Effects of modification of the hydrophobic C-1‒C-16 segment of tautomycin on its affinity to type-1 and type-2A protein phosphatases

Takai, Akira; TSUBOI, Katsunori; KOYASU, Masayoshi; Isobe, Mitsuaki

doi:10.1042/0264-6021:3500081

Cited by 21 publications

(14 citation statements)

References 39 publications

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“…PLB inhibits uptake of Ca 2+ into the SR by SERCA2a, therefore inhibiting PLB activity via PKA phosphorylation results in increased uptake. Stimulation of I1, which is itself inhibited by protein phosphatase-2A (PP2A) (Takai et al 2000), has similar consequences (increased Ca 2+ uptake by SERCA2a) because it inhibits a PLB agonist, protein phosphatase-1 (PP1) (Takai et al 2000). PP1 and PP2A can also be co-localized to the membrane where they serve as I Ca(L) inhibitors ).…”

Section: 2mentioning

confidence: 99%

Computational biology in the study of cardiac ion channels and cell electrophysiology

Rudy

Silva

2006

Quart. Rev. Biophys.

242

181

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The cardiac cell is a complex biological system where various processes interact to generate electrical excitation (the action potential, AP) and contraction. During AP generation, membrane ion channels interact nonlinearly with dynamically changing ionic concentrations and varying transmembrane voltage, and are subject to regulatory processes. In recent years, a large body of knowledge has accumulated on the molecular structure of cardiac ion channels, their function, and their modification by genetic mutations that are associated with cardiac arrhythmias and sudden death. However, ion channels are typically studied in isolation (in expression systems or isolated membrane patches), away from the physiological environment of the cell where they interact to generate the AP. A major challenge remains the integration of ion-channel properties into the functioning, complex and highly interactive cell system, with the objective to relate molecular-level processes and their modification by disease to whole-cell function and clinical phenotype. In this article we describe how computational biology can be used to achieve such integration. We explain how mathematical (Markov) models of ion-channel kinetics are incorporated into integrated models of cardiac cells to compute the AP. We provide examples of mathematical (computer) simulations of physiological and pathological phenomena, including AP adaptation to changes in heart rate, genetic mutations in SCN5A and HERG genes that are associated with fatal cardiac arrhythmias, and effects of the CaMKII regulatory pathway and β-adrenergic cascade on the cell electrophysiological function. Prologue'Things should be made as simple as possible, but not any simpler.' Albert EinsteinCardiac muscle can generate propagating electrical impulses (action potentials), a property that classifies it as an excitable tissue similar to skeletal muscle and nerve. At the single-cell level, the electrical action potential (AP) triggers mechanical contraction by inducing a transient rise of intracellular calcium which, in turn, carries the contraction message to the contractile proteins of the cell. This process that couples electrical excitation to mechanical function is termed excitation-contraction coupling. APs are generated by individual cells and are conducted from cell to cell through intercellular gap junctions, forming waves of excitation that activate and synchronize the blood pumping action of the heart. Similar to nerve and skeletal muscle, AP initiation and conduction in cardiac ventricular tissue rely mostly on a single membrane process, namely the flow of sodium ions through sodium-specific ion channels. However, unlike the short-duration APs of skeletal muscle and nerve, the cardiac ventricular AP is characterized by long plateau and repolarization phases that prevent premature arrhythmogenic excitation and provide control of mechanical contraction. In NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript contrast to the 'single-current mechanism' of...

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Section: 2mentioning

confidence: 99%

Computational biology in the study of cardiac ion channels and cell electrophysiology

Rudy

Silva

2006

Quart. Rev. Biophys.

242

181

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“…2,24,26 Since the major structural differences between TTM and TTN reside in the region distal to the dialkylmaleic anhydride, it has been proposed that these differences might be responsible for variations in their PP1 selectivity. 15,[27][28][29] The purpose of this study was to clone and characterize the ttn biosynthetic gene cluster. A long-term goal of this combinatorial biosynthesis program focused on TTN is to develop novel PP1and PP2A-specific inhibitors and T cell-specific immunosuppressors, in a manner independent of and complementary to total chemical synthesis.…”

mentioning

confidence: 99%

Characterization of the Tautomycetin Biosynthetic Gene Cluster from Streptomyces griseochromogenes Provides New Insight into Dialkylmaleic Anhydride Biosynthesis

Luo

et al. 2009

J. Nat. Prod.

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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.

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“…Interestingly, structurally simplified but characteristic spiroketals derived from the parent natural products retain biological activity (Figure 1). 10–12 The spiroketal motifs present in okadaic acid and tautomycin are enantiomers, and the stereochemistry of the spiroketal moieties could be the major determining factor for the affinity characteristics of okadaic acid and tautomycin towards the PP1 and PP2 phosphatases 13. The above findings validate the choice of the spiro[5.5]ketal as an underlying structural framework for the development of promising natural product‐derived compound collections.…”

Section: Introductionmentioning

confidence: 60%

Natural Product‐Guided Synthesis of a Spiroacetal Collection Reveals Modulators of Tubulin Cytoskeleton Integrity

et al. 2005

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The spiro[5.5]ketal moiety forms the underlying structural skeleton of numerous biologically active natural products. Since simplified but characteristic spiroketals derived from the parent natural products retain biological activity, the spiro[5.5]ketal unit can be regarded as a biologically prevalidated framework for the development of natural product‐derived compound collections. We report an enantioselective synthesis of spiro[5.5]ketals on solid support. The reaction sequence employs asymmetric boron enolate aldol reactions with the enolate bound to the polymer or in solution as the key enantiodifferentiating step. It proceeds in up to 12 steps on solid support, makes the desired spiroketals available in high overall yields and with high stereoselectivities and is amenable to structural variation of the products. The small spiroketal collection synthesized contains phosphatase inhibitors and compounds that modulate the formation of the tubulin cytoskeleton in human cancer cells without directly targeting microtubules. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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Effects of modification of the hydrophobic C-1‒C-16 segment of tautomycin on its affinity to type-1 and type-2A protein phosphatases

Cited by 21 publications

References 39 publications

Computational biology in the study of cardiac ion channels and cell electrophysiology

Computational biology in the study of cardiac ion channels and cell electrophysiology

Characterization of the Tautomycetin Biosynthetic Gene Cluster from Streptomyces griseochromogenes Provides New Insight into Dialkylmaleic Anhydride Biosynthesis

Natural Product‐Guided Synthesis of a Spiroacetal Collection Reveals Modulators of Tubulin Cytoskeleton Integrity

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