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A direct substrate-substrate interaction found in the kinase domain of the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.

Kim SG, Cavalier M, El-Maghrabi MR, Lee YH
J Mol Biol 370 14-26 (2007)
Related entries: 2dwo, 2i1v

Cited: 12 times
EuropePMC logo PMID: 17499765

Abstract

To understand the molecular basis of a phosphoryl transfer reaction catalyzed by the 6-phosphofructo-2-kinase domain of the hypoxia-inducible bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), the crystal structures of PFKFB3AMPPCPfructose-6-phosphate and PFKFB3ADPphosphoenolpyruvate complexes were determined to 2.7 A and 2.25 A resolution, respectively. Kinetic studies on the wild-type and site-directed mutant proteins were carried out to confirm the structural observations. The experimentally varied liganding states in the active pocket cause no significant conformational changes. In the pseudo-substrate complex, a strong direct interaction between AMPPCP and fructose-6-phosphate (Fru-6-P) is found. By virtue of this direct substrate-substrate interaction, Fru-6-P is aligned with AMPPCP in an orientation and proximity most suitable for a direct transfer of the gamma-phosphate moiety to 2-OH of Fru-6-P. The three key atoms involved in the phosphoryl transfer, the beta,gamma-phosphate bridge oxygen atom, the gamma-phosphorus atom, and the 2-OH group are positioned in a single line, suggesting a direct phosphoryl transfer without formation of a phosphoenzyme intermediate. In addition, the distance between 2-OH and gamma-phosphorus allows the gamma-phosphate oxygen atoms to serve as a general base catalyst to induce an "associative" phosphoryl transfer mechanism. The site-directed mutant study and inhibition kinetics suggest that this reaction will be catalyzed most efficiently by the protein when the substrates bind to the active pocket in an ordered manner in which ATP binds first.

Articles - 2dwp mentioned but not cited (3)

  1. Predicting new indications for approved drugs using a proteochemometric method. Dakshanamurthy S, Issa NT, Assefnia S, Seshasayee A, Peters OJ, Madhavan S, Uren A, Brown ML, Byers SW. J Med Chem 55 6832-6848 (2012)
  2. Structure-based development of small molecule PFKFB3 inhibitors: a framework for potential cancer therapeutic agents targeting the Warburg effect. Seo M, Kim JD, Neau D, Sehgal I, Lee YH. PLoS One 6 e24179 (2011)
  3. Investigating combinatorial approaches in virtual screening on human inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): a case study for small molecule kinases. Crochet RB, Cavalier MC, Seo M, Kim JD, Yim YS, Park SJ, Lee YH. Anal Biochem 418 143-148 (2011)


Reviews citing this publication (2)

  1. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux. Jones BC, Pohlmann PR, Clarke R, Sengupta S. Cancer Metastasis Rev 41 447-458 (2022)
  2. Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors. Alvarez R, Mandal D, Chittiboina P. Cells 10 2913 (2021)

Articles citing this publication (7)

  1. Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. Yamamoto T, Takano N, Ishiwata K, Ohmura M, Nagahata Y, Matsuura T, Kamata A, Sakamoto K, Nakanishi T, Kubo A, Hishiki T, Suematsu M. Nat Commun 5 3480 (2014)
  2. Molecular basis of the fructose-2,6-bisphosphatase reaction of PFKFB3: transition state and the C-terminal function. Cavalier MC, Kim SG, Neau D, Lee YH. Proteins 80 1143-1153 (2012)
  3. Crystal structure of heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) and the inhibitory influence of citrate on substrate binding. Crochet RB, Kim JD, Lee H, Yim YS, Kim SG, Neau D, Lee YH. Proteins 85 117-124 (2017)
  4. Tuning PFKFB3 Bisphosphatase Activity Through Allosteric Interference. Macut H, Hu X, Tarantino D, Gilardoni E, Clerici F, Regazzoni L, Contini A, Pellegrino S, Luisa Gelmi M. Sci Rep 9 20333 (2019)
  5. Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors. Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E, Cierpich A, Dudek Ł, Eggenweiler HM, Fogt J, Gaik M, Gondela A, Jakubiec K, Jurzak M, Kitlińska A, Kowalczyk P, Kujawa M, Kwiecińska K, Leś M, Lindemann R, Maciuszek M, Mikulski M, Niedziejko P, Obara A, Pawlik H, Rzymski T, Sieprawska-Lupa M, Sowińska M, Szeremeta-Spisak J, Stachowicz A, Tomczyk MM, Wiklik K, Włoszczak Ł, Ziemiańska S, Zarębski A, Brzózka K, Nowak M, Fabritius CH. ChemMedChem 14 169-181 (2019)
  6. Structure-based design of small-molecule ligands of phosphofructokinase-2 activating or inhibiting glycolysis. Pyrkov TV, Sevostyanova IA, Schmalhausen EV, Shkoporov AN, Vinnik AA, Muronetz VI, Severin FF, Fedichev PO. ChemMedChem 8 1322-1329 (2013)
  7. Tumor chemical suffocation therapy by dual respiratory inhibitions. Xu Y, Guo Y, Chen L, Ni D, Hu P, Shi J. Chem Sci 12 7763-7769 (2021)


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