Conformational Dynamics and Allostery in Pyruvate Kinase

Donovan, Katherine A.; Zhu, Shaolong; Liuni, Peter; Peng, Fen; Kessans, Sarah A.; Wilson, Derek J.; Dobson, Renwick C. J.

doi:10.1074/jbc.m115.676270

Cited by 29 publications

(49 citation statements)

References 52 publications

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“…Since the activities of enzymes involved in glucose metabolism are also regulated by allosteric mechanisms [32–34], it is also possible that the reduction in glucose levels are due to increased activities of these enzymes and this possibility requires further investigation. As for the role of SOD1 in increasing glucose metabolism in muscle, our metabolomics data show that the uptake/metabolism of 13 C glucose showed only a trend towards an increase in the muscle of CD+Nano-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling

Gopalakrishnan

Perriotte-Olson

Bhinderwala

et al. 2017

Translational Research

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Evidence suggests that superoxide dismutase 1 (SOD1) promotes glucose versus lipid metabolism depending on the diet type. We recently reported that nanoformulated SOD1 (Nano) improved lipid metabolism without altering glucose homeostasis in high fat (HF) diet-fed mice. Here, we sought to determine the effects and potential mechanisms of Nano in modulating glucose and lipid homeostasis in mice fed a normal chow diet (CD) versus HF diet. Mice were fed a CD or a HF diet (45%) for 10 wk and injected with Nano once every two days for fifteen days. The fasting glucose level was lower (P<0.05) in CD+Nano-treated mice compared to control. Conversely, blood glucose was not altered but serum triglycerides were lower in HF+Nano-treated mice. Genes involved in fatty acid synthesis were reduced by Nano in the skeletal muscle of CD but not of HF diet-fed mice. AMPK, which promotes both glucose and lipid metabolism depending on the fuel availability, is activated by Nano in CD-fed mice. Moreover, Nano increased phosphorylation of ACC, a downstream target of AMPK, in both CD and HF diet-fed mice. Nano increased mitochondrial respiration in C2C12 myocytes in the presence of glucose or fatty acid and this effect is inhibited by Compound C, an AMPK inhibitor. Our data suggest that Nano promotes glucose and lipid metabolism in CD and HF diet-fed mice, respectively, and this effect is mediated partly via AMPK signaling.

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Section: Discussionmentioning

confidence: 99%

Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling

Gopalakrishnan

Perriotte-Olson

Bhinderwala

et al. 2017

Translational Research

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“…To allow regulation of glycolytic flux in response to elevated PEP levels almost all tetrameric PyKs are homotropically activated by the substrate PEP . Moreover, PyKs are also regulated by heterotropic effectors with fructose 1,6‐bisphosphate (FBP) being the most widely known allosteric activator of bacterial, yeast, and mammalian enzymes . On the other hand, trypanosomatid PyKs are modulated by fructose 2,6‐diphosphate (FDP) .…”

Section: Evolutionary Relationships In the Allosteric Regulation Of Pyksmentioning

confidence: 99%

“…On the other hand, according to the “rigid body reorientation” model only monomers within the tetramer reorient with respect to each other and this increases the rigidity of the active site. A combination of time‐resolved electrospray ionization mass spectrometry coupled to hydrogen‐deuterium exchange studies and mutagenesis were employed to study the mechanism of allosteric activation by FBP on Ec PyK1 . These studies demonstrated enhanced conformational flexibility upon FBP binding at the allosteric site.…”

Section: Mechanisms Of Allosteric Regulationmentioning

confidence: 99%

“…Specifically, FBP binding causes destabilization of an α‐helix bridging the allosteric site and the active site in the same monomer. This results in a loss of stability in the assembly of the (β/α) 8 ‐barrel domain and the active site loops Finally, activation of PyK of Geobacillus stearothermophilus and several other bacteria (such as S. aureus ) is thought to involve an additional C‐terminal domain (C′) found in these proteins.…”

Section: Mechanisms Of Allosteric Regulationmentioning

confidence: 99%

“…11 Moreover, PyKs are also regulated by heterotropic effectors with fructose 1,6-bisphosphate (FBP) being the most widely known allosteric activator of bacterial, yeast, and mammalian enzymes. 11,[32][33][34] On the other hand, trypanosomatid PyKs are modulated by fructose 2,6-diphosphate (FDP). 10 Other effectors alone or in combination modulate different PyKs based on the metabolic needs of the cells.…”

Section: Evolutionary Relationships In the Allosteric Regulation Ofmentioning

confidence: 99%

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An overview of structure, function, and regulation of pyruvate kinases

et al. 2019

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In the last step of glycolysis Pyruvate kinase catalyzes the irreversible conversion of ADP and phosphoenolpyruvate to ATP and pyruvic acid, both crucial for cellular metabolism. Thus pyruvate kinase plays a key role in controlling the metabolic flux and ATP production. The hallmark of the activity of different pyruvate kinases is their tight modulation by a variety of mechanisms including the use of a large number of physiological allosteric effectors in addition to their homotropic regulation by phosphoenolpyruvate. Binding of effectors signals precise and orchestrated movements in selected areas of the protein structure that alter the catalytic action of these evolutionarily conserved enzymes with remarkably conserved architecture and sequences. While the diverse nature of the allosteric effectors has been discussed in the literature, the structural basis of their regulatory effects is still not well understood because of the lack of data representing conformations in various activation states. Results of recent studies on pyruvate kinases of different families suggest that members of evolutionarily related families follow somewhat conserved allosteric strategies but evolutionarily distant members adopt different strategies. Here we review the structure and allosteric properties of pyruvate kinases of different families for which structural data are available.

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The lid domain is important, but not essential, for catalysis of Escherichia coli pyruvate kinase

et al. 2020

Self Cite

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Pyruvate kinase catalyses the final step of the glycolytic pathway in central energy metabolism.The monomeric structure comprises three domains: a catalytic TIM-barrel, a regulatory domain involved in allosteric activation, and a lid domain that encloses the substrates. The lid domain is thought to close over the TIM-barrel domain forming contacts with the substrates to promote catalysis and may be involved in stabilising the activated state when the allosteric activator is bound. However, it remains unknown whether the lid domain is essential for pyruvate kinase catalytic or regulatory function. To address this, we removed the lid domain of Escherichia coli pyruvate kinase type 1 (PK TIM+Reg ) using protein engineering. Biochemical analyses demonstrate that, despite the absence of key catalytic residues in the lid domain, PK TIM+Reg retains a low-level of catalytic activity and has a reduced binding affinity for the substrate phosphoenolpyruvate. The enzyme retains allosteric activation, but the regulatory profile of the enzyme is changed relative to the wild-type enzyme. Analytical ultracentrifugation and small-angle X-ray scattering data show that, beyond the loss of the lid domain, the PK TIM+Reg structure is not significantly altered and is consistent with the wild type tetramer that is assembled through interactions at the TIM and regulatory domains. Our results highlight the contribution of the lid domain for facilitating pyruvate kinase catalysis and regulation, which could aid in the development of small molecule inhibitors for pyruvate kinase and related lid-regulated enzymes.

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Conformational Dynamics and Allostery in Pyruvate Kinase

Cited by 29 publications

References 52 publications

Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling

Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling

An overview of structure, function, and regulation of pyruvate kinases

The lid domain is important, but not essential, for catalysis of Escherichia coli pyruvate kinase

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