Dipeptidyl-peptidase IV

Dipeptidyl-peptidase IV

Clan SC  S9 | 745. Dipeptidyl-peptidase IV 3374 (2006). Crystal structure and mechanism of tripeptidyl activity of prolyl tripeptidyl aminopeptidas...

83KB Sizes 1 Downloads 67 Views

Clan SC  S9 | 745. Dipeptidyl-peptidase IV


(2006). Crystal structure and mechanism of tripeptidyl activity of prolyl tripeptidyl aminopeptidase from Porphyromonas gingivalis. J Mol Biol. 362, 228240. [4] Umezawa, Y., Yokoyama, K., Kikuchi, Y., Date, M., Ito, K., Yoshimoto, T., Matsui, H. (2004). Novel prolyl tri/tetra-peptidyl aminopeptidase from Streptomyces mobaraensis: substrate specificity and enzyme gene cloning. J. Biochem. 136, 293300.

[5] Fujimura, S., Ueda, O., Shibata, Y., Hirai, K. (2003). Isolation and properties of a tripeptidyl peptidase from a periodontal pathogen Prevotella nigrescens. FEMS Microbiol Lett. 219, 305309. [6] Xu, Y., Nakajima, Y., Ito, K., Zheng, H., Oyama, H., Heiser, U., Hoffmann, T., Gartner, U-G., Demuth, H.-U., Yoshimoto, T. (2008). Novel inhibitor for prolyl tripeptidyl aminopeptidase from Porphyromonas gingivalis and details of substrate-recognition mechanism. J. Mol. Biol. 375, 708719.

Yoshitaka Nakajima Department of Lifescience, Setsunani University Faculty of Science and Technology, Neyagawa, 572-8508, Japan. Email: [email protected]

Kiyoshi Ito Department of Biotechnology, Nagasaki University School of Pharmaceutical Sciences, Nagasaki, 8528521, Japan. Email: [email protected]

Tadashi Yoshimoto Department of Lifescience, Setsunani University Faculty of Science and Technology, Neyagawa, 572-8508, Japan. Email: [email protected] © 2013 Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/B978-0-12-382219-2.00744-4

Handbook of Proteolytic Enzymes, 3rd Edn ISBN: 978-0-12-382219-2

Chapter 745

Dipeptidyl-peptidase IV DATABANKS MEROPS name: dipeptidyl-peptidase IV (eukaryote) MEROPS classification: clan SC, family S9, subfamily S9B, peptidase S09.003 IUBMB: EC (BRENDA) Tertiary structure: Available Species distribution: subphylum Vertebrata Reference sequence from: Homo sapiens (UniProt: P27487) MEROPS name: dipeptidyl-peptidase IV (bacteria) MEROPS classification: clan SC, family S9, subfamily S9B, peptidase S09.013 Species distribution: superkingdom Bacteria sequence from: Chryseobacterium Reference meningosepticum

Name and History Dipeptidyl-peptidase IV (DPP IV) is a serine exopeptidase that cleaves Xaa-Pro dipeptides from the N-terminus of oligo- and polypeptides. It was first reported as glycylproline naphthylamidase by Hopsu-Havu & Glenner [1], and has

been named dipeptidyl aminopeptidase IV or postproline dipeptidyl peptidase IV in early work [2]. The enzyme was found to be abundant in kidney, small intestine, submaxillary gland and liver, from which it has been purified in a soluble form released by autolysis of microsomes [36]. Immunocytochemical studies revealed that the enzyme is localized in an apical domain of the plasma membrane in polarized epithelial cells [7], accounting for its enrichment in the above mentioned tissues. The entire sequence of the enzyme molecule was first determined by cloning and sequencing the cDNA for rat DPP IV [8], allowing structural comparison with other proteins [9,10]. Both CD26, a surface marker involved in transduction of mitogenic signals in thymocytes and T lymphocytes [11], and rat liver plasma membrane glycoprotein gp110 were found to be identical to DPP IV [12].

Activity and Specificity DPP IV is specific for a proline residue at the penultimate position, and hydrolyzes on the carboxyl side of this residue (Xaa-ProkXbb-). The Pro residue can be substituted

Clan SC  S9 | 745. Dipeptidyl-peptidase IV


by an Ala or a hydroxyproline, although the rates of hydrolysis for these substrates are much lower than that for the corresponding substrate containing Pro. The identity of the N-terminal residue of the substrate is not important for the enzyme activity [2] although it must have a free amino group. DPP IV cannot hydrolyze substrates with Pro [13] or hydroxyproline in the third position (P10 ) [3]. DPP IV shows quite similar substrate specificity to the unrelated Xaa-Pro dipeptidyl-peptidase of lactococci (Chapter 757) [14]. Assay of activity can be done with Gly-ProkNHPhNO2 by measuring released p-nitroaniline photometrically [15]. This synthetic substrate is available from Sigma and Peptide Institute. One unit of activity is defined as the amount of activity which is capable of cleaving 1 µmol of substrate min21 at 37 C. DPP IV requires neither metals nor any cofactors for its activity. The pH optimum is about 7.8. DPP IV shows pH stability over a wide range (pH 510), is thermostable (up to 72 C), and is remarkably resistant to denaturation with 8 M urea [2,16]. DPP IV is very sensitive to DFP, but much less sensitive to other well-known serine protease inhibitors such as diethyl p-nitrophenylphosphate and PMSF [4]. Ala-(or Pro)-boroPro dipeptide [17] and aminoacylpyrrolidine-2nitriles [18] are specific and potent inhibitors of DPP IV, but are not yet commercially available. Heavy metals such as zinc, cadmium, mercury and lead inhibit the enzyme activity remarkably [19]. Recently, DPP IV has become a target for the design of drugs, and this has driven the discovery of novel inhibitors. Amongst these are NVP-DPP728 (1-(2-[(5-cyanopyridin-2-yl)amino]ethylamino)acetyl-2-cyano-S-pyrrolidine monohydrochloride salt) [20,21], Lys[Z(NO2)]thiazolidine and Lys[Z(NO2)] pyrrolidide [22], P32/98 [23] and FE999011 [24]. It has also been found that proteins with the N-terminal sequence Xaa-Xaa-Pro inhibit DPP IV [25]. In the last decade, peptide-derived slow-tight binding inhibitors such as NVP-LAF237 (vildagliptin), MK-0431 (sitagliptin) and SYR-322 (alogliptin) have been used for preclinical and clinical studies for potential treatment of type 2 diabetes [26,27].

contains glycosylation sites (mostly in the N-terminal half), a cysteine-rich region (C-terminal half) and the catalytic active site. The presence of eight potential N-linked glycosylation sites accounts for the difference in molecular mass between the predicted polypeptide (88 kDa) and the mature form (109 kDa). In the native state, DPP IV is present on the cell surface as a noncovalently linked homodimer [26]. In the rat enzyme, the active-site Ser631 residue was identified by chemical modification and mutagenesis [27], and is in the sequence Gly-Trp-Ser-Tyr-Gly, which corresponds to the consensus motif Gly-Xaa-Ser-Xaa-Gly proposed for the active site of serine proteases generally [28]. It is of interest to note that a single substitution of either Gly residue in the motif results in retention of the newly synthesized enzyme in the endoplasmic reticulum, and rapid degradation [29,30], suggesting that both residues are also essential for correct folding of the molecule and its transport to the cell surface. Other essential residues required for the catalytic triad of the rat enzyme are Asp709 and His741 [31]. The sequential order of the catalytic triad residues (Ser/Asp/His) in DPP IV from all species is characteristic of clan SC (see Chapters 742752). A soluble form of DPP IV that occurs in human serum was characterized and found to be a proteolytic derivative cleaved on the amino side of Ser39 so as to detach the enzyme from its N-terminal membrane-insertion domain [32]. A crystal structure of DPP IV was analyzed by using purified ectodomains of recombinant human DPP IV expressed in Pichica pasteria and the insect cell Sf9 or natively prepared porcine DPP IV [33,34]. The structure shows a homodimer or tetramer in the crystal form, in agreement with the data obtained by biochemical analysis. One site substitution introduced at His750 was found to disrupt dimer formation and cause no enzyme activity, demonstrating that the dimer formation is essential for full activity of the enzyme [35].

Structural Chemistry

DPP IV is widely distributed in a variety of species and tissues, from which it has been prepared with various degrees of purity. Since it is most abundant in kidney, small intestine, submaxillary gland and placenta [3,6,7,26] and relatively enriched in liver [36], the enzyme has been purified to homogeneity from these tissues. The intact membrane form is usually prepared by solubilizing the enzyme with Triton X-100, while a soluble form is obtained by autolysis of microsomes incubated at low pH or by digestion of membranes with papain [26] which cleaves a site adjacent to the transmembrane domain and releases the enzyme with a

The entire amino acid sequences of DPP IV for human, rat and mouse have been determined by cDNA cloning and sequencing. Rat DPP IV contains 767 amino acids with a calculated molecular mass of 88 107 Da [8]. It is a type II membrane protein whose N-terminal hydrophobic sequence represents an uncleavable signal peptide that also functions as a membrane-anchoring domain. Thus, DPP IV has a short cytoplasmic tail (six residues), a transmembrane domain (23 residues) and a long extracellular domain (738 residues). The extracellular domain



slightly smaller molecular mass [8]. DPP IV was transiently expressed in COS-1 cells [29], and stably transfected CHO cells [37], mouse fibroblast Lm [31] and Jurkat cells [38] have been established. Human DPP IV has been expressed in insect Sf9 cells with a yield of about 10 mg per liter of culture [39].

Biological Aspects The gene structure of human DPP IV was elucidated by Abbott and coworkers [40]. The human DPP IV gene located at 2q24.3 spans approximately 70 kbp and contains 26 exons. The nucleotides that encode the active-site sequence (Gly-Xaa-Ser-Xaa-Gly) are split between two exons. This clearly distinguishes the genomic organization of DPP IV from that of the classical serine proteases [10]. The promoter region contains an unmethylated CpG island with several Sp1-binding sites and no consensus TATA box, which are characteristics of promoters found in housekeeping genes. In spite of these sequence features, the DPP IV promoter shows widely varying transcriptional activity that mirrors the enzyme activities in several cells [41]. These characteristics of the promoter may play a role in the ubiquitous expression of the DPP IV transcript at different levels: high expression in kidney, small intestine and placenta, moderate expression in lung, spleen and liver, and a low level of expression in heart, pancreas and brain [40,42]. DPP IV has been proposed to serve a number of different functions [43,44]. In kidney brush border membranes, the enzyme may be involved in a transport system specific for dipeptides and tripeptides [45]. DPP IV levels in rat small intestine can be increased by feeding a gelatin (high proline) diet [46]. These results suggest that DPP IV is one of the peptidases important in the digestion and assimilation of prolyl peptides. Studies of cell adhesion have suggested an involvement of DPP IV in interaction of cells with the extracellular matrix, especially with collagens [47]. Based on experiments with monoclonal antibodies that inhibit the binding of DPP IV to collagen matrix, it is proposed that a putative binding site of the enzyme against collagens is the cysteine-rich domain distinct from the catalytic domain [48]. In the immune system, DPP IV (CD26) is considered to be an activation factor on the surface of human T lymphocytes, and to play a key role in the regulation of proliferation and differentiation of the lymphocytes [44], including production of lymphokines [49]). Studies with specific inhibitors of the enzyme suggest that DPP IV contributes to T-cell activation through its dipeptidyl-peptidase activity [17]. However, experiments in which the putative catalytic Ser residue of DPP IV was mutated to Ala, eliminating catalytic activity, suggested that the peptidase activity plays an important, but not absolute role in the enhancement of interleukin 2 (IL-2) production by Jurkat cells [38].

Clan SC  S9 | 745. Dipeptidyl-peptidase IV

DPP IV is found to be identical to a protein that was known as ‘adenosine deaminase complexing protein’ [50]. Human adenosine deaminase, but not the mouse homolog, binds to DPP IV, and a cluster of charged amino acid residues seems to be responsible [51]. The kinetics of hydrolysis of a number of bioactive peptides in vitro were described by Lambeir et al. [52]. DPP IV also inactivates a number of biologically active peptides in vivo. These include the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. DPP IV inhibition with NVP-DPP728 prevents the Nterminal degradation of the endogenous incretins in vivo, resulting in increased plasma concentrations of the intact, biologically active peptides with insulinotropic activity [53]. Inhibitors such as NVP-DPP728 and FE 999011 show promise as leads to drugs in various models of diabetes and related disturbances of glucose metabolism [24,54,55]. DPP IV also removes dipeptides sequentially from the N-termini of glucagon [56] and procalcitonin [25].

Distinguishing Features The cellular localization and enzymatic properties of DPP IV are quite different from those of other dipeptidylpeptidases (dipeptidyl-peptidases I, II and III) found in mammalian tissues [57,58]. Dipeptidyl-peptidase I (Chapter 448) and dipeptidyl-peptidase II (Chapter 759) are localized in lysosomes and require acidic pH (5.06.0) for maximal activity, while dipeptidyl-peptidase III (Chapter 285) is a cytosolic enzyme with an optimum pH near 9. Dipeptidyl-peptidase II hydrolyzes substrates with Pro or Ala in the penultimate position as does DPP IV, but neither dipeptidyl-peptidase I nor dipeptidyl-peptidase III can cleave the Xaa-Pro dipeptide from substrates. Dipeptidylpeptidase I is a cysteine peptidase, DPP II and DPP IV are serine peptidases, and DPP III is a metallopeptidase. Polyclonal antisera to rat liver [8,42] and pig kidney [7] DPP IV have been produced in rabbits. Monoclonal anti-human DPP IV (Coulter, Eurogenetics), polyclonal anti-human DPP IV (Transformation Research) and polyclonal anti-pig DPP IV antibodies (Serva) are commercially available.

Further Reading A full description of the purification and assay methods for liver DPP IV has been provided by Ikehara et al. [59], and biological and clinical aspects of DPP IV have been reviewed by several investigators [6062].

References [1] Hopsu-Havu, V.K., Glenner, G.G. (1966). A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide. Histochemie 7, 197201.

Clan SC  S9 | 745. Dipeptidyl-peptidase IV

[2] Yoshimoto, T., Fischl, M.., Orlowski, R.C., Walter, R. (1978). Post-proline cleaving enzyme and post-proline dipeptidyl aminopeptidase. Comparison of two peptidases with high specificity for proline residues. J. Biol. Chem. 253, 37083716. [3] Oya, H., Harada, M., Nagatsu, T. (1974). Peptidase activity of glycylprolyl beta-naphthylamidase from human submaxillary gland. Arch. Oral Biol. 19, 489491. [4] Kenny, A.J., Booth, A.G., George, S.G., Ingram, J., Kershaw, D., Wood, E.J., Young, A.R. (1976). Dipeptidyl peptidase IV, a kidney brush-border serine peptidase. Biochem. J. 157, 169182. [5] Yoshimoto, T., Walter, R. (1977). Post-proline dipeptidyl aminopeptidase (dipeptidyl aminopeptidase IV) from lamb kidney. Purification and some enzymatic properties. Biochim. Biophys. Acta 485, 391401. [6] Svensson, B., Danielsen, M., Staun, M., Jeppesen, L., Nore´n, O., Sjo¨stro¨m, H. (1978). An amphiphilic form of dipeptidyl peptidase IV from pig small-intestinal brush-border membrane. Purification by immunoadsorbent chromatography and some properties. Eur. J. Biochem. 90, 489498. [7] Fukasawa, K.M., Fukasawa, K., Sahara, N., Harada, M., Kondo, Y., Nagatsu, I. (1981). Immunohistochemical localization of dipeptidyl aminopeptidase IV in rat kidney, liver, and salivary glands. J. Histochem. Cytochem. 29, 337343. [8] Ogata, S., Misumi, Y., Ikehara, Y. (1989). Primary structure of rat liver dipeptidyl peptidase IV deduced from its cDNA and identification of the NH2-terminal signal sequence as the membraneanchoring domain. J. Biol. Chem. 264, 35963601. [9] Misumi, Y., Hayashi, Y., Arakawa, F., Ikehara, Y. (1992). Molecular cloning and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase on the cell surface. Biochim. Biophys. Acta 1131, 333336. [10] Rawlings, N.D., Polga´r, L., Barrett, A.J. (1991). A new family of serine peptidases related to prolyl oligopeptidase. Biochem. J. 279, 907911. [11] Ulmer, A.J., Mattern, T., Feller, A.C., Heymann, E., Flad, H.-D. (1990). CD26 antigen is a surface dipeptidyl peptidase IV (DPP IV) as characterized by monoclonal antibodies clone TII-19-4-7 and 4EL1C7. Scand. J. Immunol. 31, 429435. [12] McCaughan, G.W., Wickson, J.E., Creswick, P.F., Gorrell, M.D. (1990). Identification of the bile canalicular cell surface molecule GP110 as the ectopeptidase dipeptidyl peptidase IV: an analysis by tissue distribution, purification and N-terminal amino acid sequence. Hepatology 11, 534544. [13] McDonald, J.K., Zeitman, B.B., Ellis, S. (1970). Leucine naphthylamide: an inappropriate substrate for the histochemical detection of cathepsins B and B0 . Nature 225, 10481049. [14] Yoshpe-Besancon, I., Gripon, J.C., Ribadeau-Dumas, B. (1994). Xaa-Pro-dipeptidyl-aminopeptidase from Lactococcus lactis catalyses kinetically controlled synthesis of peptide bonds involving proline. Biotechnol. Appl. Biochem. 20, 131140. [15] Nagatsu, T., Hino, M, Fuyamada, H., Hayakawa, T., Sakakibara, S. (1976). New chromogenic substrates for X-prolyl dipeptidyl-aminopeptidase. Anal. Biochem. 74, 466476. [16] Fukasawa, K.M., Fukasawa, K., Hiraoka, B.Y., Harada, M. (1981). Comparison of dipeptidyl peptidase IV prepared from pig liver and kidney. Biochem. Biophys. Res. Commun. 657, 179189. [17] Flentke, G.R., Munoz, E., Huber, B.T., Plaut, A.G., Kettner, C.A., Bachovchin, W.W. (1991). Inhibition of dipeptidyl aminopeptidase












[28] [29]



IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function. Proc. Natl Acad. Sci. USA 88, 15561559. Li, J., Wilk, E., Wilk, S. (1995). Aminoacylpyrrolidine-2-nitriles: potent and stable inhibitors of dipeptidyl-peptidase IV (CD 26). Arch. Biochem. Biophys. 323, 148154. Pu¨schel, G., Mentlein, R., Heymann, E. (1982). Isolation and characterization of dipeptidyl peptidase IV from human placenta. Eur. J. Biochem. 126, 359365. Hughes, T.E., Mone, M.D., Russell, M.E., Weldon, S.C., Villhauer, E.B. (1999). NVP-DPP728-(1-[[[2-[(5-cyanopyridin-2yl) amino]ethyl] amino] acetyl]-2-cyano-(S)-pyrrolidine), a slowbinding inhibitor of dipeptidyl peptidase IV. Biochemistry 38, 1159711603. Villhauer, E.B., Brinkman, J.A., Naderi, G.B., Dunning, B.E., Mangold, B.L., Mone, M.D., Russell, M.E., Weldon, S.C., Hughes, T.E. (2002). 1-[2-[(5-Cyanopyridin-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 45, 23622365. Sto¨ckel-Maschek, A., Mrestani-Klaus, C., Stiebitz, B., Demuth, H.U., Neubert, K. (2000). Thioxo amino acid pyrrolidides and thiazolidides: new inhibitors of proline specific peptidases. Biochim.Biophys.Acta Protein Struct. Mol. Enzymol. 1479, 1531. Pospisilik, J.A., Stafford, S.G., Demuth, H.U., Brownsey, R., Parkhouse, W., Finegood, D.T., McIntosh, C.H.S., Pederson, R.A. (2002). Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 51, 943950. Sudre, B., Broqua, P., White, R.B., Ashworth, D., Evans, D.M., Haigh, R., Junien, J.L., Aubert, M.L. (2002). Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats. Diabetes 51, 14611469. Wrenger, S., Ka¨hne, T., Bohuon, C., Weglo¨hner, W., Ansorge, S., Reinhold, D. (2000). Amino-terminal truncation of procalcitonin, a marker for systemic bacterial infections, by dipeptidyl peptidase IV (DP IV). FEBS Lett. 466, 155159. Macnair, D.C., Kenny, A.J. (1979). Proteins of the kidney microvillar membrane. The amphipathic form of dipeptidyl peptidase IV. Biochem. J. 179, 379395. Ogata, S., Misumi, Y., Tsuji, E., Takami, N., Oda, K., Ikehara, Y. (1992). Identification of the active site residues in dipeptidyl peptidase IV by affinity labeling and site-directed mutagenesis. Biochemistry 31, 25822587. Brenner, S. (1988). The molecular evolution of genes and proteins: a tale of two serines. Nature 334, 528530. Tsuji, E., Misumi, Y., Fujiwara, T., Takami, N., Ogata, S., Ikehara, Y. (1992). An active-site mutation (Gly633-Arg) of dipeptidyl peptidase IV causes its retention and rapid degradation in the endoplasmic reticulum. Biochemistry 31, 1192111927. Fujiwara, T., Tuji, E., Misumi, Y., Takami, N., Ikehara, Y. (1992). Selective cell-surface expression of dipeptidyl peptidase IV with mutations at the active site sequence. Biochem. Biophys. Res. Commun. 185, 776784. David, F., Bernard, A.M., Pierres, M., Marguet, D. (1993). Identification of serine 624, aspartic acid 702, and histidine 734 as

Clan SC  S9 | 745. Dipeptidyl-peptidase IV






[36] [37]







[44] [45]


the catalytic triad residues of mouse dipeptidyl-peptidase IV (CD26). A member of a novel family of nonclassical serine hydrolases. J. Biol. Chem. 268, 1724717252. Iwaki-Egawa, S., Watanabe, Y., Kikuya, Y., Fujimoto, Y. (1998). Dipeptidyl peptidase IV from human serum: purification, characterization, and N-terminal amino acid sequence. J. Biochem. (Tokyo) 124, 428433. Thomas, R., Loffler, B., Stihle, M., Huber, W., Ruf, A., Hennig, M. (2003). Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure 11, 947959. Rasmussen, H.H., Brenner, S., Wiberg, F.C., Wagtman, N. (2003). Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat. Struct. Biol. 10, 1925. Engel, M., Chien, C.H., Huang, L.H., Chou, C.Y., Han, Y.S., Chang, G.G., Lian, P.H., Chen, X. (2004). One site mutation disrupts dimer formation in human DPP-IV protein. J. Biol. Chem. 279, 5233852345. Elovson, J. (1980). Biogenesis of plasma membrane glycoproteins. J. Biol. Chem. 255, 58075815. Hong, W.J., Piazza, G.A., Hixson, D.C., Doyle, D. (1989). Expression of enzymatically active rat dipeptidyl peptidase IV in Chinese hamster ovary cells after transfection. Biochemistry 28, 84748479. Tanaka, T., Kameoka, J., Yaron, A., Schlossman, S.F., Morimoto, C. (1993). The costimulatory activity of the CD26 antigen requires dipeptidyl peptidase IV enzymatic activity. Proc. Natl Acad. Sci. USA 90, 45864590. Dobers, J., Zimmermann-Kordmann, M., Leddermann, M., Schewe, T., Reutter, W., Fan, H. (2002). Expression, purification, and characterization of human dipeptidyl peptidase IV/CD26 in Sf9 insect cells. Protein Expr. Purif. 25, 527. Abbott, C.A., Baker, E., Sutherland, G.R., McCaughan, G.W. (1994). Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics 40, 331338. Bo¨hm, S.K., Gum, J.R., Erickson, R.H., Hicks, J.W., Kim, Y.S. (1995). Human dipeptidyl peptidase IV gene promoter: tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter. Biochem. J. 311, 835843. Hong, W.J., Petell, J.K., Swank, D., Sanford, J., Hixson, D.C., Doyle, D. (1989). Expression of dipeptidyl peptidase IV in rat tissues is mainly regulated at the mRNA levels. Exp. Cell Res. 182, 256266. Lambeir, A.M., Durinx, C., Scharpre, S., De Meester, I. (2003). Dipeptidyl-peptidase IV from bench to bedside; an uupdate on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit. Rev. Clin. Lab. Sci. 40, 209294. Boonacker, E., Van Noorden, C.J. (2003). The multifunctional or moonlighting protein CD26/DPPIV. Eur. J. Cell Biol. 82, 5373. Tiruppathi, C., Ganapathy, V., Leibach, F.H. (1990). Evidence for tripeptide-proton symport in renal brush border membrane vesicles. Studies in a novel rat strain with a genetic absence of dipeptidyl peptidase IV. J. Biol. Chem. 265, 20482053. Suzuki, Y., Erickson, R.H., Sedlmayer, A., Chang, S.-K., Ikehara, Y., Kim, Y.S. (1993). Dietary regulation of rat intestinal angiotensin-converting enzyme and dipeptidyl peptidase IV. Am. J. Physiol. 264, G1153G1159.

[47] Johnson, R.C., Zhu, D., Augustin-Voss, H.G., Pauli, B.U. (1993). Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells. J. Cell Biol. 121, 14231432. [48] Lo¨ster, K., Zeilinger, K., Schuppan, D., Reutter, W. (1995). The cysteine-rich region of dipeptidyl peptidase IV (CD 26) is the collagen-binding site. Biochem. Biophys. Res. Commun. 217, 341348. [49] Reinhold, D., Bank, U., Bu¨hling, F., Ka¨hne, T., Kunt, D., Faust, J., Neubert, K., Ansorge, S. (1994). Inhibitors of dipeptidyl peptidase IV (DP IV, CD26) specifically suppress proliferation and modulate cytokine production of strongly CD26 expressing U937 cells. Immunobiology 192, 121136. [50] Ben-Shooshan, I., Parola, A.H. (1998). The CP-I subunit of adenosine deaminase complexing protein from calf kidney is identical to human, mouse, and rat dipeptidyl peptidase IV. Comp. Biochem. Physiol. B 119B, 289292. [51] Richard, E., Alam, S.M., Arredondo-Vega, F.X., Patel, D.D., Hershfield, M.S. (2002). Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing Protein CD26/Dipeptidyl Peptidase IV. J. Biol. Chem. 277, 1972019726. [52] Lambeir, A.M., Durinx, C., Proost, P., Van Damme, J., Scharpe´, S., De Meester, I. (2001). Kinetic study of the processing by dipeptidyl-peptidase IV/CD26 of neuropeptides involved in pancreatic insulin secretion. FEBS Lett. 507, 327330. [53] Deacon, C.F., Wamberg, S., Bie, P., Hughes, T.E., Holst, J.J. (2002). Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs. J. Endocrinol. 172, 355362. [54] Mitani, H., Takimoto, M., Kimura, M. (2002). Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity. Jpn. J. Pharmacol. 88, 451458. [55] Reimer, M.K., Holst, J.J., Ahren, B. (2002). Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur. J. Endocrinol. 146, 717727. [56] Hinke, S.A., Pospisilik, J.A., Demuth, H.U., Mannhart, S., Ku¨hnWache, K., Hoffmannn, T., Nishimura, E., Pederson, R.A., McIntosh, C.H.S. (2000). Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon  Characterization of glucagon degradation products and DPIV-resistant analogs. J. Biol. Chem. 275, 38273834. [57] McDonald, J.K., Schwabe, C. (1977). Intracellular exopeptidases, in: Proteinases in Mammalian Cells and Tissues, Barrett, A.J., ed., Amsterdam: North-Holland Publishing, pp. 331391. [58] McDonald, J.K., Barrett, A.J. (1986). Mammalian Proteases: a Glossary and Bibliography, Vol. 2, Exopeptidases, London: Academic Press. [59] Ikehara, Y., Ogata, S., Misumi, Y. (1994). Dipeptidyl-peptidase IV from rat liver. Methods Enzymol. 244, 215227. [60] Augustyns, K., Van der Veken, P., Senten, K., Haemers, A. (2005). The therapeutic potential of inhibitors of dipeptidyl peptidase IV (DPP IV) and related proline-specific dipeptidyl aminopeptidases. Curr. Med. Chem. 12, 971998. [61] Amori, R.E., Lau, J., Pittas, A.G. (2007). Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and metaanalysis. JAMA 298, 194206.

Clan SC  S9 | 745. Dipeptidyl-peptidase IV

[62] Ansorge, S., Bank, U., Heinburg, A., Helmuth, M., Koch, G., Tadje, J., Lendeckel, U., Wolke, C., Neubert, K., Faust, J., Fuchs, P., Reinhold, D., Tager, M. (2009). Recent insights into the


role of dipeptidyl aminopeptidase IV (DPPIV) and aminopeptidase (APN) families in immune functions. Clin. Chem. Lab. Med. 47, 253261.

Yoshio Misumi Department of Cell Biology, Fukuoka University School of Medicine, Jonan-ku, Fukuoka 814-0181, Japan. Email: [email protected]

Yukio Ikehara Fukuoka University (Professor emeritus), Sawara-ku, Fukuoka 814-0171, Japan. Email: [email protected] Handbook of Proteolytic Enzymes, 3rd Edn ISBN: 978-0-12-382219-2

© 2013 Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/B978-0-12-382219-2.00745-6