PMID- 36493513
OWN - NLM
STAT- MEDLINE
DCOM- 20230117
LR  - 20230328
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 59
DP  - 2023 Feb
TI  - Identification of galectin-1 and other cellular targets of alpha,beta-unsaturated 
      carbonyl compounds, including dimethylfumarate, by use of click-chemistry probes.
PG  - 102560
LID - S2213-2317(22)00332-9 [pii]
LID - 10.1016/j.redox.2022.102560 [doi]
LID - 102560
AB  - alpha,beta-Unsaturated carbonyls are a common motif in environmental toxins (e.g. 
      acrolein) as well as therapeutic drugs, including dimethylfumarate (DMFU) and 
      monomethylfumarate (MMFU), which are used to treat multiple sclerosis and 
      psoriasis. These compounds form adducts with protein Cys residues as well as 
      other nucleophiles. The specific targets ('adductome') that give rise to their 
      therapeutic or toxic activities are poorly understood. This is due, at least in 
      part, to the absence of antigens or chromophores/fluorophores in these compounds. 
      We have recently reported click-chemistry probes of DMFU and MMFU (Redox Biol., 
      2022, 52, 102299) that allow adducted proteins to be visualized and enriched for 
      further characterization. In the current study, we hypothesized that adducted 
      proteins could be 'clicked' to agarose beads and thereby isolated for LC-MS 
      analysis of DMFU/MMFU targets in primary human coronary artery smooth muscle 
      cells. We show that the probes react with thiols with similar rate constants to 
      the parent drugs, and give rise to comparable patterns of gene induction, 
      confirming similar biological actions. LC-MS proteomic analysis identified  approximately 2970 
      cellular targets of DMFU,  approximately 1440 for MMFU, and  approximately 140 for the control 
      (succinate-probe) treated samples. The most extensively modified proteins were 
      galectin-1, annexin-A2, voltage dependent anion channel-2 and vimentin. Other 
      previously postulated DMFU targets, including glyceraldehyde-3-phosphate 
      dehydrogenase (GAPDH), cofilin, p65 (RELA) and Keap1 were also identified as 
      adducted species, though at lower levels with the exception of GAPDH. These data 
      demonstrate the utility of the click-chemistry approach to the identification of 
      cellular protein targets of both exogenous and endogenous compounds.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Sauerland, Max B
AU  - Sauerland MB
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Copenhagen, 2200, Denmark.
FAU - Helm, Christina
AU  - Helm C
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Copenhagen, 2200, Denmark.
FAU - Lorentzen, Lasse G
AU  - Lorentzen LG
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Copenhagen, 2200, Denmark.
FAU - Manandhar, Asmita
AU  - Manandhar A
AD  - Department of Drug Design and Pharmacology, Jagtvej 162, University of 
      Copenhagen, Copenhagen, 2100, Denmark.
FAU - Ulven, Trond
AU  - Ulven T
AD  - Department of Drug Design and Pharmacology, Jagtvej 162, University of 
      Copenhagen, Copenhagen, 2100, Denmark.
FAU - Gamon, Luke F
AU  - Gamon LF
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Copenhagen, 2200, Denmark.
FAU - Davies, Michael J
AU  - Davies MJ
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Copenhagen, 2200, Denmark. Electronic address: davies@sund.ku.dk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221201
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - FO2303MNI2 (Dimethyl Fumarate)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (Galectin 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 45IUB1PX8R (monomethyl fumarate)
RN  - 0RQ6CXO9KD (citraconic acid)
SB  - IM
MH  - Humans
MH  - *Dimethyl Fumarate/pharmacology
MH  - Kelch-Like ECH-Associated Protein 1
MH  - *Galectin 1
MH  - Proteomics
MH  - NF-E2-Related Factor 2
PMC - PMC9731849
OTO - NOTNLM
OT  - Click chemistry
OT  - Dimethylfumarate
OT  - Electrophile
OT  - Galectin
OT  - Michael adduct
OT  - Unsaturated carbonyls
EDAT- 2022/12/10 06:00
MHDA- 2023/01/18 06:00
PMCR- 2022/12/01
CRDT- 2022/12/09 18:14
PHST- 2022/11/16 00:00 [received]
PHST- 2022/11/26 00:00 [revised]
PHST- 2022/11/26 00:00 [accepted]
PHST- 2022/12/10 06:00 [pubmed]
PHST- 2023/01/18 06:00 [medline]
PHST- 2022/12/09 18:14 [entrez]
PHST- 2022/12/01 00:00 [pmc-release]
AID - S2213-2317(22)00332-9 [pii]
AID - 102560 [pii]
AID - 10.1016/j.redox.2022.102560 [doi]
PST - ppublish
SO  - Redox Biol. 2023 Feb;59:102560. doi: 10.1016/j.redox.2022.102560. Epub 2022 Dec 
      1.