DPP3

DPP3
Identifiers
AliasesDPP3, DPPIII, dipeptidyl peptidase 3
External IDsOMIM: 606818; MGI: 1922471; GeneCards: DPP3
Available structures
PDBOrtholog search: PDBe RCSB
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
3.4.14.4↗↗↗↗
Orthologs
DatabasesNCBI: entry; OMA: entry
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 MbChr 19: 4.96 – 4.98 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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 helps degrade a variety of bioactive peptides, including angiotensins and endogenous opioids like enkephalins and endomorphins.[16][17][18] It does this by removing dipeptides from the end of each peptide molecule, whose length is typically in the range of 4 to 10 residues.[11][19][20]

One of its best-characterized substrate is angiotensin II (Ang II),[21] a key hormone produced by the body to increase blood pressure.[22] Recent research indicates that DPP3 actively degrades Ang II in vivo, in particular leading to reduced blood pressure in hypertensive mice.[23] Other studies suggest that DPP3 increases renal blood flow, and this appears to be due to reduced activation of Angiotensin II receptor type 1.[21]

Oxidative stress

Within cells, DPP3 activates the KEAP1-NRF2 antioxidant pathway, which helps combat oxidative stress. It does this by competing with NRF2 to bind to KEAP1, releasing it to translocate to the nucleus.[24] DPP3 is overexpressed in the brain under conditions of oxidative stress, such as loss of blood supply to the brain, and plays a significant role in reducing inflammation and cell death in those circumstances.[25] Similarly, studies in mice suggest it has a role in reducing oxidative stress and damage to bones.[24][20]

Clinical significance

Role as a Biomarker

Blood DPP3 levels have been proposed as a biomarker for circulatory shock. This is because high levels of DPP3 in the blood are associated with reduce heart function, organ failure, and shock in critically ill patients.[26][27]

Role in shock and circulatory failure

Beyond being a marker, there is some evidence that blood DPP3 levels are causally related to poor outcomes. During shock, the body increases production and/or release of vasoconstrictive hormones like Angiotensin II to try to restore blood pressure.[28] However, DPP3 acts to degrade Angiotensins, so high levels may make it harder for the body to correct the problem.[27]

As a drug target

DPP3 is being researched as the target of certain drugs intended to treat cardiac shock. The idea is to prevent DPP3 from breaking down Angiotensin II, and therefore make it easier for the body to restore blood pressure. Anti-DPP3 antibody treatments such as Procizumab have shown promising results in animal studies.[29][27]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000254986 – Ensembl, May 2017
  2. ^ a b c 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. ^ 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. ^ 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. ^ a b 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. ^ 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. ^ 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.
  20. ^ a b 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.
  21. ^ a b 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. ^ 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.
  23. ^ 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.
  24. ^ a b 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.
  25. ^ 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.
  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. ^ a b c 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.
  28. ^ 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.
  29. ^ 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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