Project

Back to overview

Chemical Biology of Polyphosphorylated Natural Products

English title Chemical Biology of Polyphosphorylated Natural Products
Applicant Jessen Henning
Number 157607
Funding scheme SNSF Professorships
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Organic Chemistry
Start/End 01.03.2015 - 30.11.2016
Approved amount 523'827.00
Show all

All Disciplines (3)

Discipline
Organic Chemistry
Biochemistry
Molecular Biology

Keywords (11)

Chemical Biology; Polyphosphate; Total synthesis; Diphosphoinositol polyphosphates; Bioorthogonal Tagging; Automated synthesis; STED microscopy; Posttranslational Protein Modification; Antibiotic; Cellular signaling; Phosphorylation

Lay Summary (German)

Lead
Die Synthese von polaren Substanzen ist ein bedeutendes Forschungsfeld in der Organischen Chemie. Solche Verbindungen haben grosse Bedeutung in der Kommunikation von Zellen. Die zielgerichtete Herstellung und Modifikation von geladenen Verbindungen kann unser Verständnis verbessern, wie Zellen auf dem molekularen Level kommunizieren.
Lay summary

Zellen sind biologische Einheiten, die zur Replikation befähigt sind. Einzelne Zellen grenzen sich von der Umwelt über eine Membran ab, um so einen räumlich begrenzten Stoffwechsel zu ermöglichen.  Man kann Zellen als biochemische Reaktoren verstehen, die befähigt sind, definierte Reaktionen zum Selbsterhalt durchzuführen, sowie zeitlich zu koordinieren. Solche Vorgänge werden u.a. über zelluläre Botenstoffe reguliert. Wie genau Zellen hierzu in der Lage sind, ist eine der faszinierendsten Fragen der Wissenschaft. Botenstoffe, die nur innerhalb einer Zelle wirksam sind, werden auch als Sekundärbotenstoffe bezeichnet (intrazelluläre Signale). Die hohe Polarität solcher Sekundärbotenstoffe unterbindet die Möglichkeit einer Passage durch die Zellmembran, die für geladene Stoffe undurchlässig ist. Somit bleibt das Signal auf die Zelle begrenzt.  In den meisten Fällen wird die Ladung durch eine Modifikation der chemischen Verbindung mit Phosphatgruppen erzeugt.
Die Entwicklung von Synthesemethoden zur Herstellung von geladenen, biologisch relevanten Verbindungen ist ein wichtiger Schritt, wenn man eine funktionale Analyse von Signalen innerhalb von Zellen durchführen will. Wir werden uns daher  mit effizienten Synthesemethoden von geladenen Verbindungen beschäftigen. Ein weiterer Arbeitsbereich, wird sich mit dem Transport von geladenen Verbindungen durch Zellmembranen beschäftigen. Denn es gilt hier im Umkehrschluss: Wenn geladene Verbindungen nicht aus den Zellen heraus gelangen, dann können synthetische Proben auch nicht in Zellen hinein gelangen. Wir werden daher Verfahren entwickeln, die es uns erlauben, geladene Verbindungen dahingehend zu modifizieren, dass sie in lebende Zellen hinein gelangen. Dies wird es uns erlauben, die Effekte solcher Sekundärbotenstoffe in Zellen zu studieren. Da viele Krankheiten auf Fehler in der intrazellulären Kommunikation zurückzuführen sind, können solche Studien neuartige Ansatzpunkte in der Therapie von Krankheiten liefern. 






Direct link to Lay Summary Last update: 22.02.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors.
Baughman B. M., Wang H., An Y., Kireev D., Stashko A., Jessen H. J., Pearce K. H., Frye S.V., Shears S. B. (2016), A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors., in PLOS ONE, 11, e0165286.
Chemoselective Dimerization of Phosphates
Hofer A., Marques E., Kieliger N., Gatter S.-K.N., Jordi S., Ferrari E., Hofmann M., Fitzpatrick T.B., Hottiger M.O., Jessen H.J. (2016), Chemoselective Dimerization of Phosphates, in Organic Letters, 18(13), 3222-3225.
Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains
Wild Rebekka, Gerasimaite Ruta, Jung Ji-Yul, Truffault Vincent, Pavlovic Igor, Schmidt Andrea, Saiardi Adolfo, Jessen Henning Jacob, Poirier Yves, Hothorn Michael, Mayer Andreas (2016), Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains, in Science, 352(6288), 986-990.
Identifying Kinase Substrates via a Heavy ATP Kinase Assay and Quantitative Mass Spectrometry
Müller A.C., Giambruno R., Wei{ß}er J., M{á}jek P., Hofer A., Bigenzahn J.W., Superti-Furga G., Jessen H.J., Bennett K.L. (2016), Identifying Kinase Substrates via a Heavy ATP Kinase Assay and Quantitative Mass Spectrometry, in Scientific Reports, 6, 28107.
Inositol Pyrophosphate Profiling of Two HCT116 Cell Lines Uncovers Variation in InsP8 Levels.
Gu C., Wilson M., Jessem H. J., Saiardi A., Shears S.B. (2016), Inositol Pyrophosphate Profiling of Two HCT116 Cell Lines Uncovers Variation in InsP8 Levels., in PLOS ONE, 11, e0165286.
Inositol pyrophosphates inhibit synaptotagmindependent exocytosis
Lee T.-S., Lee J.-Y., Kyung J.W., Yang Y., Park S.J., Lee S., Pavlovic I., Kong B., Jho Y.S., Jessen H.J., Kweon D.-H., Shin Y.-K., Kim S.H., Yoon T.-Y., Kim S. (2016), Inositol pyrophosphates inhibit synaptotagmindependent exocytosis, in Proceedings of the National Academy of Sciences of the United States of America, 113(29), 8314-8319.
Synthesis of 2-diphospho-myo-inositol 1,3,4,5,6-pentakisphosphate and a photocaged analogue
Pavlovic I., Thakor D.T., Jessen H.J. (2016), Synthesis of 2-diphospho-myo-inositol 1,3,4,5,6-pentakisphosphate and a photocaged analogue, in Organic and Biomolecular Chemistry, 14(24), 5559-5562.
Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast.
Desfougeres Yann, Gerasimaite Ruta, Jessen Henning Jacob, Mayer Andreas (2016), Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast., in J Biol Chem, 291, 22262.
A Modular Synthesis of Modified Phosphoanhydrides
Hofer A., Cremosnik G.S., Müller A.C., Giambruno R., Trefzer C., Superti-Furga G., Bennett K.L., Jessen H.J. (2015), A Modular Synthesis of Modified Phosphoanhydrides, in Chemistry - A European Journal, 21(28), 10116-10122.
Asp1 from Schizosaccharomyces pombe Binds a [2Fe-2S]2+ Cluster Which Inhibits Inositol Pyrophosphate 1-Phosphatase Activity.
Jessen Henning (2015), Asp1 from Schizosaccharomyces pombe Binds a [2Fe-2S]2+ Cluster Which Inhibits Inositol Pyrophosphate 1-Phosphatase Activity., in Biochemistry, 54, 6462-6474.
Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites
Duss M., Capolicchio S., Linden A., Ahmed N., Jessen H.J. (2015), Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites, in Bioorganic and Medicinal Chemistry, 23(12), 2854-2861.
Prometabolites of 5-Diphospho- myo -inositol Pentakisphosphate
Pavlovic Igor, Thakor Divyeshsinh T., Bigler Laurent, Wilson Miranda S. C., Laha Debabrata, Schaaf Gabriel, Saiardi Adolfo, Jessen Henning J. (2015), Prometabolites of 5-Diphospho- myo -inositol Pentakisphosphate, in Angewandte Chemie, 127(33), 9758-9762.
Rational Development of Nucleoside Diphosphate Prodrugs: DiPPro-Compounds.
Jessen Henning (2015), Rational Development of Nucleoside Diphosphate Prodrugs: DiPPro-Compounds., in Current Medicinal Chemistry, 22, 3933-3950.
The 8th Young Faculty Meeting – An Active Crowd Attuned to Modern Challenges
Simon Yoan C., Jessen Henning J., Merz Leo (2015), The 8th Young Faculty Meeting – An Active Crowd Attuned to Modern Challenges, in {CHIMIA} International Journal for Chemistry, 69(7), 475-477.
VIH2 regulates the synthesis of inositol pyrophosphate InsP8 and jasmonate-dependent defenses in arabidopsis
Laha D., Johnen P., Azevedo C., Dynowski M., Weiß M., Capolicchio S., Mao H., Iven T., Steenbergen M., Freyer M., Gaugler P., De Campos M.K., Zheng N., Feussner I., Jessen H.J., Van Wees S.C., Saiardi A., Schaaf G. (2015), VIH2 regulates the synthesis of inositol pyrophosphate InsP8 and jasmonate-dependent defenses in arabidopsis, in Plant Cell, 27(4), 1082-1097.
Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo
Pavlovic Igor, Thakor Divyesh T., Vargas Jessica R., McKinlay Colin J., Hauke Sebastian, Anstaett Philipp, Camuna Rafael C., Bigler Laurent, Gasser Gilles, Schultz Carsten, Wender Paul A., Jessen Henning J., Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo, in Nature Communications.

Collaboration

Group / person Country
Types of collaboration
Stephen Shears / NIEH, NIH, North Carolina United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Ehud Landau / University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dorothea Fiedler / FMP Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Solomon Snyder / Johns Hopkins Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Teresa Fitzpatrick / University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Adam Resnick / The Children's Hospital of Philadelphia / University of Pennsylvania United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Victor Raboy / United States Department of Agriculture / Idaho United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Keiryn Bennett / CeMM, Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Adolfo Saiardi / University College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Daniel Eberli/ University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Gabriel Schaaf / University of Tübingen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Michael Hottiger / University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
A. Mayer / UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
Ruzicka Preis der ETH Zürich 2015

Associated projects

Number Title Start Funding scheme
136816 Dissection of Inositol-Phosphate Dependent Signaling Pathways with Novel Chemical Tools 01.04.2012 Ambizione

Abstract

Polyphosphorylated natural products are ubiquitous in nature and regulate many important biological processes. The ability to synthesize and derivatize polyphosphorylated natural products in an efficient way is an enabling proficiency to study biological processes both in vitro and in vivo. We are aiming to synthesize natural products containing multiple phosphoanhydride bonds, especially diphosphoinositol polyphosphates and inorganic polyphosphate. We will use these molecules to understand their rich biology and try to find other molecules that will interfere with these biological processes. In essence, this may lead to the discovery of novel drug candidates.
-