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

Schormann, Norbert; Hayden, Katherine; Lee, Paul Yong Kyu; Banerjee, Surajit; Chattopadhyay, Debasish

doi:10.1002/pro.3691

Cited by 87 publications

(67 citation statements)

References 88 publications

(250 reference statements)

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“…An analysis of 26 PYK protein sequences from diverse eukaryotes revealed strong conservation, showing 45–93% agreement with the consensus sequence called from the alignment (Fig D). The T343A mutation was in a region of the protein that is annotated as part of the ADP binding pocket in homologous proteins (Schormann et al , ). The threonine residue in the reference (laboratory) strain of S. pombe was unique in this highly conserved region of all PYK sequences.…”

Section: Resultsmentioning

confidence: 99%

Pyruvate kinase variant of fission yeast tunes carbon metabolism, cell regulation, growth and stress resistance

Kamrad

Großbach

Rodríguez-López

et al. 2020

Molecular Systems Biology

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Cells balance glycolysis with respiration to support their metabolic needs in different environmental or physiological contexts. With abundant glucose, many cells prefer to grow by aerobic glycolysis or fermentation. Using 161 natural isolates of fission yeast, we investigated the genetic basis and phenotypic effects of the fermentationrespiration balance. The laboratory and a few other strains depended more on respiration. This trait was associated with a single nucleotide polymorphism in a conserved region of Pyk1, the sole pyruvate kinase in fission yeast. This variant reduced Pyk1 activity and glycolytic flux. Replacing the "low-activity" pyk1 allele in the laboratory strain with the "high-activity" allele was sufficient to increase fermentation and decrease respiration. This metabolic rebalancing triggered systems-level adjustments in the transcriptome and proteome and in cellular traits, including increased growth and chronological lifespan but decreased resistance to oxidative stress. Thus, low Pyk1 activity does not lead to a growth advantage but to stress tolerance. The genetic tuning of glycolytic flux may reflect an adaptive trade-off in a species lacking pyruvate kinase isoforms.

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Section: Resultsmentioning

confidence: 99%

Pyruvate kinase variant of fission yeast tunes carbon metabolism, cell regulation, growth and stress resistance

Kamrad

Großbach

Rodríguez-López

et al. 2020

Molecular Systems Biology

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“…PykA is a highly conserved homotetramer that catalyzes the final reaction of glycolysis, converting PEP and ADP into pyruvate and ATP. Its 3D structure has been solved for many organisms (Schormann et al, 2019) and residues of the catalytic site important for PEP, ADP binding and for phosphoryl transfer have been identified (Fig. S1A).…”

Section: Introductionmentioning

confidence: 99%

Glycolytic pyruvate kinase moonlighting activities in DNA replication initiation and elongation

Horemans

Pitoulias

Holland

et al. 2020

Preprint

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SUMMARYCells have evolved a metabolic control of DNA replication to respond to a wide range of nutritional conditions. Accumulating data suggest that this poorly understood control depends, at least in part, on Central Carbon Metabolism (CCM). In Bacillus subtilis, the glycolytic pyruvate kinase (PykA) is intricately linked to replication. This 585 amino-acid-long enzyme comprises a catalytic (Cat) domain that binds to phosphoenolpyruvate (PEP) and ADP to produce pyruvate and ATP, and a C-terminal domain of unknown function. Interestingly, the C-terminal domain termed PEPut interacts with Cat and is homologous a domain that, in other metabolic enzymes, are phosphorylated at a conserved TSH motif at the expense of PEP and ATP to drive sugar import and catalytic or regulatory activities. To gain insights into the role of PykA in replication, DNA synthesis was analyzed in various Cat and PEPut mutants grown in a medium where the metabolic activity of PykA is dispensable for growth. Measurements of replication parameters (ori/ter ratio, C period and fork speed) and of the pyruvate kinase activity showed that PykA mutants exhibit replication defects resulting from side chain modifications in the PykA protein rather than from a reduction of its metabolic activity. Interestingly, Cat and PEPut have distinct commitments in replication: while Cat impacts positively and negatively replication fork speed, PEPut stimulates initiation through a process depending on Cat-PEPut interaction and growth conditions. Residues binding to PEP and ADP in Cat, stabilizing the Cat-PEPut interaction and belonging to the TSH motif of PEPut were found important for the commitment of PykA in replication. In vitro, PykA affects the activities of replication enzymes (the polymerase DnaE, helicase DnaC and primase DnaG) essential for initiation and elongation and genetically linked to pykA. Our results thus connect replication initiation and elongation to CCM metabolites (PEP, ATP and ADP), critical Cat and PEPut residues and to multiple links between PykA and the replication enzymes DnaE, DnaC and DnaG. We propose that PykA is endowed with a moonlighting activity that senses the concentration of signaling metabolites and interacts with replication enzymes to convey information on the cellular metabolic state to the replication machinery and adjust replication initiation and elongation to metabolism. This defines a new type of replication regulator proposed to be part of the metabolic control that gates replication in the cell cycle.

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“…Moreover, the glucose entry into the enterocyte could be modulated through the regulation of glucose transporter 1 (GLUT1), a constitutive glucose transporter that is insulin-independent, and through the regulation of enzymes involved in gluconeogenesis/glycolysis. Hexokinase 1 (HK1) and L-type pyruvate kinase (PKLR) are the two main enzymes that regulate the glycolysis pathway [12,13]. These pathways could play an important role in the remission of T2DM after bariatric surgery.…”

Section: Introductionmentioning

confidence: 99%

Jejunal Insulin Signalling Is Increased in Morbidly Obese Subjects with High Insulin Resistance and Is Regulated by Insulin and Leptin

Gutiérrez-Repiso

Ho-Plágaro

Santiago‐Fernández

et al. 2020

JCM

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Little is known about the jejunal insulin signalling pathways in insulin resistance/diabetes states and their possible regulation by insulin/leptin. We study in jejunum the relation between insulin signalling and insulin resistance in morbidly obese subjects with low (MO-low-IR) or with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM), and the effect of insulin/leptin on intestinal epithelial cells (IEC). Insulin receptor substrate-1 (IRS1) and the catalytic p110β subunit (p110β) of phosphatidylinositol 3-kinase (PI3K) were higher in MO-high-IR than in MO-low-IR. The regulatory p85α subunit of PI3K (p85α)/p110β ratio was lower in MO-high-IR and MO-metf-T2DM than in MO-low-IR. Akt-phosphorylation in Ser473 was reduced in MO-high-IR compared with MO-low-IR. IRS1 and p110-β were associated with insulin and leptin levels. The improvement of body mass index (BMI) and HOMA-IR (homeostasis model assessment of insulin resistance index) after bariatric surgery was associated with a higher IRS1 and a lower p85α/p110β ratio. IEC (intestinal epithelial cells) incubation with a high glucose + insulin dose produced an increase of p85α and p110β. High dose of leptin produced an increase of IRS1, p85α and p110β. In conclusion, despite the existence of insulin resistance, the jejunal expression of genes involved in insulin signalling was increased in MO-high-IR. Their expressions were regulated mainly by leptin. IRS1 and p85α/p110β ratio was associated with the evolution of insulin resistance after bariatric surgery.

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

Cited by 87 publications

References 88 publications

Pyruvate kinase variant of fission yeast tunes carbon metabolism, cell regulation, growth and stress resistance

Pyruvate kinase variant of fission yeast tunes carbon metabolism, cell regulation, growth and stress resistance

Glycolytic pyruvate kinase moonlighting activities in DNA replication initiation and elongation

Jejunal Insulin Signalling Is Increased in Morbidly Obese Subjects with High Insulin Resistance and Is Regulated by Insulin and Leptin

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