Many biologically important peptide sequences contain proline. It confers unique conformational constraints on the peptide chain in that the side-chain is cyclized back onto the backbone amide position. Inside an alpha-helix the possibility of making hydrogen bonds to the preceding turn is lost and a kink will be introduced. The conformational restrictions imposed by proline motifs in a peptide chain appear to imply important structural or biological functions as can be deduced from their often remarkably high degree of conservation as found in many proteins and peptides, especially cytokines, growth factors, G-protein-coupled receptors, V3 loops of the HIV envelope glycoprotein gp 120, and neuro- and vasoactive peptides. Only a limited number of peptidases are known to be able to hydrolyze proline adjacent bonds. Their activity is influenced by the isomeric state (cis-trans) as well as the position of proline in the peptide chain. The three proline specific metallo-peptidases (aminopeptidase P, carboxypeptidase P and prolidase) are activated by Mn2+, whereas the three serine type peptidases cleaving a post proline bond (prolyl oligopeptidase, dipeptidyl peptidase IV, and prolylcarboxypeptidase) share the sequential order of the catalytic Ser-Asp-His triade, which differentiates them from the chymotrypsin (His-Asp-Ser) and subtilisin (Asp-His-Ser) families. An endo or C terminal Pro-Pro bond and an endo pre-Pro peptide bond possess a high degree of resistance to any mammalian proteolytic enzyme.
The gastrointestinal barrier is - with approximately 400 m2 - the human body’s largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
Prolyl oligopeptidase (EC 3.4.21.26) activity was measured in human tissue homogenates and body fluids. The enzyme was ubiquitously present, revealing high activity in renal cortex, epithelial cells, fibroblasts, testis, lymphocytes and thrombocytes. The activity in the body fluids was low. Prolyl oligopeptidase activity was significant higher in tumours of prostate, lung and sigmoid, than in the healthy tissues. Sera of individuals suffering from HIV infection, malaria, prostate cancer or benign prostate hypertrophy contained lowered activity. Interestingly, the low serum activity during prostate carcinoma increased upon medical treatment with anti-androgens. This suggests hormonal control of the gene transcript. A positive correlation with angiotensin converting enzyme activity in hypertensive patients was demonstrated and this further supports the possible involvement of prolyl oligopeptidase in the renin-angiotensin system and in the pathogenesis of hypertension.
Chemokines are proinflammatory cytokines that play a role in leukocyte migration and activation. Recent reports showed that RANTES (regulated on activation normal T-cell expressed and secreted chemokine), eotaxin, macrophage-derived chemokine (MDC), and stromal cell–derived factor-1 (SDF-1) are NH2-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH2-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1. The potential CD26/DPP IV substrate macrophage inflammatory protein–1β (MIP-1β) and the related chemokine, LD78α (ie, one of the MIP-1α isoforms), were not affected by this protease. However, CD26/DPP IV cleaved LD78β, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus–1 (HIV-1) infection, into LD78β(3-70). Naturally truncated LD78β(3-70), but not truncated MIP-1β, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78β(3-70) had increased chemotactic activity in comparison to intact LD78β. With a minimal effective concentration of 30 pmol/L, LD78β(3-70) became the most efficient monocyte chemoattractant. LD78β(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78β(3-70) was 30-fold more potent than intact LD78β. Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78β. CD26/DPP IV–cleaved LD78β(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti–HIV-1 activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions.
Selective leukocyte trafficking towards sites of inflammation is mediated by chemokines. RANTES is a CC chemokine that attracts lymphocytes, monocytes, dendritic cells, eosinophils, basophils and NK cells. A natural form of human RANTES lacking two N-terminal residues was isolated from stimulated sarcoma cells, fibroblasts, and leukocytes. RANTES(3-68) showed a more than tenfold reduction in chemotactic potency for monocytes and eosinophils. To elucidate the mechanism involved, receptor recognition studies were performed. In cells transfected with the CC chemokine receptor (CCR) 5, the major coreceptor for macrophage-tropic HIV-1 strains, RANTES(3-68) mobilized calcium and desensitized RANTES(1-68)-induced calcium fluxes equally well as RANTES(1-68). However, RANTES(3-68) was ineffective on CCR1 and CCR3 transfectants. The reduced potency of natural RANTES(3-68) by selective loss of receptor-activating characteristics was confirmed with recombinant RANTES(3-68). In chemotaxis assays using monocytic cells, RANTES(3-68) inhibited RANTES(1-68), macrophage inflammatory protein-1 § (MIP-1 § ), MIP-1 g or monocyte chemotactic protein-3 (MCP-3), but not MCP-1-or MCP-2-induced chemotaxis. Thus, a minor post-translational modification has a remarkable impact on the biological activities of RANTES and a pathophysiologically induced change in the relative amounts of intact and truncated RANTES might affect the outcome of inflammation or HIV infection.
CD26/dipeptidyl peptidase (DPP)4 is a membrane-bound protein found in many cell types of the body, and a soluble form is present in body fluids. There is longstanding evidence that various primary tumors and also metastases express CD26/DPP4 to a variable extent. By cleaving dipeptides from peptides with a proline or alanine in the penultimate position at the N-terminus, it regulates the activity of incretin hormones, chemokines and many other peptides. Due to these effects and interactions with other molecules, a tumor promoting or suppressing role can be attributed to CD26/DPP4.In this review, we discuss the existing evidence on the expression of soluble or membrane-bound CD26/DPP4 in malignant diseases, along with the most recent findings on CD26/DPP4 as a therapeutic target in specific malignancies. The expression and possible involvement of the related DPP8 and DPP9 in cancer are also reviewed.A higher expression of CD26/DPP4 is found in a wide variety of tumor entities, however more research on CD26/DPP4 in the tumor microenvironment is needed to fully explore its use as a tumor biomarker. Circulating soluble CD26/DPP4 has also been studied as a cancer biomarker, however, the observed decrease in most cancer patients does not seem to be cancer specific. Encouraging results from experimental work and a recently reported first phase clinical trial targeting CD26/DPP4 in mesothelioma, renal and urological tumors pave the way for follow-up clinical studies, also in other tumor entities, possibly leading to the development of more effective complementary therapies against cancer.
Increased expression of serine proteases and activity together with increased expression of downstream molecules at the colonic and DRG level and in CGRP-positive sensory nerve fibres imply a role for serine proteases in post-inflammatory visceral hypersensitivity. Our results support further investigation of serine protease inhibitors as an interesting treatment strategy for IBS-related visceral pain.
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