title: Uric acid inhibition of dipeptidyl peptidase IV in vitro is dependent on the intracellular formation of triuret.
abstract: Uric acid affects endothelial and adipose cell function and has been linked to diseases such as hypertension, metabolic syndrome, and cardiovascular disease. Interestingly uric acid has been shown to increase endothelial progenitor cell (EPC) mobilization, a potential mechanism to repair endothelial injury. Since EPC mobilization is dependent on activity of the enzyme CD26/dipeptidyl peptidase (DPP)IV, we examined the effect uric acid will have on CD26/DPPIV activity. Uric acid inhibited the CD26/DPPIV associated with human umbilical vein endothelial cells but not human recombinant (hr) CD26/DPPIV. However, triuret, a product of uric acid and peroxynitrite, could inhibit cell associated and hrCD26/DPPIV. Increasing or decreasing intracellular peroxynitrite levels enhanced or decreased the ability of uric acid to inhibit cell associated CD26/DPPIV, respectively. Finally, protein modeling demonstrates how triuret can act as a small molecule inhibitor of CD26/DPPIV activity. This is the first time that uric acid or a uric acid reaction product has been shown to affect enzymatic activity and suggests a novel avenue of research in the role of uric acid in the development of clinically important diseases.
authors.affiliation: Renal Section, North Florida/South Georgia Veterans Health System, Gainesville, FL, United States; Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States. Electronic address: rajesh.mohandas@medicine.ufl.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mohandas
authors.affiliation: Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Sautina
authors.affiliation: Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States.
authors.forename: Elaine
authors.initials: E
authors.lastname: Beem
authors.affiliation: Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Schuler
authors.affiliation: Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States.
authors.forename: Wai-Yan
authors.initials: WY
authors.lastname: Chan
authors.affiliation: Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: John
authors.initials: J
authors.lastname: Domsic
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado-Denver, Aurora, CO, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.affiliation: Renal Section, North Florida/South Georgia Veterans Health System, Gainesville, FL, United States; Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100224, Gainesville, FL 32610-0266, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Segal
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D008958:Models, Molecular; D016877:Oxidants / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D016877:Oxidants; D011994:Recombinant Proteins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D014527:Uric Acid; C017781:triuret; D006997:Hypochlorous Acid; D014508:Urea; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: CD26/DPPIV; Triuret; Uric acid