Tautomycin
Tautomycin
Purpose
Tautomycin is a potent inhibitor of protein phos-phatases, a class of enzymes that remove phosphate moieties from proteins. Protein phosphatases oppose the actions of protein kinases, enzymes that add phosphate groups to proteins. This reversible cycle of protein phosphorylation-dephosphorylation regulates the function of proteins and, as such, is a target for therapeutic drugs that may affect various cellular processes. Tautomycin also has antibiotic properties and is naturally produced by the bacterium streptomyces spiroverticillatus.
Description
Reversible phosphorylation is an important mechanism for regulating the biologic activity of many proteins that affect a diverse array of cellular processes, including protein interactions, gene transcription, cell-cycle progression, and cell death. Protein phosphatases are highly regulated enzymes. The development of compounds that alter the activity of specific phosphatases is emerging as an important area in drug discovery. The cycle of protein phosphorylation-dephosphorylation is a candidate drug target because dysregulation of this process may underlie, or is a consequence of, many diseases. Protein kinase inhibitors (for example, Glee-vec for chronic myelogenic leukemia) have been successfully used therapeutically in nonsolid tumor treatment. Protein phosphatase inhibitors have potential benefit as drug targets because they can result in cell
KEY TERMS
Apoptosis —A form of cell death in which a programmed sequence of events leads to the elimination of the cell.
Protein kinase —An enzyme that catalyzes the addition of a phosphate group to a protein.
Protein phosphatase —An enzyme that catalyzes the removal of a phosphate moiety from a protein.
Tumor supressor —A class of genes that, when mutated, predispose an individual to cancer by causing the loss of function of the particular tumor suppressor protein encoded by the gene.
cycle arrest and apoptosis; they appear not to be mutated in human cancers; and there are many ways to modulate phosphatase function.
Because protein phosphorylation occurs primarily on serine and threonine residues, the identification of agents that alter the activity of specific serine/threo-nine phosphatases is especially promising for drug development. There are two distinct gene families of serine/threonine phosphatases: the PPP-gene family (12 members), which includes PP1, PP2A, PP2B (cal-cineurin), PP4, PP5, PP6 and PP7; and the PPM family (8 members), which includes PP2C, PHLPP (PH domain leucine-rich repeat protein phosphatase), and PDP (pyruvate dehydrogenase phosphatase). Tauto-mycin is a natural product that was found to be a potent inhibitor of PP1 and PP2A and has been used as an investigational tool to examine the role of these protein phosphatases in cellular processes. Interestingly, distinct parts of the tautomycin molecule are responsible for inhibition of phosphatase activity and induction of apoptosis, suggesting that derivatives of tautomycin might have anticancer activity via multiple mechanisms.
Recommended dosage
Because tautomycin is an investigational drug and not currently approved for any therapeutic modality, there is no currently recommended dosage.
Side effects
While tautomycin has not been used clinically, the presently known phosphatase inhibitors that have been examined in clinical trials (for example, fostrie-cin) have significant systemic side effects, including nausea and vomiting, due to their lack of specificity.
Resources
PERIODICALS
Honkanen, R. E., and T. Golden. “Regulators of Serine/Threonine Protein Phosphatases at the Dawn of a Clinical Era?” Current Medicinal Chemistry 9.22 (2002): 2055–75.
Liu, W., and others. “The Selective Inhibition of Phosphatases by Natural Toxins: The Anhydride Domain of Tautomycin is Not a Primary Factor in Controlling PP1/PP2A Selectivity.” Bioorganic and Medicinal Chemistry Letters. 13.9 (2003): 1597–1600.
Schmid, A. C., and R. Woscholski. “Phosphatases as Small-Molecule Targets: Inhibiting the Endogenous Inhibitors of Kinases.” Biochemical Society Transactions 32.2 (2004): 348–49.
Andrew J. Bean, PhD