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Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations

Phosphofructokinase-1 (PFK1), the “gatekeeper” of glycolysis, catalyses the committed step of the glycolytic pathway by converting fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate. Allosteric activation and inhibition of PFK1 by over 10 metabolites and in response to hormonal signaling fine-t...

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Autores principales: Webb, Bradley A., Forouhar, Farhad, Szu, Fu-En, Seetharaman, Jayaraman, Tong, Liang, Barber, Diane L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510984/
https://www.ncbi.nlm.nih.gov/pubmed/25985179
http://dx.doi.org/10.1038/nature14405
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author Webb, Bradley A.
Forouhar, Farhad
Szu, Fu-En
Seetharaman, Jayaraman
Tong, Liang
Barber, Diane L.
author_facet Webb, Bradley A.
Forouhar, Farhad
Szu, Fu-En
Seetharaman, Jayaraman
Tong, Liang
Barber, Diane L.
author_sort Webb, Bradley A.
collection PubMed
description Phosphofructokinase-1 (PFK1), the “gatekeeper” of glycolysis, catalyses the committed step of the glycolytic pathway by converting fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate. Allosteric activation and inhibition of PFK1 by over 10 metabolites and in response to hormonal signaling fine-tune glycolytic flux to meet energy requirements(1). Mutations inhibiting PFK1 activity cause glycogen storage disease type VII, also known as Tarui disease(2), and mice deficient in muscle PFK1 have decreased fat stores(3). Additionally, PFK1 is suggested to have important roles in metabolic reprograming in cancer(4,5). Despite its critical role in glucose flux, the biologically relevant crystal structure of the mammalian PFK1 tetramer has not been determined. We report here the first structures of the mammalian PFK1 tetramer, for the human platelet isoform (PFKP), in complex with ATP-Mg(2+) and ADP at 3.1 and 3.4 Å, respectively. The structures reveal substantial conformational changes in the enzyme upon nucleotide hydrolysis as well as a unique tetramer interface. Mutations of residues in this interface can affect tetramer formation, enzyme catalysis and regulation, indicating the functional importance of the tetramer. With altered glycolytic flux being a hallmark of cancers(6), these new structures allow a molecular understanding of the functional consequences of somatic PFK1 mutations identified in human cancers. We characterized three of these mutations and show they have distinct effects on allosteric regulation of PFKP activity and lactate production. The PFKP structural blueprint for somatic mutations as well as the catalytic site can guide therapeutic targeting of PFK1 activity to control dysregulated glycolysis in disease.
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spelling pubmed-45109842016-01-02 Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations Webb, Bradley A. Forouhar, Farhad Szu, Fu-En Seetharaman, Jayaraman Tong, Liang Barber, Diane L. Nature Article Phosphofructokinase-1 (PFK1), the “gatekeeper” of glycolysis, catalyses the committed step of the glycolytic pathway by converting fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate. Allosteric activation and inhibition of PFK1 by over 10 metabolites and in response to hormonal signaling fine-tune glycolytic flux to meet energy requirements(1). Mutations inhibiting PFK1 activity cause glycogen storage disease type VII, also known as Tarui disease(2), and mice deficient in muscle PFK1 have decreased fat stores(3). Additionally, PFK1 is suggested to have important roles in metabolic reprograming in cancer(4,5). Despite its critical role in glucose flux, the biologically relevant crystal structure of the mammalian PFK1 tetramer has not been determined. We report here the first structures of the mammalian PFK1 tetramer, for the human platelet isoform (PFKP), in complex with ATP-Mg(2+) and ADP at 3.1 and 3.4 Å, respectively. The structures reveal substantial conformational changes in the enzyme upon nucleotide hydrolysis as well as a unique tetramer interface. Mutations of residues in this interface can affect tetramer formation, enzyme catalysis and regulation, indicating the functional importance of the tetramer. With altered glycolytic flux being a hallmark of cancers(6), these new structures allow a molecular understanding of the functional consequences of somatic PFK1 mutations identified in human cancers. We characterized three of these mutations and show they have distinct effects on allosteric regulation of PFKP activity and lactate production. The PFKP structural blueprint for somatic mutations as well as the catalytic site can guide therapeutic targeting of PFK1 activity to control dysregulated glycolysis in disease. 2015-05-18 2015-07-02 /pmc/articles/PMC4510984/ /pubmed/25985179 http://dx.doi.org/10.1038/nature14405 Text en Reprints and permissions information is available at www.nature.com/reprints.
spellingShingle Article
Webb, Bradley A.
Forouhar, Farhad
Szu, Fu-En
Seetharaman, Jayaraman
Tong, Liang
Barber, Diane L.
Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
title Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
title_full Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
title_fullStr Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
title_full_unstemmed Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
title_short Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
title_sort structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510984/
https://www.ncbi.nlm.nih.gov/pubmed/25985179
http://dx.doi.org/10.1038/nature14405
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