Intracellular kinases protein transfer phosphate groups from ATP to serine, threonine, or tyrosine residues on protein peptide substrates, directly affecting the activity and function of the target. Radiolabel studies suggest that approximately 30% of proteins in eukaryotic cells are subject to phosphorylation. Kinase activity, a crucial post-translational modification, regulates a broad range of cellular activities including the cell cycle, differentiation, metabolism, and neuronal communication. In addition, abnormal activity of Akt, ERK, JNK, PKC, PKA, p38, and other MAPK are implicated in many disease states.
Classification of Intracellular kinases protein
Kinases can be divided into three groups through their substrates, including protein kinases, lipid kinases, and carbohydrate kinases.
Protein kinases, also known as phosphotransferases, phosphorylate target proteins in cells by covalently linking the phosphate to the side chain of a serine, threonine or tyrosine residue. It has subsequently been shown that kinases play an important role in the first step of intracellular immune cell signaling. For example, kinases are associated with intracellular components of receptors on the cell surface of T and B lymphocytes, and once these receptors bind to their extracellular ligands, intracellular signal cascades within these cells are initiated. Since protein kinases have been identified as a fundamental driver of inflammatory cell signaling, they have been investigated as therapeutic targets for a variety of diseases.
As for the lipid kinase, the most typical is phosphoinositide kinase associated with lipid phosphoinositide. Lipid phosphoinositides are essential mediators for many membranes signaling events, and their temporal and spatial locations in cells must be tightly regulated. Phosphatidylinositol transports in oriented membranes, recruits signaling mechanisms to specific phosphoinositides, mediates lipid transport in gradients, and regulates ion channel regulation. Phosphoinositide is produced by the modulating activity of phosphoinositide kinase and phosphatase. Phosphoinositide kinases and phosphatases can be sequentially recruited in the membrane trafficking pathway to produce specific phosphoinositides. The dysregulation of phosphoinositide kinase, which occurs mainly in the class I phosphoinositide 3-kinase (PI3Ks) that produces phosphatidylinositol 3,4,5-triphosphate (PIP3), has been found in many human diseases. Mutations lead to enzymatic increases or decreases in activity that are closely related to cancer, developmental disorders, and primary immunodeficiency. Although other phosphoinositide kinases are not frequently mutated in disease, they are still involved in a myriad of diseases and have been found to play a key role in mediating infections of various viral and bacterial pathogens. Due to the critical role of many of these phosphoinositide kinases in disease, a great deal of work has been applied to the development of small molecule inhibitors.
Carbohydrate kinases play an important role in almost all metabolic pathways. In glycolysis, two important reactions are catalyzed by carbohydrate kinases, including hexokinase and phosphofructokinase. When hexokinase enters the cell, it can convert D-glucose to glucose-6-phosphate by transferring the gamma phosphate of ATP to the C6 position. By phosphorylation, it traps glucose in the cells. By dephosphorylation, glucose can move through the membrane. If a mutation is present in the hexokinase gene, it can lead to a deficiency of hexokinase and lead to non-small cell hemolytic anemia. Phosphofructokinase or PFK also regulates the glycolysis process by catalyzing the conversion of fructose-6-phosphate to fructose-1,6-diphosphate. In addition, mutations in the PFK gene will result in decreased PFK activity, leading to a very rare disease called Tarui's disease, a glycogen storage disease that causes exercise intolerance.
Most importantly, there are still some kinases that act on many other substrates, including those involved in nucleotide interactions, such as nucleoside-phosphate kinases and nucleoside-diphosphate kinases. In addition, there are substrates for kinases including creatine, phosphoglycerate, riboflavin, dihydroxyacetone, shikimic acid, etc.
Because protein kinases have profound effects on a cell, their activity is highly regulated. Kinases are turned on or off by phosphorylation (sometimes by the kinase itself - cis-phosphorylation/autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates.
1. Ren Sun.; et al. Thymidine Kinase 2 Enzyme Kinetics Elucidate the Mechanism of Thymidine-Induced Mitochondrial DNA Depletion. Biochemistry. 2014, 53: 6142-6150.