrophils". Biochemical and Biophysical Research Communications. 273 (2): 393–397. doi:10.1006/bbrc.2000.2827. PMID 10873616.
• Abramić M, Schleuder D, Dolovcak L, Schröder W, Strupat K, Sagi D, et al. (December 2000). "Human and rat dipeptidyl peptidase III: biochemical and mass spectrometric arguments for similarities and differences". Biological Chemistry. 381 (12): 1233–1243. doi:10.1515/BC.2000.151. PMID 11209758. S2CID 22245963.

External links

• DPP3 human gene location in the UCSC Genome Browser.
• DPP3 human gene details in the UCSC Genome Browser.