Premium
PTP1B Inhibitors for Type 2 Diabetes Treatment
Author(s) -
Zachar Mark,
Dorsey Amya,
Mckinney Tariq,
Nguyen Hanh,
Slater Brittany,
AnguianoGamino Melissa,
Otukoya Babatunde,
Carmicheal April,
Birmingham Kelly,
Spaeth Justin
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb144
Subject(s) - insulin , insulin receptor , diabetes mellitus , blood sugar , receptor , active site , binding site , chemistry , endocrinology , medicine , type 2 diabetes , enzyme , pharmacology , biochemistry , biology , insulin resistance
People with diabetes have difficulty regulating their blood sugar leading to the malfunctions of the heart, kidney, nerves, and brain if their blood sugar is too high. Most diabetics use insulin to control their condition. Insulin binds to its surface receptor in muscle and fat cells to trigger removal of sugar from the blood. PTP1B affects blood sugar regulation by dephosphorylating the insulin receptor and reducing its activity. Studying PTP1B can help us understand how its inhibitors can slow down the removal of phosphate from the insulin receptor, affecting the blood sugar regulation process. PTP1B normally functions to remove the phosphate group from the insulin receptor. Since PTP1B ordinarily reduces insulin receptor activity, blocking PTP1B could increase insulin sensitivity. The PTP1B active site has a highly positive binding pocket which binds to the highly negative phosphates on the phosphorylated insulin receptor. Many of the current inhibitors of PTP1B act by binding to this active site. However, these inhibitors have difficulty penetrating the cell membrane because of their formal charge, and are unable to inhibit PTP1B inside cells. LZP25 avoids this issue by not having a formal negative charge, but instead a polar area of similar size to phosphate. Binding to the PTP1B active site pocket (sites SER 216, ALA 217, ILE 219, GLN 262, GLN 266), its bulky side groups then prevent a key loop in the enzyme active site from closing. If PTP1B is inhibited in the insulin pathway by a potential drug based on LZP25, people who have type 2 diabetes as a result of insufficient insulin receptor activity could better regulate their blood sugar. If the insulin receptor would signal appropriately, the body's normal control of blood sugar would improve, preventing problems with the heart, kidney, nerves, and brain. Support or Funding Information Messmer Catholic High School SMART (Students Modeling A Research Topic) Team has designed a model of PTP1B with LZP25 using 3D printing technology to investigate their structure/function relationships.Tyrosine‐protein phosphatase non‐receptor type 1 (PTP1B) with LZP25.