User:Karisma Moll/Sandbox 1

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DPPIV in Humans

1 Introduction
- 1.1 History
- 1.2 Function
2 Structure
3 Relevance
- 3.1 Diabetes
- 3.2 HIV/AIDS

Introduction

Image of DPPIV

Proline Peptidase Overview

History

Dipeptidyl Peptidase IV's role in the inactivation of incretin hormones was discovered in the 1990s. Animal studies were conducted in the late 1990s, followed by human studies in the early 2000s. The first DPPIV inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin, and linagliptin) were approved starting in 2006, and now serve as monotherapy or add-on to other therapies in a glucose-lowering capacity. ^[1] Since their approval, there have been multiple long-term trials to continue exploring the long-term effects of these medications. It is known that gliptins directly impact the pancreas, kidney, heart, and vessels. The most investigated thus far is the effects of gliptins on real and cardiovascular functioning. ^[2] Results of phase II and III trails indicated that gliptins did not harm the cardiovascular system. A meta-analysis implicated two possible beneficial effects for patients treated with these medications: a reduction in cardiovascular effects and a direct renoprotective effect. ^[3]

Function

town tartness

Structure

Something about interactions... ^[4]

Overview

Catalytic Triad

^[4]

Mechanism

The picture of the mechanism is inserted but not visible, maybe too high of a quality? Once a substrate is bound in the active site, DPPIV utilizes a covalent catalysis mechanism to cleave the substrate at the penultimate position. Asp708 of the (Ser630, His 740, Asp708) pulls electron density from His740 allowing the histidine to pull electron density from Ser630, making serine a stronger nucleophile. The water molecule attacks the carbonyl carbon, breaking the newly formed covalent bond, and releasing the first two residues of the starting substrate. The active site resets.

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Figure 5. Mechanism of the catalytic triad of DPPIV.

Inhibitors

Relevance

Diabetes

HIV/AIDS

References

↑ Ahrén B. DPP-4 Inhibition and the Path to Clinical Proof. Front Endocrinol (Lausanne). 2019 Jun 19;10:376. PMID:31275243 doi:10.3389/fendo.2019.00376
↑ Khalse M, Bhargava A. A Review on Cardiovascular Outcome Studies of Dipeptidyl Peptidase-4 Inhibitors. Indian J Endocrinol Metab. 2018 Sep-Oct;22(5):689-695. PMID:30294582 doi:10.4103/ijem.IJEM_104_18
↑ Hocher B, Reichetzeder C, Alter ML. Renal and cardiac effects of DPP4 inhibitors--from preclinical development to clinical research. Kidney Blood Press Res. 2012;36(1):65-84. PMID:22947920 doi:10.1159/000339028
↑ ^4.0 ^4.1 Hiramatsu H, Kyono K, Higashiyama Y, Fukushima C, Shima H, Sugiyama S, Inaka K, Yamamoto A, Shimizu R. The structure and function of human dipeptidyl peptidase IV, possessing a unique eight-bladed beta-propeller fold. Biochem Biophys Res Commun. 2003 Mar 21;302(4):849-54. PMID:12646248

Student Contributors

Karisma Moll
Merritt Jugo
Sam Magnabosco

Proteopedia Page Contributors and Editors (what is this?)

Karisma Moll

Retrieved from "http://52.214.119.220/wiki/index.php/User:Karisma_Moll/Sandbox_1"

@@ Line 20: / Line 20: @@
 === Mechanism ===
 The picture of the mechanism is inserted but not visible, maybe too high of a quality?
-Once a substrate is bound in the active site, DPPIV utilizes a [https://en.wikipedia.org/wiki/Enzyme_catalysis#Covalent_catalysis covalent catalysis] mechanism to cleave the substrate at the penultimate position. Asp708 of the <scene name='10/1037489/Catalytic_triad/1'>catalytic triad</scene> (Ser630, His 740, Asp708) pulls electron density from His740 allowing the histidine to pull electron density from Ser630, making serine a stronger nucleophile. The water molecule attacks the carbonyl carbon, breaking the newly formed  covalent bond, and releasing the first two residues of the starting substrate. The active site resets.
+Once a substrate is bound in the active site, DPPIV utilizes a [https://en.wikipedia.org/wiki/Enzyme_catalysis#Covalent_catalysis covalent catalysis] mechanism to cleave the substrate at the penultimate position. Asp708 of the <scene name='10/1037489/Catalytic_triad/2'>catalytic triad</scene> (Ser630, His 740, Asp708) pulls electron density from His740 allowing the histidine to pull electron density from Ser630, making serine a stronger nucleophile. The water molecule attacks the carbonyl carbon, breaking the newly formed  covalent bond, and releasing the first two residues of the starting substrate. The active site resets.
 [[Image:mech_dppiv.png|500 px|right|thumb|Figure 5. Mechanism of the catalytic triad of DPPIV.]]
 === Inhibitors ===