tautomycin and tautomycetin

The recent progress in synthetic and SAR studies of the specific protein phosphatase inhibitors tautomycin and tautomycetin is reviewed. This article covers the total synthesis of tautomycin and synthetic studies of the spiroketal and the anhydride segments and tautomycetin, and SAR studies on PP inhibition and apoptosis-inducing activity of tautomycin.

Topics: Antifungal Agents; Enzyme Inhibitors; Furans; Humans; Lipids; Phosphoprotein Phosphatases; Pyrans; Spiro Compounds; Structure-Activity Relationship

SHP2 phosphatase is a positive transducer of growth factor and cytokine signaling. SHP2 is also a bona fide oncogene; gain-of-function SHP2 mutations leading to increased phosphatase activity cause Noonan syndrome, as well as multiple forms of leukemia and solid tumors. We report that tautomycetin (TTN), an immunosuppressor in organ transplantation, and its engineered analog TTN D-1 are potent SHP2 inhibitors. TTN and TTN D-1 block T cell receptor-mediated tyrosine phosphorylation and ERK activation and gain-of-function mutant SHP2-induced hematopoietic progenitor hyperproliferation and monocytic differentiation. Crystal structure of the SHP2⋅TTN D-1 complex reveals that TTN D-1 occupies the SHP2 active site in a manner similar to that of a peptide substrate. Collectively, the data support the notion that SHP2 is a cellular target for TTN and provide a potential mechanism for the immunosuppressive activity of TTN. Moreover, the structure furnishes molecular insights upon which therapeutics targeting SHP2 can be developed on the basis of the TTN scaffold.

Topics: Amino Acid Sequence; Cell Differentiation; Cell Proliferation; Enzyme Activation; Enzyme Inhibitors; Furans; Hematopoietic Stem Cells; Humans; Immunosuppressive Agents; Jurkat Cells; Lipids; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Molecular; Molecular Sequence Data; Monocytes; Phosphorylation; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrans; Signal Transduction; Spiro Compounds; Substrate Specificity; Tyrosine

Tautomycetin (TTN) is a highly potent and specific protein phosphatase inhibitor isolated from Streptomyces griseochromogenes. The biological activity of TTN makes it an important lead for drug discovery, whereas its rare dialkylmaleic anhydride moiety and structural similarity to tautomycin (TTM), another potent phosphatase inhibitor with tremendous medicinal potential, draws attention to novel biosynthetic chemistries responsible for its production. To elucidate the biosynthetic machinery associated with TTN production, the ttn biosynthetic gene cluster from S. griseochromogenes was isolated and characterized, and its involvement in TTN biosynthesis confirmed by gene inactivation and complementation experiments. The ttn cluster was localized to a 79 kb DNA region, consisting of 19 open reading frames that encode two modular type I polyketide synthases (TtnAB), one type II thioesterase (TtnH), eight proteins for dialkylmaleic anhydride biosynthesis (TtnKLMNOPRS), four tailoring enzymes (TtnCDFI), two regulatory proteins (TtnGQ), and one resistance protein (TtnJ). A model for TTN biosynthesis is proposed on the basis of functional assignments from sequence analysis, which agrees well with previous feeding experiments, has been supported by in vivo gene inactivation experiments, and is supported by analogy to the recently reported ttm cluster. These findings set the stage to fully investigate TTN biosynthesis and to biosynthetically engineer new TTN analogues.

Topics: Furans; Genes, Bacterial; Lipids; Maleic Anhydrides; Models, Biological; Molecular Structure; Polyketide Synthases; Pyrans; Spiro Compounds; Streptomyces

The biosynthetic gene cluster for tautomycin (TTM), a potent protein phosphatase (PP) inhibitor has recently been characterized. Inactivation of ttmM, which encodes a putative C3' hydroxylase, afforded mutant SB6005 which accumulated three new 3'-deshydroxy TTM analogs, supporting the function of TtmM and the previously proposed linear pathway for TTM biosynthesis. Bioassays reveal the importance of the C3' OH moiety in PP inhibition and that PP inhibition is not the exclusive mechanism driving TTM-induced cell death.

Topics: Furans; Gene Expression Regulation, Bacterial; Lipids; Molecular Structure; Multigene Family; Phosphoprotein Phosphatases; Pyrans; Spiro Compounds; Streptomyces; Structure-Activity Relationship

Medullary thyroid cancer (MTC) is a relatively uncommon neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Unfortunately, MTC frequently metastasizes, precluding curative surgical resection and causing significant morbidity. Thus, there is an urgent need for new treatment modalities. Tautomycin and tautomycetin are antifungal antibiotics isolated from Streptomyces spiroverticillatus and Streptomyces griseochromogens, respectively. Glycogen synthase kinase-3beta is a serine/threonine protein kinase that regulates multiple cellular processes and is important in various cancers, including MTC. Treatment with tautomycin and tautomycetin decreased neuroendocrine markers, suppressed hormonal secretion, and inhibited growth through apoptosis in MTC cells. Importantly, we describe a novel action of these compounds: inhibition of glycogen synthase kinase-3beta.

Topics: Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Calcitonin; Carcinoma, Medullary; Cell Proliferation; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Furans; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lipids; Phosphoprotein Phosphatases; Pyrans; RNA, Small Interfering; Spiro Compounds; Thyroid Neoplasms; Tumor Cells, Cultured

Natural product extracts have proven to be a rich source of small molecules that potently inhibit the catalytic activity of certain PPP-family ser/thr protein phosphatases. To date, the list of inhibitors includes okadaic acid (produced by marine dinoflagelates, Prorocentrum sp. and Dinophysis sp.), calyculin A, dragmacidins (isolated from marine sponges), microcystins, nodularins (cyanobacteria, Microcystis sp. and Nodularia sp.), tautomycin, tautomycetin, cytostatins, phospholine, leustroducsins, phoslactomycins, fostriecin (soil bacteria, Streptomyces sp.), and cantharidin (blister beetles, approx 1500 species). Many of these compounds share structural similarities, and several have become readily available for research purposes. Here we will review the specificity of available inhibitors and present methods for their use in studying sensitive phosphatases. Common mistakes in the employment of these compounds will also be addressed briefly, notably the widespread misconception that they only inhibit the activity of PP1 and PP2A. Inhibitors of PP2B (calcineurin) will only be mentioned in passing, except to state that, in our hands, cypermethrin, deltamethrin, and fenvalerate, which are sold as potent inhibitors of PP2B, do not inhibit the catalytic activity of PP2B.

Topics: Cantharidin; Enzyme Inhibitors; Furans; Indole Alkaloids; Lactones; Lipids; Marine Toxins; Microcystins; Okadaic Acid; Organophosphates; Organophosphorus Compounds; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Pyrans; Pyrones; Spiro Compounds

Tautomycetin was isolated as a regulator of secondary metabolite production for Penicillium urticae. It induced the simultaneous production of a yellow compound, named patulodin, and of patulolides against P. urticae P3, which does not produce such metabolites under the usual conditions. Tautomycin, a phosphatase inhibitor, also caused the same phenomenon.

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Culture Media; Epoxy Compounds; Furans; Lipids; Macrolides; Magnetic Resonance Spectroscopy; Penicillium; Phosphoric Monoester Hydrolases; Pyrans; Spiro Compounds; Structure-Activity Relationship