DPP3

Last updated

DPP3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DPP3 , DPPIII, dipeptidyl peptidase 3
External IDs OMIM: 606818; MGI: 1922471; HomoloGene: 40210; GeneCards: DPP3; OMA:DPP3 - orthologs
Orthologs
SpeciesHumanMouse
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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Dipeptidyl-peptidase 3 is an enzyme that in humans is encoded by the DPP3 gene. [5] [6]

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. [7]

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. [8] 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. [9] [10]

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. [11] [12] [13] [14] 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. [15]

Function

DPP3 degrades a variety of bioactive peptides, including angiotensins and endogenous opioids like enkephalins and endomorphins [16] [17] [18] 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. [19] [20] 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. [21]

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. [11] [22] [23]

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. [24] [25] [23] Consequently, DPP3 knockout mice exhibit sustained oxidative stress, disrupted bone homeostasis, and dysregulation of the renin-angiotensin-aldosterone system (RAAS) peptides in the blood. [25] [16] DPP3 is highly conserved among higher animals, underscoring its biological importance. [23]

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 [8] [23] [26] [27] [28] [29] [10] [30] [31] [32]

Role in shock and circulatory failure

During shock, Angiotensin II production increases to restore blood pressure. [33] However, this compensatory mechanism is often impaired by factors such as myocardial infarction medications, endothelial dysfunction, and angiotensin-converting enzyme (ACE) dysfunction. [34] [35] 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. [36]

As a drug target

DPP3 is the drug target of Procizumab, an anti-DPP3 antibody in clinical development by 4TEEN4 Pharmaceuticals. 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 [23] [37] 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000254986 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000063904 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Fukasawa KM, Fukasawa K, Harada M (Jun 2000). "Assignment of the dipeptidyl peptidase III gene (DPP3) to human chromosome 11 band q12→q13.1 by in situ hybridization". Cytogenetics and Cell Genetics. 88 (1–2): 99–100. doi:10.1159/000015498. PMID   10773679. S2CID   202603.
  6. ↑ "DPP3 dipeptidyl peptidase 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-05-16.
  7. ↑ "DPP3 dipeptidyl peptidase 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-05-16.
  8. 1 2 Deniau B, Rehfeld L, Santos K, Dienelt A, Azibani F, Sadoune M, et al. (February 2020). "Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics". European Journal of Heart Failure. 22 (2): 290–299. doi:10.1002/ejhf.1601. PMID   31472040.
  9. ↑ Harjola VP, Lassus J, Sionis A, Køber L, Tarvasmäki T, Spinar J, et al. (May 2015). "Clinical picture and risk prediction of short-term mortality in cardiogenic shock". European Journal of Heart Failure. 17 (5): 501–509. doi:10.1002/ejhf.260. hdl: 11573/910722 . PMID   25820680.
  10. 1 2 Takagi K, Blet A, Levy B, Deniau B, Azibani F, Feliot E, et al. (February 2020). "Circulating dipeptidyl peptidase 3 and alteration in haemodynamics in cardiogenic shock: results from the OptimaCC trial". European Journal of Heart Failure. 22 (2): 279–286. doi:10.1002/ejhf.1600. PMID   31472039.
  11. 1 2 Cruz-Diaz N, Wilson BA, Pirro NT, Brosnihan KB, Marshall AC, Chappell MC (September 2016). "Identification of dipeptidyl peptidase 3 as the Angiotensin-(1-7) degrading peptidase in human HK-2 renal epithelial cells". Peptides. 83: 29–37. doi:10.1016/j.peptides.2016.06.005. PMC   5500233 . PMID   27315786.
  12. ↑ Shimamori Y, Watanabe Y, Fujimoto Y (August 1986). "Purification and characterization of dipeptidyl aminopeptidase III from human placenta". Chemical & Pharmaceutical Bulletin. 34 (8): 3333–3340. doi:10.1248/cpb.34.3333. PMID   3791505.
  13. ↑ Vanha-Perttula, T (October 1988). "Dipeptidyl peptidase III and alanyl aminopeptidase in the human seminal plasma: Origin and biochemical properties". Clin. Chim. Acta. 177 (2): 179–195. doi:10.1016/0009-8981(88)90140-4. PMID   2906822.
  14. ↑ Sato H, Kimura K, Yamamoto Y, Hazato T (March 2003). "[Activity of DPP III in human cerebrospinal fluid derived from patients with pain]". Masui. The Japanese Journal of Anesthesiology (in Japanese). 52 (3): 257–263. PMID   12703067.
  15. ↑ Rehfeld L, Funk E, Jha S, Macheroux P, Melander O, Bergmann A (May 2019). "Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples". The Journal of Applied Laboratory Medicine. 3 (6): 943–953. doi:10.1373/jalm.2018.027995. PMID   31639686.
  16. 1 2 Jha S, Taschler U, Domenig O, Poglitsch M, Bourgeois B, Pollheimer M, et al. (October 2020). "Dipeptidyl peptidase 3 modulates the renin-angiotensin system in mice". The Journal of Biological Chemistry. 295 (40): 13711–13723. doi: 10.1074/jbc.RA120.014183 . PMC   7535908 . PMID   32546481.
  17. ↑ Barsun M, Jajcanin N, Vukelić B, Spoljarić J, Abramić M (March 2007). "Human dipeptidyl peptidase III acts as a post-proline-cleaving enzyme on endomorphins". Biological Chemistry. 388 (3): 343–348. doi:10.1515/BC.2007.039. PMID   17338643.
  18. ↑ Lee CM, Snyder SH (October 1982). "Dipeptidyl-aminopeptidase III of rat brain. Selective affinity for enkephalin and angiotensin". The Journal of Biological Chemistry. 257 (20): 12043–12050. doi: 10.1016/S0021-9258(18)33674-3 . PMID   6749851.
  19. ↑ Ferrario CM (March 2006). "Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research". Journal of the Renin-Angiotensin-Aldosterone System. 7 (1): 3–14. doi:10.3317/jraas.2006.003. PMID   17083068.
  20. ↑ Pang X, Shimizu A, Kurita S, Zankov DP, Takeuchi K, Yasuda-Yamahara M, et al. (September 2016). "Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension". Hypertension. 68 (3): 630–641. doi:10.1161/HYPERTENSIONAHA.116.07357. PMID   27456521.
  21. ↑ Picod A, Placier S, Genest M, Callebert J, Julian N, Zalc M, et al. (April 2024). "Circulating Dipeptidyl Peptidase 3 Modulates Systemic and Renal Hemodynamics Through Cleavage of Angiotensin Peptides". Hypertension. 81 (4): 927–935. doi:10.1161/HYPERTENSIONAHA.123.21913. PMC   10956665 . PMID   38334001.
  22. ↑ Prajapati SC, Chauhan SS (September 2011). "Dipeptidyl peptidase III: a multifaceted oligopeptide N-end cutter". The FEBS Journal. 278 (18): 3256–3276. doi:10.1111/j.1742-4658.2011.08275.x. PMID   21794094.
  23. 1 2 3 4 5 Malovan G, Hierzberger B, Suraci S, Schaefer M, Santos K, Jha S, et al. (May 2023). "The emerging role of dipeptidyl peptidase 3 in pathophysiology". The FEBS Journal. 290 (9): 2246–2262. doi: 10.1111/febs.16429 . PMID   35278345.
  24. ↑ Ren X, Yu J, Guo L, Ma H (July 2021). "Dipeptidyl-peptidase 3 protects oxygen-glucose deprivation/reoxygenation-injured hippocampal neurons by suppressing apoptosis, oxidative stress and inflammation via modulation of Keap1/Nrf2 signaling". International Immunopharmacology. 96 107595. doi:10.1016/j.intimp.2021.107595. PMID   33812256.
  25. 1 2 Menale C, Robinson LJ, Palagano E, Rigoni R, Erreni M, Almarza AJ, et al. (November 2019). "Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss". Journal of Bone and Mineral Research. 34 (11): 2133–2148. doi:10.1002/jbmr.3829. PMC   7203631 . PMID   31295380.
  26. ↑ Wenzl FA, Bruno F, Kraler S, Klingenberg R, Akhmedov A, Ministrini S, et al. (October 2023). "Dipeptidyl peptidase 3 plasma levels predict cardiogenic shock and mortality in acute coronary syndromes". European Heart Journal. 44 (38): 3859–3871. doi:10.1093/eurheartj/ehad545. PMID   37632743.
  27. ↑ Pöss J, Büttner P, Thiele H (October 2023). "Circulating dipeptidyl peptidase 3: new hope for a specific treatment to improve prognosis in cardiogenic shock?". European Heart Journal. 44 (38): 3872–3874. doi:10.1093/eurheartj/ehad568. PMID   37632844.
  28. ↑ Ye P, Duan W, Leng YQ, Wang YK, Tan X, Wang WZ (2022). "DPP3: From biomarker to therapeutic target of cardiovascular diseases". Frontiers in Cardiovascular Medicine. 9: 974035. doi: 10.3389/fcvm.2022.974035 . PMC   9605584 . PMID   36312232.
  29. ↑ Méndez Hernández R, Ramasco Rueda F (February 2023). "Biomarkers as Prognostic Predictors and Therapeutic Guide in Critically Ill Patients: Clinical Evidence". Journal of Personalized Medicine. 13 (2): 333. doi: 10.3390/jpm13020333 . PMC   9965041 . PMID   36836567.
  30. ↑ Blet A, Deniau B, Santos K, van Lier DP, Azibani F, Wittebole X, et al. (February 2021). "Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study". Critical Care. 25 (1) 61. doi: 10.1186/s13054-021-03471-2 . PMC   7885215 . PMID   33588925.
  31. ↑ van Lier D, Beunders R, Kox M, Pickkers P (December 2023). "Associations of dipeptidyl-peptidase 3 with short-term outcome in a mixed admission ICU-cohort". Journal of Critical Care. 78 154383. doi: 10.1016/j.jcrc.2023.154383 . PMID   37482013.
  32. ↑ Iborra-Egea O, Montero S, Bayes-Genis A (August 2020). "An outlook on biomarkers in cardiogenic shock". Current Opinion in Critical Care. 26 (4): 392–397. doi:10.1097/MCC.0000000000000739. PMID   32452847.
  33. ↑ Corrêa TD, Takala J, Jakob SM (March 2015). "Angiotensin II in septic shock". Critical Care. 19 (1) 98. doi: 10.1186/s13054-015-0802-3 . PMC   4360936 . PMID   25886853.
  34. ↑ Reynolds HR, Hochman JS (February 2008). "Cardiogenic shock: current concepts and improving outcomes". Circulation. 117 (5): 686–697. doi:10.1161/CIRCULATIONAHA.106.613596. PMID   18250279.
  35. ↑ Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, et al. (November 2020). "Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial". American Journal of Respiratory and Critical Care Medicine. 202 (9): 1253–1261. doi:10.1164/rccm.201911-2172OC. PMC   7605187 . PMID   32609011.
  36. ↑ Picod A, Deniau B, Vaittinada Ayar P, Genest M, Julian N, Azibani F, et al. (February 2021). "Alteration of the Renin-Angiotensin-Aldosterone System in Shock: Role of the Dipeptidyl Peptidase 3". American Journal of Respiratory and Critical Care Medicine. 203 (4): 526–527. doi:10.1164/rccm.202010-3873LE. PMC   7885828 . PMID   33152252.
  37. ↑ Deniau B, Blet A, Santos K, Vaittinada Ayar P, Genest M, Kästorf M, et al. (2020). "Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: A proof of concept study". PLOS ONE. 15 (8): e0238039. Bibcode:2020PLoSO..1538039D. doi: 10.1371/journal.pone.0238039 . PMC   7451654 . PMID   32853284.

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