English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR.

Doulliet, D. C., Pinson, B., Ceschin, J., Hürlimann, H. C., Saint-Marc, C., Laporte, D., et al. (2019). Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR. Journal of Biological Chemistry, 294, 805-815. doi:10.1074/jbc.RA118.004964.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/21.11116/0000-0002-92FA-F Version Permalink: http://hdl.handle.net/21.11116/0000-0002-D62E-A
Genre: Journal Article

Files

show Files
hide Files
:
3010747.pdf (Publisher version), 3MB
Name:
3010747.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
3010747_Suppl.pdf (Supplementary material), 4MB
Name:
3010747_Suppl.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show

Creators

show
hide
 Creators:
Doulliet, D. C., Author
Pinson, B., Author
Ceschin, J., Author
Hürlimann, H. C., Author
Saint-Marc, C., Author
Laporte, D., Author
Claverol, S., Author
Konrad, M.1, Author              
Bonneu, M., Author
Daignan-Fornier, B., Author
Affiliations:
1Research Group of Enzyme Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578612              

Content

show
hide
Free keywords: drug metabolism; nucleoside/nucleotide analogue; proteomics; purine; small molecule; yeast genetics; yeast metabolism
 Abstract: AICAR (Acadesine; 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside) is a precursor of the monophosphate derivative ZMP, an intermediate in de novo purine biosynthesis. AICAR proved promising anti-proliferative properties, though the molecular basis of its toxicity is poorly understood. To exert cytotoxicity, AICAR needs to be metabolized, but the AICAR-derived toxic metabolite was not identified. Here, we show that ZMP is the major toxic derivative of AICAR in yeast and establish that its metabolization to SZMP (succinyl-ZMP), ZDP or ZTP (di- and tri-phosphate derivatives of AICAR) strongly reduced its toxicity. Affinity chromatography identified 74 ZMP-binding proteins, including 41 that were found neither as AMP-, nor as AICAR- or SZMP-binders. Overexpression of karyopherin-β Kap123, one of the ZMP-specific binders, partially rescued AICAR-toxicity. Quantitative proteomic analyses revealed 57 proteins significantly less abundant on nuclei-enriched fractions from AICAR-fed cells, this effect being compensated by overexpression of KAP123 for 15 of them. These results reveal nuclear protein trafficking as a function affected by AICAR.

Details

show
hide
Language(s): eng - English
 Dates: 2018-11-262019-01-18
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.RA118.004964
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Journal of Biological Chemistry
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 294 Sequence Number: - Start / End Page: 805 - 815 Identifier: -