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Cited by 158Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressBiochemical and Molecular Research

Selective activation of PFKL suppresses the phagocytic oxidative burst

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Amara, Neri, Cooper, Madison P., Voronkova, Maria A., Webb, Bradley A., Lynch, Eric M., Kollman, Justin M., Ma, Taylur, Yu, Kebing +7 more·2021·Cell
DOI 10.1016/j.cell.2021.07.004PMC PMC8802628
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Abstract

In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.

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  • NLRP3 inflammasome activation increases glycolytic metabolites such as fructose 1,6-biphosphate via PFK-1 and reduces NAD, with no change in cystine or betaine.

    “NLRP3 inflammasome activation also increased glycolytic metabolites45 such as fructose 1, 6-biphosphate via phosphofructokinase-1,46 alongside reduced nicotinamide adenine dinucleotide (NAD) (Figure 2A), a key cofactor in redox reactions,47 with no change in cystine (the oxidized dimeric form of cysteine) or betaine, an organic osmolyte in the methionine cycle (Figures 2B and Figure S2C).”

    From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [46]

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Authors
Amara, N., Cooper, M. P., Voronkova, M. A., Webb, B. A., Lynch, E. M., Kollman, J. M., Ma, T., Yu, K., Lai, Z., Sangaraju, D., Kayagaki, N., Newton, K., Bogyo, M., Staben, S. T., & Dixit, V. M.
Affiliations
  • Genentech (US)
  • West Virginia University (US)
  • University of Washington (US)
  • Stanford University (US)
Corresponding author
Dixit, Vishva M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-08
Volume
184
Issue
17
Pages
4480-4494.e15
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.07.004
PMC
PMC8802628
OpenAlex
W3186137292
Cited by
158
References
3
Citations by year
2026: 23 · 2025: 38 · 2024: 41 · 2023: 32 · 2022: 21 · 2021: 2
FWCI
9.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
Funders
  • University of Washington
  • Genentech (1008579R)
  • West Virginia University
  • National Institutes of Health (R01GM118396)
  • Indiana Clinical and Translational Sciences Institute (U54 GM104942)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
PFKL, NOX2, NADPH oxidase, neutrophil respiratory burst, pentose phosphate pathway, NADPH, NETosis, acute respiratory distress syndrome, allosteric activation, chemoproteomics, enzyme structure
MeSH terms
Gasdermins, Adenosine Diphosphate, Adenosine Monophosphate, Allosteric Regulation, Enzyme Activation, Epithelial Cells, Glycolysis, Humans, Kinetics, Models, Molecular, Neutrophils, Phagocytosis, Recombinant Proteins, Tetradecanoylphorbol Acetate, Respiratory Burst, NADPH Oxidases, Phosphofructokinase-1, Liver Type, Phosphate-Binding Proteins, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Microbial Viability

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