title: The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins.
abstract: The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India ; Plant Sciences Department, University of California, Davis, CA, 95616, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Unidad de Bio, Universidad del Pais Vasco, Bilbao, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Rendón-Ramírez
authors.affiliation: Science Institute, Department of Biochemistry, University of Iceland, IS-107 Reykjavik, Iceland.
authors.forename: Bjarni
authors.initials: B
authors.lastname: Ásgeirsson
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India.
authors.forename: Mouparna
authors.initials: M
authors.lastname: Dutta
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India.
authors.forename: Anindya S
authors.initials: AS
authors.lastname: Ghosh
authors.affiliation: Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8514, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Oda
authors.affiliation: Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Venkatramani
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India.
authors.forename: Basuthkar J
authors.initials: BJ
authors.lastname: Rao
authors.affiliation: Plant Sciences Department, University of California, Davis, CA, 95616, USA.
authors.forename: Abhaya M
authors.initials: AM
authors.lastname: Dandekar
authors.affiliation: Unidad de Bio, Universidad del Pais Vasco, Bilbao, Spain.
authors.forename: Félix M
authors.initials: FM
authors.lastname: Goñi
keywords: Bacillus cereus; PI-PLC; diabetes; lipase; serine protease