Background[1-3]
Human low molecular weight phosphotyrosine protein phosphatase is a low molecular weight protein produced by constructing a vector using molecular cloning technology and expressing the human phosphotyrosine protein phosphatase gene through an E. coli expression system. Phosphotyrosine protein phosphatase contains a catalytic domain composed of 240 amino acid residues, 71 of which are highly conserved, and the catalytic active center is a sequence composed of 11 amino acid residues, namely (I/ V) HCXAGXXR(S/T)G, in which the cysteine residue (Cys215) and arginine residue (Ary221) play a crucial role in the activity of PTP-1B enzyme. If substituted, the enzyme Loss of catalytic activity.
Phosphotyrosine protein phosphatase is widely found in adipocytes, liver tissue cells, muscle tissue cells and epithelial cells. Fluorescence immunoassay in situ hybridization showed that PTP-1B is mainly located in the cytoplasmic endoplasmic reticulum tissue, binding to the endoplasmic reticulum with 35 specific amino acids at the C terminus, and its N terminus contains cysteine and arginine residues. base, the catalytic center of the arginine residue faces the cytoplasm. Phosphotyrosine protein phosphatase is an intracellular PTP located in the endoplasmic reticulum and expressed in various tissues of the human body; it together with protein tyrosine kinases (PTK) maintains tyrosine protein phosphorylation Chemical balance, participate in cell signal transduction, regulate cell growth, differentiation, metabolism, gene transcription and immune response, etc.
Phosphotyrosine protein phosphatase belongs to the protein tyrosine phosphatase family. It is an enzyme that specifically hydrolyzes aromatic phosphates, such as phosphorylated phosphate groups on tyrosine (phosphotyrosyl, pTyr) residues, through the insulin receptor. Or the dephosphorylation of tyrosine residues on its substrate negatively regulates insulin signal transduction. Overexpression of PTP-1B in tissue cells will reduce the activity of PTK, making the insulin receptor unable to bind to insulin, thereby causing Insulin resistance eventually leads to type 2 diabetes.
Apply[4][5]
For screening research on antidiabetic drugs targeting PTP1B
Diabetes mellitus (DM) is a chronic disease caused by insulin deficiency or insulin function deficiency, which is accompanied by a series of metabolic disorders. The prevalence of DM continues to increase globally. According to the latest statistics from the International Diabetes Federation (IDF), as of 2013, 382 million people worldwide were suffering from diabetes, and this number is expected to rise to 592 million by 2035. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, accounting for approximately 90% of diabetes worldwide, and is characterized by hyperglycemia, dyslipidemia, and insulin resistance in metabolic target tissues. Type 2 diabetes can lead to serious complications, including kidney failure, blindness, slow wound healing, and cardiovascular disease. Protein tyrosine phosphatase (PTP) regulates many key physiological processes in cells that rely on tyrosine phosphorylation and plays an important role in metabolism. Abnormalities in PTP activity have been found in many human diseases. PTP1B is the first PTP superfamily member to be successfully isolated and characterized from human placenta. Its molecular weight is approximately 50kDa (435 amino acids). It contains a highly conserved catalytic motif, in which Cys215 and Arg221 are its phosphates. Enzyme catalytic activity is crucial. PTP1B is a key negative regulatory protein in the insulin signal transduction pathway. It blocks insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR), thereby affecting the phosphorylation of the insulin receptor (IRS-1) and its Downstream pathways. Normally, insulin triggers a cascade of phosphorylation events, starting with autophosphorylation of multiple tyrosine residues on the IR, which increases the kinase activity of the IR and leads to its recruitment and activation of IRS-1. , then activates phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB, also known as AKT), and finally activates glucose transporter 4 (GLUT4) and extracellular signal-regulated kinase 1/2 (ERK1/2). Activated GLUT4 can be transported to the cell membrane, thereby affecting glucose uptake; phosphorylated ERK1/2 can enter the nucleus and affect gene expression and translation. Overexpression of PTP1B or an increase in its enzymatic activity was found in patients with insulin resistance and obesity.
