The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Antonina Roll-mecak - One of the best experts on this subject based on the ideXlab platform.
-
Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes
Nature Structural & Molecular Biology, 2020Co-Authors: Kishore K. Mahalingan, E. Keith Keenan, Madeleine Strickland, Yanjie Liu, Haydn L. Ball, Martin E. Tanner, Nico Tjandra, Antonina Roll-mecakAbstract:Glutamylation, introduced by tubulin tyrosine Ligase-like (TTLL) enzymes, is the most abundant modification of brain tubulin. Essential effector proteins read the tubulin glutamylation pattern, and its misregulation causes neurodegeneration. TTLL glutamylases post-translationally add glutamates to internal glutamates in tubulin carboxy-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize in initiation or elongation, but the mechanistic basis for regioselectivity is unknown. We present cocrystal structures of murine TTLL6 bound to tetrahedral intermediate analogs that delineate key active-site residues that make this enzyme an elongase. We show that TTLL4 is exclusively an initiase and, through combined structural and phylogenetic analyses, engineer TTLL6 into a branch-initiating enzyme. TTLL glycylases add glycines post-translationally to internal glutamates, and we find that the same active-site residues discriminate between initiase and elongase glycylases. These active-site specializations of TTLL glutamylases and glycylases ultimately yield the chemical complexity of cellular microtubules. A combination of structural and protein-chemistry approaches along with phylogenetic analyses provide insights into the specific activities of mouse tubulin tyrosine Ligase-like enzymes as initiases or elongases of glutamylation.
-
Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes.
Nature structural & molecular biology, 2020Co-Authors: Kishore K. Mahalingan, Madeleine Strickland, Yanjie Liu, Haydn L. Ball, Martin E. Tanner, Nico Tjandra, E. Keith Keenan, Antonina Roll-mecakAbstract:Glutamylation, introduced by tubulin tyrosine Ligase-like (TTLL) enzymes, is the most abundant modification of brain tubulin. Essential effector proteins read the tubulin glutamylation pattern, and its misregulation causes neurodegeneration. TTLL glutamylases post-translationally add glutamates to internal glutamates in tubulin carboxy-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize in initiation or elongation, but the mechanistic basis for regioselectivity is unknown. We present cocrystal structures of murine TTLL6 bound to tetrahedral intermediate analogs that delineate key active-site residues that make this enzyme an elongase. We show that TTLL4 is exclusively an initiase and, through combined structural and phylogenetic analyses, engineer TTLL6 into a branch-initiating enzyme. TTLL glycylases add glycines post-translationally to internal glutamates, and we find that the same active-site residues discriminate between initiase and elongase glycylases. These active-site specializations of TTLL glutamylases and glycylases ultimately yield the chemical complexity of cellular microtubules.
-
Crystal structure of tubulin tyrosine Ligase-like 3 reveals essential architectural elements unique to tubulin monoglycylases.
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Christopher P. Garnham, Antonina Roll-mecakAbstract:Glycylation and glutamylation, the posttranslational addition of glycines and glutamates to genetically encoded glutamates in the intrinsically disordered tubulin C-terminal tails, are crucial for the biogenesis and stability of cilia and flagella and play important roles in metazoan development. Members of the diverse family of tubulin tyrosine Ligase-like (TTLL) enzymes catalyze these modifications, which are part of an evolutionarily conserved and complex tubulin code that regulates microtubule interactions with cellular effectors. The site specificity of TTLL enzymes and their biochemical interplay remain largely unknown. Here, we report an in vitro characterization of a tubulin glycylase. We show that TTLL3 glycylates the β-tubulin tail at four sites in a hierarchical order and that TTLL3 and the glutamylase TTLL7 compete for overlapping sites on the tubulin tail, providing a molecular basis for the anticorrelation between glutamylation and glycylation observed in axonemes. This anticorrelation demonstrates how a combinatorial tubulin code written in two different posttranslational modifications can arise through the activities of related but distinct TTLL enzymes. To elucidate what structural elements differentiate TTLL glycylases from glutamylases, with which they share the common TTL scaffold, we determined the TTLL3 X-ray structure at 2.3-A resolution. This structure reveals two architectural elements unique to glycyl initiases and critical for their activity. Thus, our work sheds light on the structural and functional diversification of TTLL enzymes, and constitutes an initial important step toward understanding how the tubulin code is written through the intersection of activities of multiple TTLL enzymes.
-
Multivalent Microtubule Recognition by Tubulin Tyrosine Ligase-like Family Glutamylases.
Cell, 2015Co-Authors: Christopher P. Garnham, Agnieszka Szyk, Annapurna Vemu, Elizabeth M. Wilson-kubalek, Gabriel C. Lander, Ronald A. Milligan, Antonina Roll-mecakAbstract:Glutamylation, the most prevalent tubulin posttranslational modification, marks stable microtubules and regulates recruitment and activity of microtubule- interacting proteins. Nine enzymes of the tubulin tyrosine Ligase-like (TTLL) family catalyze glutamylation. TTLL7, the most abundant neuronal glutamylase, adds glutamates preferentially to the β-tubulin tail. Coupled with ensemble and single-molecule biochemistry, our hybrid X-ray and cryo-electron microscopy structure of TTLL7 bound to the microtubule delineates a tripartite microtubule recognition strategy. The enzyme uses its core to engage the disordered anionic tails of α- and β-tubulin, and a flexible cationic domain to bind the microtubule and position itself for β-tail modification. Furthermore, we demonstrate that all single-chain TTLLs with known glutamylase activity utilize a cationic microtubule-binding domain analogous to that of TTLL7. Therefore, our work reveals the combined use of folded and intrinsically disordered substrate recognition elements as the molecular basis for specificity among the enzymes primarily responsible for chemically diversifying cellular microtubules.
-
Tubulin tyrosine Ligase - structural and functional studies
Acta Crystallographica Section A Foundations and Advances, 2014Co-Authors: Agnieszka Szyk, Grzegorz Piszczek, Alexandra M. Deaconescu, Antonina Roll-mecakAbstract:Microtubules are polymers essential for cell morphogenesis, cell division and intracellular transport. This polymer's basic building block is the α/β tubulin heterodimer, which associates head-to-tail and laterally to form the microtubule. Tubulin is subject to diverse, abundant and evolutionarily conserved post-translational modifications that mark subpopulations of microtubules. The highest density and variety of post-translational modifications are found in neurons or cilia. Not surprisingly, tubulin modification enzymes have been linked to human diseases including cancers and neurodegenerative disorders. We will present our recent work using a combination of X-ray crystallography, small angle X-ray scattering and functional assays to investigate the mechanism of tubulin tyrosine Ligase (TTL). TTL catalyzes the ATP-dependent post-translational addition of a tyrosine to the C-terminal end of detyrosinated α-tubulin. The detyrosination/tyrosination cycle regulates recruitment of motors and proteins that track with the growing end of the microtubule. TTL function is essential for neuronal development and reduction in TTL levels is strongly associated with aggressive tumors resistant to chemotherapy. Our first X-ray crystal structure of TTL, defines the structural fold of the TTL-like family of tubulin-modifying enzymes. We show that TTL recognizes tubulin via a dual strategy: it engages the tubulin tail through low-affinity, high-specificity interactions through a conserved positively charged surface, and co-opts what is otherwise a homo-oligomerization interface in structurally related enzymes to form a tight hetero-oligomeric complex with tubulin. TTL forms an elongated complex with the tubulin dimer and prevents incorporation of the dimer into microtubules by capping the tubulin polymerization interface. Interestingly, TTL and stathmin, a ubiquitously expressed tubulin sequestering protein, compete for tubulin binding in vitro and stathmin inhibits tubulin tyrosination. These results suggest that TTL and stathmin have either a partially overlapping footprint on the tubulin dimer or that stathmin induces a tubulin conformation incompatible with stable TTL binding.
Jonas Helma - One of the best experts on this subject based on the ideXlab platform.
-
One-Step Fluorescent Protein Labeling by Tubulin Tyrosine Ligase.
Methods of Molecular Biology, 2019Co-Authors: Dominik Schumacher, Christian P. R. Hackenberger, Heinrich Leonhardt, Jonas HelmaAbstract:Tub-tag labeling, a novel chemoenzymatic protein functionalization method, facilitates one-step fluorescent labeling of functional biomolecules. The enzyme tubulin tyrosine Ligase incorporates coumarin-amino acids to the terminal carboxylic acid of proteins containing a short peptidic recognition sequence called Tub-tag. Here we describe the one-step Tub-tag protein modification protocol in detail and explain its utilization to generate fluorescently labeled proteins for advanced applications in imaging and diagnostics.
-
Tubulin Tyrosine Ligase-Mediated Modification of Proteins.
Methods in molecular biology (Clifton N.J.), 2019Co-Authors: Marcus Gerlach, Tina Stoschek, Christian P. R. Hackenberger, Dominik Schumacher, Heinrich Leonhardt, Jonas HelmaAbstract:Tubulin tyrosine Ligase (TTL) catalyzes the addition of tyrosine derivatives to the C-terminal carboxylic acid of proteins. The enzyme binds to a 14-amino acid recognition sequence, termed Tub-tag, and allows for the introduction of tyrosine derivatives that carry a unique chemical handle. These handles enable subsequent bioorthogonal reactions with a great variety of probes or effector molecules. Clearly, this two-step chemoenzymatic approach, facilitates the site-specific functionalization of proteins. Furthermore, due to its broad substrate tolerance, tubulin tyrosine Ligase also enables an enzymatic one-step modification. For example, a coumarin amino acid was utilized to generate fluorescently labeled proteins for advanced applications in imaging and diagnostics. Here we describe the modification of proteins using TTL in detail via a one-step as well as two-step procedure and highlight its practicability for applications in imaging, diagnostics, and cell biology.
-
TuPPL: Tub-tag mediated C-terminal protein–protein-ligation using complementary click-chemistry handles
Organic and Biomolecular Chemistry, 2019Co-Authors: Andreas Stengl, Christian P. R. Hackenberger, Marcus Gerlach, Dominik Schumacher, Marc‐andré Kasper, Heinrich Leonhardt, Jonas HelmaAbstract:We introduce a chemoenzymatic strategy for straightforward in vitro generation of C-terminally linked fusion proteins. Tubulin tyrosine Ligase is used for the incorporation of complementary click chemistry handles facilitating subsequent formation of functional bispecific antibody-fragments. This simple strategy may serve as central conjugation hub for a modular protein ligation platform.
-
Tub-Tag Labeling; Chemoenzymatic Incorporation of Unnatural Amino Acids.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Jonas Helma, Christian P. R. Hackenberger, Heinrich Leonhardt, Dominik SchumacherAbstract:Tub-tag labeling is a chemoenzymatic method that enables the site-specific labeling of proteins. Here, the natural enzyme tubulin tyrosine Ligase incorporates noncanonical tyrosine derivatives to the terminal carboxylic acid of proteins containing a 14-amino acid recognition sequence called Tub-tag. The tyrosine derivative carries a unique chemical reporter allowing for a subsequent bioorthogonal modification of proteins with a great variety of probes. Here, we describe the Tub-tag protein modification protocol in detail and explain its utilization to generate labeled proteins for advanced applications in cell biology, imaging, and diagnostics.
-
broad substrate tolerance of tubulin tyrosine Ligase enables one step site specific enzymatic protein labeling
Chemical Science, 2017Co-Authors: Dominik Schumacher, Oliver Lemke, Lena Gerszonowicz, Verena Waller, Tina Stoschek, Patrick Durkin, Nediljko Budisa, Jonas Helma, Heinrich Leonhardt, Bettina G KellerAbstract:The broad substrate tolerance of tubulin tyrosine Ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations. This feature enabled one-step C-terminal biotinylation and fluorescent coumarin labeling of various functional proteins as demonstrated with ubiquitin, an antigen binding nanobody, and the apoptosis marker Annexin V. Its broad substrate tolerance establishes tubulin tyrosine Ligase as a powerful tool for in vitro enzyme-mediated protein modification with single functional amino acids in a specific structural context.
Dominik Schumacher - One of the best experts on this subject based on the ideXlab platform.
-
One-Step Fluorescent Protein Labeling by Tubulin Tyrosine Ligase.
Methods of Molecular Biology, 2019Co-Authors: Dominik Schumacher, Christian P. R. Hackenberger, Heinrich Leonhardt, Jonas HelmaAbstract:Tub-tag labeling, a novel chemoenzymatic protein functionalization method, facilitates one-step fluorescent labeling of functional biomolecules. The enzyme tubulin tyrosine Ligase incorporates coumarin-amino acids to the terminal carboxylic acid of proteins containing a short peptidic recognition sequence called Tub-tag. Here we describe the one-step Tub-tag protein modification protocol in detail and explain its utilization to generate fluorescently labeled proteins for advanced applications in imaging and diagnostics.
-
Tubulin Tyrosine Ligase-Mediated Modification of Proteins.
Methods in molecular biology (Clifton N.J.), 2019Co-Authors: Marcus Gerlach, Tina Stoschek, Christian P. R. Hackenberger, Dominik Schumacher, Heinrich Leonhardt, Jonas HelmaAbstract:Tubulin tyrosine Ligase (TTL) catalyzes the addition of tyrosine derivatives to the C-terminal carboxylic acid of proteins. The enzyme binds to a 14-amino acid recognition sequence, termed Tub-tag, and allows for the introduction of tyrosine derivatives that carry a unique chemical handle. These handles enable subsequent bioorthogonal reactions with a great variety of probes or effector molecules. Clearly, this two-step chemoenzymatic approach, facilitates the site-specific functionalization of proteins. Furthermore, due to its broad substrate tolerance, tubulin tyrosine Ligase also enables an enzymatic one-step modification. For example, a coumarin amino acid was utilized to generate fluorescently labeled proteins for advanced applications in imaging and diagnostics. Here we describe the modification of proteins using TTL in detail via a one-step as well as two-step procedure and highlight its practicability for applications in imaging, diagnostics, and cell biology.
-
TuPPL: Tub-tag mediated C-terminal protein–protein-ligation using complementary click-chemistry handles
Organic and Biomolecular Chemistry, 2019Co-Authors: Andreas Stengl, Christian P. R. Hackenberger, Marcus Gerlach, Dominik Schumacher, Marc‐andré Kasper, Heinrich Leonhardt, Jonas HelmaAbstract:We introduce a chemoenzymatic strategy for straightforward in vitro generation of C-terminally linked fusion proteins. Tubulin tyrosine Ligase is used for the incorporation of complementary click chemistry handles facilitating subsequent formation of functional bispecific antibody-fragments. This simple strategy may serve as central conjugation hub for a modular protein ligation platform.
-
Tub-Tag Labeling; Chemoenzymatic Incorporation of Unnatural Amino Acids.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Jonas Helma, Christian P. R. Hackenberger, Heinrich Leonhardt, Dominik SchumacherAbstract:Tub-tag labeling is a chemoenzymatic method that enables the site-specific labeling of proteins. Here, the natural enzyme tubulin tyrosine Ligase incorporates noncanonical tyrosine derivatives to the terminal carboxylic acid of proteins containing a 14-amino acid recognition sequence called Tub-tag. The tyrosine derivative carries a unique chemical reporter allowing for a subsequent bioorthogonal modification of proteins with a great variety of probes. Here, we describe the Tub-tag protein modification protocol in detail and explain its utilization to generate labeled proteins for advanced applications in cell biology, imaging, and diagnostics.
-
broad substrate tolerance of tubulin tyrosine Ligase enables one step site specific enzymatic protein labeling
Chemical Science, 2017Co-Authors: Dominik Schumacher, Oliver Lemke, Lena Gerszonowicz, Verena Waller, Tina Stoschek, Patrick Durkin, Nediljko Budisa, Jonas Helma, Heinrich Leonhardt, Bettina G KellerAbstract:The broad substrate tolerance of tubulin tyrosine Ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations. This feature enabled one-step C-terminal biotinylation and fluorescent coumarin labeling of various functional proteins as demonstrated with ubiquitin, an antigen binding nanobody, and the apoptosis marker Annexin V. Its broad substrate tolerance establishes tubulin tyrosine Ligase as a powerful tool for in vitro enzyme-mediated protein modification with single functional amino acids in a specific structural context.
Heinrich Leonhardt - One of the best experts on this subject based on the ideXlab platform.
-
One-Step Fluorescent Protein Labeling by Tubulin Tyrosine Ligase.
Methods of Molecular Biology, 2019Co-Authors: Dominik Schumacher, Christian P. R. Hackenberger, Heinrich Leonhardt, Jonas HelmaAbstract:Tub-tag labeling, a novel chemoenzymatic protein functionalization method, facilitates one-step fluorescent labeling of functional biomolecules. The enzyme tubulin tyrosine Ligase incorporates coumarin-amino acids to the terminal carboxylic acid of proteins containing a short peptidic recognition sequence called Tub-tag. Here we describe the one-step Tub-tag protein modification protocol in detail and explain its utilization to generate fluorescently labeled proteins for advanced applications in imaging and diagnostics.
-
Tubulin Tyrosine Ligase-Mediated Modification of Proteins.
Methods in molecular biology (Clifton N.J.), 2019Co-Authors: Marcus Gerlach, Tina Stoschek, Christian P. R. Hackenberger, Dominik Schumacher, Heinrich Leonhardt, Jonas HelmaAbstract:Tubulin tyrosine Ligase (TTL) catalyzes the addition of tyrosine derivatives to the C-terminal carboxylic acid of proteins. The enzyme binds to a 14-amino acid recognition sequence, termed Tub-tag, and allows for the introduction of tyrosine derivatives that carry a unique chemical handle. These handles enable subsequent bioorthogonal reactions with a great variety of probes or effector molecules. Clearly, this two-step chemoenzymatic approach, facilitates the site-specific functionalization of proteins. Furthermore, due to its broad substrate tolerance, tubulin tyrosine Ligase also enables an enzymatic one-step modification. For example, a coumarin amino acid was utilized to generate fluorescently labeled proteins for advanced applications in imaging and diagnostics. Here we describe the modification of proteins using TTL in detail via a one-step as well as two-step procedure and highlight its practicability for applications in imaging, diagnostics, and cell biology.
-
TuPPL: Tub-tag mediated C-terminal protein–protein-ligation using complementary click-chemistry handles
Organic and Biomolecular Chemistry, 2019Co-Authors: Andreas Stengl, Christian P. R. Hackenberger, Marcus Gerlach, Dominik Schumacher, Marc‐andré Kasper, Heinrich Leonhardt, Jonas HelmaAbstract:We introduce a chemoenzymatic strategy for straightforward in vitro generation of C-terminally linked fusion proteins. Tubulin tyrosine Ligase is used for the incorporation of complementary click chemistry handles facilitating subsequent formation of functional bispecific antibody-fragments. This simple strategy may serve as central conjugation hub for a modular protein ligation platform.
-
Tub-Tag Labeling; Chemoenzymatic Incorporation of Unnatural Amino Acids.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Jonas Helma, Christian P. R. Hackenberger, Heinrich Leonhardt, Dominik SchumacherAbstract:Tub-tag labeling is a chemoenzymatic method that enables the site-specific labeling of proteins. Here, the natural enzyme tubulin tyrosine Ligase incorporates noncanonical tyrosine derivatives to the terminal carboxylic acid of proteins containing a 14-amino acid recognition sequence called Tub-tag. The tyrosine derivative carries a unique chemical reporter allowing for a subsequent bioorthogonal modification of proteins with a great variety of probes. Here, we describe the Tub-tag protein modification protocol in detail and explain its utilization to generate labeled proteins for advanced applications in cell biology, imaging, and diagnostics.
-
broad substrate tolerance of tubulin tyrosine Ligase enables one step site specific enzymatic protein labeling
Chemical Science, 2017Co-Authors: Dominik Schumacher, Oliver Lemke, Lena Gerszonowicz, Verena Waller, Tina Stoschek, Patrick Durkin, Nediljko Budisa, Jonas Helma, Heinrich Leonhardt, Bettina G KellerAbstract:The broad substrate tolerance of tubulin tyrosine Ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations. This feature enabled one-step C-terminal biotinylation and fluorescent coumarin labeling of various functional proteins as demonstrated with ubiquitin, an antigen binding nanobody, and the apoptosis marker Annexin V. Its broad substrate tolerance establishes tubulin tyrosine Ligase as a powerful tool for in vitro enzyme-mediated protein modification with single functional amino acids in a specific structural context.
Nunziatina De Tommasi - One of the best experts on this subject based on the ideXlab platform.
-
A fast and efficient LC-MS/MS method for detection, identification and quantitative analysis of bioactive sesterterpenes in Salvia dominica crude extracts.
Journal of pharmaceutical and biomedical analysis, 2009Co-Authors: Fabrizio Dal Piaz, Laura Lepore, Ammar Bader, Salvatore Imparato, Nunziatina De TommasiAbstract:Sesterterpenes are a small group of terpenoids showing a number of interesting pharmacological properties, including cytotoxicity, anti-inflammatory, anti-microbial and anti-angiogenic activities and platelet aggregation inhibition. Recently, some sesterterpene lactones isolated from Salvia dominica have been shown to modulate enzymatic activity of tubulin tyrosine Ligase (TTL), a promising target for new anticancer therapeutic strategies. However, to allow a direct use of S. dominica extracts as a source of TTL inhibitors, analytical method aimed to their fast qualitative and quantitative characterization is required. Despite the structural features and diverse biological activities of sesterterpenoids, actually no analytical method for their quantization into complex mixtures has been published. Here we describe an LC–MS/MS method aimed to qualitative and quantitative analysis of sesterterpenes lactones in the crude extracts obtained from different parts of S. dominica. This approach allowed us to characterize all the sesterterpenes by a single step analysis and also to identify two unknown compounds. Moreover, a quantitative comparison of the composition in sesterterpenes of extracts obtained from S. dominica leaves, roots and leaf galls was performed, leading to the definition of both leaves and leaf galls as suitable sources of TTL inhibitors.
-
Sesterterpenes as Tubulin Tyrosine Ligase Inhibitors. First Insight of Structure−Activity Relationships and Discovery of New Lead
Journal of medicinal chemistry, 2009Co-Authors: Fabrizio Dal Piaz, Antonio Vassallo, Laura Lepore, Alessandra Tosco, Ammar Bader, Nunziatina De TommasiAbstract:Twenty-four new sesterterpenes, compounds 1−24, were isolated from the aerial parts of Salvia dominica. Their structures were elucidated by 1D and 2D NMR experiments as well as ESIMS analysis and chemical methods. The evaluation of the biological activity of Salvia dominica sesterterpenes by means of a panel of chemical and biological approaches, including chemical proteomics, surface plasmon resonance (SPR) measurements, and biochemical assays were realized. Obtained results showed that 18 out of the 24 sesterterpene lactones isolated from Salvia dominica interact with tubulin−tyrosine Ligase (TTL) an enzyme involved in the tyrosination cycle of the C-terminal of tubulin, and inhibit TTL activity in cancer cells. Besides, results of our studies provided an activity/structure relationship that can be used to design effective TTL inhibitors.
-
Sesterterpenes as Tubulin Tyrosine Ligase Inhibitors. First Insight of Structure−Activity Relationships and Discovery of New Lead
Journal of medicinal chemistry, 2009Co-Authors: Fabrizio Dal Piaz, Antonio Vassallo, Laura Lepore, Alessandra Tosco, Ammar Bader, Nunziatina De TommasiAbstract:Twenty-four new sesterterpenes, compounds 1−24, were isolated from the aerial parts of Salvia dominica. Their structures were elucidated by 1D and 2D NMR experiments as well as ESIMS analysis and c...
-
Sesterterpenes as Tubulin Tyrosine Ligase Inhibitors. First Insight of Structure-Activity Relationships and Discovery of New Lead
2009Co-Authors: Fabrizio Dal Piaz, Antonio Vassallo, Laura Lepore, Alessandra Tosco, Ammar Bader, Nunziatina De TommasiAbstract:Twenty-four new sesterterpenes, compounds 1-24, were isolated from the aerial parts of SalVia dominica. Their structures were elucidated by 1D and 2D NMR experiments as well as ESIMS analysis and chemical methods. The evaluation of the biological activity of SalVia dominica sesterterpenes by means of a panel of chemical and biological approaches, including chemical proteomics, surface plasmon resonance (SPR) measurements, and biochemical assays were realized. Obtained results showed that 18 out of the 24 sesterterpene lactones isolated from SalVia dominica interact with Tubulin-Tyrosine Ligase (TTL) an enzyme involved in the tyrosination cycle of the C-terminal of tubulin, and inhibit TTL activity in cancer cells. Besides, results of our studies provided an activity/structure relationship that can be used to design effective TTL inhibitors
