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This Sandbox is Reserved from Jan 06, 2014, through Aug 22, 2014 for use by the Biochemistry II class at the Butler University at Indianapolis, IN USA taught by R. Jeremy Johnson. This reservation includes Sandbox Reserved 911 through Sandbox Reserved 922.

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Contents 1 Dipeptidyl Peptidase IV 1.1 Introduction 1.2 Structure 1.3 Medical Relevancy 1.4 References

Dipeptidyl Peptidase IV

Introduction

Dipeptidyl Peptidase IV (commonly abbreviated as DPP IV) is a regulatory protease and binding glycoprotein that carries out numerous functions in humans making it a prime candidate for medicinal and pharmaceutical research. DPP IV, discovered by V.K. Hopsu-Havu and G.G. Glenner in homogenized rat liver tissue, was originally believed to serve a specific role in breaking 2-Naphthylamine off of Gly-Pro-2-napthylamide, hence its original name glycylproline napthylamidase. However, further research into the specificity of DPP IV eventually showed that it serves a more generic function as a hydrolase (a serine exopeptidase), breaking N-terminal Xaa-Pro bonds (though it can also catalyze alanine bonds). DPP IV is the founding member of the DPP-IV and/or structure homologue (DASH) family, who all share this serine protease catalysis of post-proline peptide bonds. ^[1] These penultimate prolines of the N-terminus are known for their ability to resist attacks from most proteases and also induce a conformational change of their respective proteins. Also, DPP IV serves as a binding glycoprotein on the membrane of cells, binding ligands such as adenosine deaminase with high affinity.^[2] Though this interaction has no known significance as of yet, DPP IV and its ability to catalyze N-terminal prolines gives it a unique specificity and target for pharmaceutical companies to take advantage of. ^[3]

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Structure

spinqualitylabelsall models Biological Dimer of DPP IV Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Binding Pocket The specificity of the DPP IV in its ability to discern the proline from other amino acids can be seen in the binding pocket, where two glutamates, , fill space, allowing only small residues like proline or alanine to fit. The glutamates form a salt bridge with the N-terminus, positioning the substrate so that only two amino acids can fit into position for hydrolyses. [2] Examples of DPP IV substrates with alanine or proline at their N-terminus are: Substrate N-terminus Function GLP-1 His-Ala-Glu- Increases insulin secretion; decreases glucagon secretion GIP His-Ala-Asp- Increases insulin secretion; decreases glucagon secretion NPY Tyr-Pro-Ser- Vasoconstrictor; growth of fat tissue CXCL12 Lys-Pro-Val Chemotaxis of lymphocytes; angiogenesis [2] Active Site These substrates, along with many others, are cleaved by DPP IV at its active site containing a catalytic triad composed of . This Serine-Histadine-Asparatate motif, best known in the enzyme chymotrypsin, uses acid-base chemistry to facilitate the binding, cleaving, and release of the given substrate. The mechanism of the reaction is as follows: Substrate binds to enzyme and carbonyl carbon is positioned by active site. Histadine, via hydrogen bond with asparatate, becomes more electronegative and therefore readily accepts the hydrogen from the -OH group on serine, making it nucleophilic. Arrow Pushing Mechanism The nucleophilic serine attacks the carbonyl carbon, generating a tetrahedral intermediate (as seen in the arrow pushing mechanism). The peptide bond is cleaved and the electrons from it move to attack the hydrogen on the histadine. This half of the substrate now dissociates, leaving the other half still bound to serine. Histadine then deprotonates a water molecule, forming a nucleophilic hydroxide group that attacks the serine-bound carbonyl carbon. As the electrons move from the oxygen back down to reform the double bond, serine dissociates as a leaving group and the other half of the substrate dissociates from the enzyme. The negative oxygen on serine readily accepts the hydrogen from histadine and in doing so regenerates the active site of the enzyme.

Medical Relevancy

References