4.6: Transducer Mechanism: Enzyme-Linked Receptors
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
- Receptor tyrosine kinases:
Receptor tyrosine kinases (RTKs) phosphorylate specific tyrosines on the signaling proteins. RTKs include various growth factor receptors, toll-like receptors, and insulin receptors that play essential roles in cell proliferation, differentiation, survival, and immune response. Upon activation, these receptors mediate a cascade of phosphorylation, activating mitogen-activated protein (MAP) kinases, which are essential regulators of gene transcription. Drugs such as becaplermin, a recombinant platelet-derived growth factor, bind the ligand-binding domain of these receptors and help in healing foot ulcers in diabetes patients. Several other drugs are direct inhibitors of tyrosine kinase activity. Examples include imatinib and erlotinib, which are approved for cancer therapy.
- Cytokine receptors:
Cytokine receptors associate with intracellular tyrosine kinases such as Janus kinase, which phosphorylate signal transducers and activators of transcription (STATs) downstream. Phosphorylated STATs translocate to the nucleus to regulate the transcription of genes. Ligands such as interferons and colony-stimulating factors activate these receptors, generating immune responses and stimulating cell growth and differentiation. Various recombinant cytokines are available as drugs to stimulate immune cell production. For example, aldesleukin helps treat melanoma and renal cell carcinoma, while filgrastim is used for neutropenia which is often a side effect caused by cancer drugs.
- Receptor serine/threonine kinases:
Receptor serine/threonine kinases phosphorylate specific serines or threonines on signaling proteins. Transforming growth factor (TGF) is a prominent example. These receptors are involved in angiogenesis and bone development pathways, making them helpful drug targets for cancer and bone therapy. Dibotermin alfa, the recombinant form of bone morphogenetic protein, is available to treat acute tibia fractures in adults.
- Receptor tyrosine phosphatases:
Receptor tyrosine phosphatases remove phosphate groups from specific tyrosines of target proteins. They help regulate phosphorylation levels and control cell growth, division, survival, and differentiation. They are well-known drug targets for type II diabetes and obesity and have recently been explored for breast cancer.
- Receptor guanylyl cyclases:
Receptor guanylyl cyclase directly converts GTP into cyclic GMP, a second messenger that mediates several signaling pathways. Major ligands of these receptors are natriuretic peptides released by cardiac cells and the vascular system, such as atrial natriuretic peptide (ANP) and its structural analogs B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These ligands stimulate pathways to lower blood pressure, reduce cardiac hypertrophy and initiate the growth of long bones in the body. So, these receptors are valuable targets for various cardiovascular diseases. Currently, nesiritide, a BNP agonist, and sacubitril, an inhibitor, are used for treating congestive heart failure.
