Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Mechanism of action of compound-13 : An α1-selective small molecule activator of AMPK. / Hunter, Roger W.; Foretz, Marc; Bultot, Laurent; Fullerton, Morgan D.; Deak, Maria; Ross, Fiona A.; Hawley, Simon A.; Shpiro, Natalia; Viollet, Benoit; Barron, Denis; Kemp, Bruce E.; Steinberg, Gregory R.; Hardie, D. Grahame; Sakamoto, Kei.

In: Chemistry and Biology, Vol. 21, No. 7, 17.07.2014, p. 866-879.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hunter, RW, Foretz, M, Bultot, L, Fullerton, MD, Deak, M, Ross, FA, Hawley, SA, Shpiro, N, Viollet, B, Barron, D, Kemp, BE, Steinberg, GR, Hardie, DG & Sakamoto, K 2014, 'Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK', Chemistry and Biology, vol. 21, no. 7, pp. 866-879. https://doi.org/10.1016/j.chembiol.2014.05.014

APA

Hunter, R. W., Foretz, M., Bultot, L., Fullerton, M. D., Deak, M., Ross, F. A., Hawley, S. A., Shpiro, N., Viollet, B., Barron, D., Kemp, B. E., Steinberg, G. R., Hardie, D. G., & Sakamoto, K. (2014). Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK. Chemistry and Biology, 21(7), 866-879. https://doi.org/10.1016/j.chembiol.2014.05.014

Vancouver

Hunter RW, Foretz M, Bultot L, Fullerton MD, Deak M, Ross FA et al. Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK. Chemistry and Biology. 2014 Jul 17;21(7):866-879. https://doi.org/10.1016/j.chembiol.2014.05.014

Author

Hunter, Roger W. ; Foretz, Marc ; Bultot, Laurent ; Fullerton, Morgan D. ; Deak, Maria ; Ross, Fiona A. ; Hawley, Simon A. ; Shpiro, Natalia ; Viollet, Benoit ; Barron, Denis ; Kemp, Bruce E. ; Steinberg, Gregory R. ; Hardie, D. Grahame ; Sakamoto, Kei. / Mechanism of action of compound-13 : An α1-selective small molecule activator of AMPK. In: Chemistry and Biology. 2014 ; Vol. 21, No. 7. pp. 866-879.

Bibtex

@article{1f7ab0c8fa804a39a680a62e2ee7fd82,
title = "Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK",
abstract = "Summary AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.",
author = "Hunter, {Roger W.} and Marc Foretz and Laurent Bultot and Fullerton, {Morgan D.} and Maria Deak and Ross, {Fiona A.} and Hawley, {Simon A.} and Natalia Shpiro and Benoit Viollet and Denis Barron and Kemp, {Bruce E.} and Steinberg, {Gregory R.} and Hardie, {D. Grahame} and Kei Sakamoto",
year = "2014",
month = jul,
day = "17",
doi = "10.1016/j.chembiol.2014.05.014",
language = "English",
volume = "21",
pages = "866--879",
journal = "Chemistry and Biology",
issn = "2451-9448",
publisher = "Elsevier",
number = "7",

}

RIS

TY - JOUR

T1 - Mechanism of action of compound-13

T2 - An α1-selective small molecule activator of AMPK

AU - Hunter, Roger W.

AU - Foretz, Marc

AU - Bultot, Laurent

AU - Fullerton, Morgan D.

AU - Deak, Maria

AU - Ross, Fiona A.

AU - Hawley, Simon A.

AU - Shpiro, Natalia

AU - Viollet, Benoit

AU - Barron, Denis

AU - Kemp, Bruce E.

AU - Steinberg, Gregory R.

AU - Hardie, D. Grahame

AU - Sakamoto, Kei

PY - 2014/7/17

Y1 - 2014/7/17

N2 - Summary AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.

AB - Summary AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.

UR - http://www.scopus.com/inward/record.url?scp=84904556335&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2014.05.014

DO - 10.1016/j.chembiol.2014.05.014

M3 - Journal article

C2 - 25036776

AN - SCOPUS:84904556335

VL - 21

SP - 866

EP - 879

JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 2451-9448

IS - 7

ER -

ID: 239213236