Tuning PFKFB3 Bisphosphatase Activity Through Allosteric Interference.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 12 2019
30 12 2019
Historique:
received:
12
09
2019
accepted:
28
11
2019
entrez:
1
1
2020
pubmed:
1
1
2020
medline:
12
11
2020
Statut:
epublish
Résumé
The human inducible phospho-fructokinase bisphosphatase isoform 3, PFKFB3, is a crucial regulatory node in the cellular metabolism. The enzyme is an important modulator regulating the intracellular fructose-2,6-bisphosphate level. PFKFB3 is a bifunctional enzyme with an exceptionally high kinase to phosphatase ratio around 740:1. Its kinase activity can be directly inhibited by small molecules acting directly on the kinase active site. On the other hand, here we propose an innovative and indirect strategy for the modulation of PFKFB3 activity, achieved through allosteric bisphosphatase activation. A library of small peptides targeting an allosteric site was discovered and synthesized. The binding affinity was evaluated by microscale thermophoresis (MST). Furthermore, a LC-MS/MS analytical method for assessing the bisphosphatase activity of PFKFB3 was developed. The new method was applied for measuring the activation on bisphosphatase activity with the PFKFB3-binding peptides. The molecular mechanical connection between the newly discovered allosteric site to the bisphosphatase activity was also investigated using both experimental and computational methods.
Identifiants
pubmed: 31889092
doi: 10.1038/s41598-019-56708-0
pii: 10.1038/s41598-019-56708-0
pmc: PMC6937325
doi:
Substances chimiques
Peptides
0
PFKFB3 protein, human
EC 2.7.1.105
Phosphofructokinase-2
EC 2.7.1.105
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20333Références
Amino Acids. 2012 Nov;43(5):1995-2003
pubmed: 22476346
SLAS Discov. 2018 Jan;23(1):11-22
pubmed: 28945981
Oncotarget. 2014 Aug 30;5(16):6670-86
pubmed: 25115398
Nat Commun. 2018 Sep 24;9(1):3872
pubmed: 30250201
FEBS Lett. 2004 Oct 8;576(1-2):14-20
pubmed: 15474002
J Biol Chem. 2004 Dec 17;279(51):53562-70
pubmed: 15466858
Trends Biochem Sci. 2001 Jan;26(1):30-5
pubmed: 11165514
Nucleic Acids Res. 2008 Jan;36(Database issue):D360-7
pubmed: 17962302
J Biol Chem. 2002 Feb 22;277(8):6183-7
pubmed: 11744734
Fundam Clin Pharmacol. 2008 Dec;22(6):633-48
pubmed: 19049668
J Comput Chem. 2004 Jul 15;25(9):1157-74
pubmed: 15116359
Biofactors. 1999;10(1):1-14
pubmed: 10475585
Mol Cancer Ther. 2008 Jan;7(1):110-20
pubmed: 18202014
J Chem Inf Model. 2009 Jan;49(1):84-96
pubmed: 19125657
FEBS Lett. 2003 Nov 20;554(3):264-70
pubmed: 14623077
Proteins. 2012 Apr;80(4):1143-53
pubmed: 22275052
J Chem Inf Model. 2012 Jul 23;52(7):1757-68
pubmed: 22587354
Mol Cancer Ther. 2013 Aug;12(8):1461-70
pubmed: 23674815
J Chem Theory Comput. 2015 Aug 11;11(8):3696-713
pubmed: 26574453
J Biochem. 1997 Jul;122(1):122-8
pubmed: 9276680
Biochem J. 1980 Dec 15;192(3):897-901
pubmed: 6453589
J Biochem. 2004 Sep;136(3):273-7
pubmed: 15598882
Biochem J. 1980 Dec 15;192(3):887-95
pubmed: 6453588
J Med Chem. 2015 Apr 23;58(8):3611-25
pubmed: 25849762
Biophys J. 2005 Jul;89(1):76-9
pubmed: 15834004
ChemMedChem. 2019 Jan 8;14(1):169-181
pubmed: 30378281
Bioorg Med Chem. 2014 Feb 1;22(3):1029-39
pubmed: 24398380
J Mol Biol. 2007 Jun 29;370(1):14-26
pubmed: 17499765
Biochem J. 2000 Apr 15;347(Pt 2):459-67
pubmed: 10749675
J Mol Graph Model. 2006 Oct;25(2):247-60
pubmed: 16458552
PLoS One. 2011;6(9):e24179
pubmed: 21957443
J Bioenerg Biomembr. 2007 Jun;39(3):223-9
pubmed: 17661163
Adv Enzyme Regul. 2004;44:123-54
pubmed: 15581487
J Biol Chem. 2006 Feb 3;281(5):2939-44
pubmed: 16316985
J Comput Chem. 2003 Jul 15;24(9):1016-25
pubmed: 12759902