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TitleSelective activation of PFKL suppresses the phagocytic oxidative burst.
Journal, issue, pagesCell, Vol. 184, Issue 17, Page 4480-4494.e15, Year 2021
Publish dateAug 19, 2021
AuthorsNeri Amara / Madison P Cooper / Maria A Voronkova / Bradley A Webb / Eric M Lynch / Justin M Kollman / Taylur Ma / Kebing Yu / Zijuan Lai / Dewakar Sangaraju / Nobuhiko Kayagaki / Kim Newton / Matthew Bogyo / Steven T Staben / Vishva M Dixit /
PubMed AbstractIn neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading ...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.
External linksCell / PubMed:34320407 / PubMed Central
MethodsEM (single particle)
Resolution2.9 Å
Structure data

23544

7lw1

EMDB-23544, PDB-7lw1:
Human phosphofructokinase-1 liver type bound to activator NA-11
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-YG1:
N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide

ChemComp-FBP:
1,6-di-O-phosphono-beta-D-fructofuranose / Fructose 1,6-bisphosphate

ChemComp-F6P:
6-O-phosphono-beta-D-fructofuranose / Fructose 6-phosphate

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / glycolysis / phosphofructokinase / liver type / activated

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