Protein Kinase

A kinase is an enzyme that transfers phosphate groups from high-energy donor molecules to specific target molecules in a process known as phosphorylation. More specifically, protein kinases are a family of enzymes that phosphorylate other proteins. These protein kinases catalyze the transfer of a phosphoryl group from ATP to the OH group of a [Page 647]serine, threonine, and/or tyrosine residue. The purpose of phosphorylation is to alter the function of the target molecule in one of several different ways. These changes include activating or upregulating activity of the molecule, inhibition of molecular activity, or binding to other molecules to initiate or inhibit a specific signaling system.

The human genome contains over 500 genes meant to encode protein kinase enzymes, which is nearly 2 percent of all human genes. These genes are essential for production of the protein kinases, which are the primary agonists for signal transduction in human cells. Signal transduction is the process of converting one type of stimulus to another, generally through biochemical reactions involving “second messenger” systems in which a cascade occurs with few proteins being involved at the beginning, and numerous proteins becoming involved as the reaction occurs. Protein kinases also control many other cellular processes, including metabolism, transcription, cell movement, apoptosis, and differentiation. Protein phosphorylation also plays a critical role in intercellular communication during development, homeostasis, and in the functioning of the nervous and immune systems.

Two primary sources of protein kinase activity of interest to those interested in the obesity/diabetes epidemics are insulin-like growth factor-1 receptor (IGF-1R) and AMP-activated kinase (AMPK). IGF-1R is a transmembrane protein that displays intrinsic tyrosine kinase activity. Insulin-like growth factor-1 (IGF-1) is a polypeptide stimulated by growth hormone that acts similarly to insulin and affects cells throughout the body. IGF-1R binds to IGF-1 at a significantly higher rate than does the insulin receptor.

As for AMPK, it is a fuel-sensing enzyme that responds to decreases in cellular energy state by activating processes that generate ATP (such as fatty acid oxidation) and inhibiting nonessential functions that consume ATP. A decrease or improper functioning of AMPK has been implicated in the metabolic syndrome. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The effects of AMPK activation include stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells. Protein kinase activity, such as those of IGF-1R and AMPK, warrant further research and targeting from drug therapies in the fight against obesity and Type 2 diabetes.