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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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1 Dipeptidyl Peptidase IV

Dipeptidyl Peptidase IV

Image:1x70 dimer.png

Cartoon representation of DPP-IV designed in PyMol from PDB 1X70

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^[1], 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 alΌso 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. ^[2] 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.^[3] 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. ^[1]

Structure

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, orient the substrate 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 hydrolysis. ^[3] 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

^[3]

Active Site

These substrates, along with many others, are cleaved by DPP IV at its active site containing a catalytic triad composed of . The substrate shown is a DPP IV inhibitor. This Serine-Histidine-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.
Histidine, 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 histidine. This half of the substrate now dissociates, leaving the other half still bound to serine.
Histidine 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 histidine and in doing so regenerates the active site of the enzyme.

In addition to the glutamates holding the substrate in close proximity, and the catalytic triad using acid base chemistry to cleave the peptide bond, there is a tyrosine, , which is depicted in orange and notably only 4.08 angstroms away from the substrate, Sitagliptin. Based off of the crystal structure, this tyrosine is believed to stabilize the tetrahedral intermediate, another important function in enzymatic processes. ^[3] The active site in its entirety is considered to contain residues 39-51 and 501-766 and is known as the

Lastly, the homodimerization of DPP IV is critical to the catalytic function. Though there are domains that play key roles in the formation of this dimer, a particular histadine () has been shown to inhibit the formation of the dimer if point mutated to glutamate. From this information it could be extrapolated that the histadine is forming some ionic interaction with the opposing chain, with the mutation from positive charge to negative charge creating a repulsive effect thus eliminating the ability to dimerize. ^[3]

Propeller Domain

Medical Relevancy

References

↑ ^1.0 ^1.1 Mentlein R. Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept. 1999 Nov 30;85(1):9-24. PMID:10588446
↑ Lankas GR, Leiting B, Roy RS, Eiermann GJ, Beconi MG, Biftu T, Chan CC, Edmondson S, Feeney WP, He H, Ippolito DE, Kim D, Lyons KA, Ok HO, Patel RA, Petrov AN, Pryor KA, Qian X, Reigle L, Woods A, Wu JK, Zaller D, Zhang X, Zhu L, Weber AE, Thornberry NA. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005 Oct;54(10):2988-94. PMID:16186403
↑ ^3.0 ^3.1 ^3.2 ^3.3 ^3.4 Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci (Lond). 2005 Apr;108(4):277-92. PMID:15584901 doi:http://dx.doi.org/10.1042/CS20040302

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_918"

@@ Line 16: / Line 16: @@
 <StructureSection load='1X70' size='350' frame='true' align='right' caption='Biological Dimer of DPP IV' scene='57/573132/1x70_basic_dimer/1'>
 ===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, <scene name='57/573132/1x70_glutamates/3'>Glu205-Glu206</scene> orient the substrate allowing only small residues like proline or alanine to fit. The [http://en.wikipedia.org/wiki/Glutamic_acid glutamates] form a [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridge] with the N-terminus, positioning the substrate so that only two amino acids can fit into position for hydrolyses. <ref name="Gorrell">PMID: 15584901</ref> Examples of DPP IV substrates with alanine or proline at their N-terminus are:
+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, <scene name='57/573132/1x70_glutamates/3'>Glu205-Glu206</scene> orient the substrate allowing only small residues like proline or alanine to fit. The [http://en.wikipedia.org/wiki/Glutamic_acid glutamates] form a [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridge] with the N-terminus, positioning the substrate so that only two amino acids can fit into position for hydrolysis. <ref name="Gorrell">PMID: 15584901</ref> Examples of DPP IV substrates with alanine or proline at their N-terminus are:
 {| class="wikitable" style="text-align:center; width:550px; height:200px;"
 |+
@@ Line 42: / Line 42: @@
 ===Active Site===
-These substrates, along with many others, are cleaved by DPP IV at its active site containing a [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] composed of <scene name='57/573132/1x70_catalytictriad/1'>Ser630, His740, and Asp708</scene>. The substrate shown is a DPP IV inhibitorThis Serine-Histadine-Asparatate motif, best known in the enzyme [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin], uses acid-base chemistry to facilitate the binding, cleaving, and release of the given substrate. The mechanism of the reaction is as follows:
+These substrates, along with many others, are cleaved by DPP IV at its active site containing a [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] composed of <scene name='57/573132/1x70_catalytictriad/1'>Ser630, His740, and Asp708</scene>. The substrate shown is a DPP IV inhibitor. This Serine-Histidine-Asparatate motif, best known in the enzyme [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin], uses acid-base chemistry to facilitate the binding, cleaving, and release of the given substrate. The mechanism of the reaction is as follows:
 <div style="text-align: left;">
 # Substrate binds to enzyme and carbonyl carbon is positioned by [http://en.wikipedia.org/wiki/Active_site active site].
-# Histadine, via hydrogen bond with asparatate, becomes more [http://en.wikipedia.org/wiki/Electronegativity electronegative] and therefore readily accepts the hydrogen from the -OH group on serine, making it [http://en.wikipedia.org/wiki/Nucleophile nucleophilic]. [[Image:Serine_protease_mechanism_by_snellios.png|right|thumb|150px|<font size=".8"><div style="text-align: center;"> Arrow Pushing Mechanism  </div></font>]]
+# Histidine, via hydrogen bond with asparatate, becomes more [http://en.wikipedia.org/wiki/Electronegativity electronegative] and therefore readily accepts the hydrogen from the -OH group on serine, making it [http://en.wikipedia.org/wiki/Nucleophile nucleophilic]. [[Image:Serine_protease_mechanism_by_snellios.png|right|thumb|150px|<font size=".8"><div style="text-align: center;"> Arrow Pushing Mechanism  </div></font>]]
 # The nucleophilic serine attacks the [http://en.wikipedia.org/wiki/Carbonyl carbonyl] carbon, generating a [http://goldbook.iupac.org/T06289.html tetrahedral intermediate] (as seen in the [http://en.wikipedia.org/wiki/Arrow_pushing 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.
+# The peptide bond is cleaved and the electrons from it move to attack the hydrogen on the histidine. This half of the substrate now dissociates, leaving the other half still bound to serine.
-# Histadine then deprotonates a water molecule, forming a nucleophilic [http://en.wikipedia.org/wiki/Hydroxide hydroxide group] that attacks the serine-bound carbonyl carbon.
+# Histidine then deprotonates a water molecule, forming a nucleophilic [http://en.wikipedia.org/wiki/Hydroxide hydroxide group] that attacks the serine-bound carbonyl carbon.
 # As the electrons move from the oxygen back down to reform the double bond, serine [http://en.wikipedia.org/wiki/Dissociation_(chemistry) 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.
+# The negative oxygen on serine readily accepts the hydrogen from histidine and in doing so regenerates the active site of the enzyme.
  </div>

Sandbox Reserved 918

From Proteopedia

Revision as of 17:51, 31 March 2014

Contents

Dipeptidyl Peptidase IV

Introduction

Structure

Binding Pocket

Active Site

Propeller Domain

Medical Relevancy

References

Views

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