Natural Substrates of Dipeptidyl Peptidase IV

Meester, Ingrid De; Durinx, Christine; Bal, Gunther; Proost, Paul; Struyf, Sofie; Goossens, Filip; Augustyns, Koen; Scharpé, Simon

doi:10.1007/0-306-46826-3_7

Cited by 76 publications

(35 citation statements)

References 70 publications

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“…This class of prolyl peptidases includes DPP-IV, prolyl oligopeptidase (POP), DPP-II, DPP8, DPP9, and fibroblast activation protein (FAP) (12,13). Unlike classic serine proteases, the POP family of enzymes is highly selective toward peptides that have a proline residue at the penultimate position (18). The x-ray structures of DPP-IV and POP have shed light on the catalytic mechanisms, which differ significantly from those of the classic serine proteases, such as trypsin and subtilisin (12, 14 -18).…”

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confidence: 99%

One Site Mutation Disrupts Dimer Formation in Human DPP-IV Proteins

Chien

Huang

Chou

et al. 2004

Journal of Biological Chemistry

103

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DPP-IV is a prolyl dipeptidase, cleaving the peptide bond after the penultimate proline residue. It is an important drug target for the treatment of type II diabetes. DPP-IV is active as a dimer, and monomeric DPP-IV has been speculated to be inactive. In this study, we have identified the C-terminal loop of DPP-IV, highly conserved among prolyl dipeptidases, as essential for dimer formation and optimal catalysis. The conserved residue His 750 on the loop contributes significantly for dimer stability. We have determined the quaternary structures of the wild type, H750A, and H750E mutant enzymes by several independent methods including chemical crosslinking, gel electrophoresis, size exclusion chromatography, and analytical ultracentrifugation. Wild-type DPP-IV exists as dimers both in the intact cell and in vitro after purification from human semen or insect cells. The H750A mutation results in a mixture of DPP-IV dimer and monomer. H750A dimer has the same kinetic constants as those of the wild type, whereas the H750A monomer has a 60-fold decrease in k cat . Replacement of His 750 with a negatively charged Glu (H750E) results in nearly exclusive monomers with a 300-fold decrease in catalytic activity. Interestingly, there is no dynamic equilibrium between the dimer and the monomer for all forms of DPP-IVs studied here. This is the first study of the function of the C-terminal loop as well as monomeric mutant DPP-IVs with respect to their enzymatic activities. The study has important implications for the discovery of drugs targeted to the dimer interface.

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confidence: 99%

One Site Mutation Disrupts Dimer Formation in Human DPP-IV Proteins

Chien

Huang

Chou

et al. 2004

Journal of Biological Chemistry

103

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“…DPP‐4 is a proteolytic enzyme with several biochemical substrates 16, including GLP‐1 and glucose‐dependent insulinotropic peptide, which play critical roles in blood glucose regulation. GLP‐1 acts primarily by stimulating pancreatic β cells for insulin secretion after meal intake, suppressing glucagon production, delaying gastric emptying and inducing satiety 17.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Empagliflozin/linagliptin single‐tablet combination: first‐in‐class treatment option

Woo

2015

Int J Clin Pract

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SummaryBackgroundThe availability of a dual sodium glucose co‐transporter 2/dipeptidyl peptidase‐4 inhibitor combination in a single‐tablet combination (STC) represents a new therapeutic option for patients with type 2 diabetes. Empagliflozin/linagliptin STC has been recently approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).AimThe aim of this study was to describe the latest clinical evidence on the efficacy and safety profiles of empagliflozin/linagliptin STCs in comparison with the individual components. Juxtaposition of the STC with dapagliflozin/saxagliptin combination was also presented.ResultsEmpagliflozin/linagliptin STC given as initial therapy or on metformin background lowered mean glycated haemoglobin (HbA1c) by approximately 1.1% (mean baseline HbA1c, 8.0%). Furthermore, the STC reduced mean body weight by 2.0–3.0 kg from baseline. With the STC treatment, no confirmed incidents of hypoglycaemia were reported in drug‐naïve patients; in patients taking metformin hypoglycaemia occurred at low rates which were comparable with monotherapy. Use of STCs in the treatment of T2DM can simplify drug dosing regimen, reduce pill burden and increase treatment adherence. Empagliflozin/linagliptin STC is a combination that offers potential additional benefits such as body weight loss and moderate reductions in blood pressure, without increasing risk of hypoglycaemia.ConclusionEmpagliflozin/linagliptin STC appears to be a rational choice for a wide range of patients in need of multiple agents for controlling hyperglycaemia. The STC should be particularly useful in patients in whom hypoglycaemia, weight gain and treatment adherence are of concern.

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“…DPP-4 selectively cleaves peptides with a proline or alanine residue in the penultimate amino-terminal position (see beginning of section III), which includes, in addition to GLP-1, approximately 30 other compounds (Table 4), mainly hormones, neuropeptides, cytokines, and chemokines (Mentlein et al, 1993;Mentlein, 1999;De Meester et al, 2000;de Meester et al, 2003), thus influencing the regulation of immune, nervous, and endocrine functions Gorrell, 2005). This should be an issue that needs to be monitored regarding long-term safety.…”

Section: E Other Compoundsmentioning

confidence: 99%

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Verspohl

2012

Pharmacol Rev

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Natural Substrates of Dipeptidyl Peptidase IV

Cited by 76 publications

References 70 publications

One Site Mutation Disrupts Dimer Formation in Human DPP-IV Proteins

One Site Mutation Disrupts Dimer Formation in Human DPP-IV Proteins

Empagliflozin/linagliptin single‐tablet combination: first‐in‐class treatment option

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

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