Platelet-activating factor acetylhydrolase

Function

Lipoprotein-associated calcium-independent phospholipase A2 involved in phospholipid catabolism during inflammatory and oxidative stress response. At the lipid-aqueous interface, hydrolyzes the ester bond of fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity). Specifically targets phospholipids with a short-chain fatty acyl group at sn-2 position. Can hydrolyze phospholipids with long fatty acyl chains, only if they carry oxidized functional groups. Hydrolyzes and inactivates platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a potent pro-inflammatory signaling lipid that acts through PTAFR on various innate immune cells. Hydrolyzes oxidatively truncated phospholipids carrying an aldehyde group at omega position, preventing their accumulation in low-density lipoprotein (LDL) particles and uncontrolled pro-inflammatory effects. As part of high-density lipoprotein (HDL) particles, can hydrolyze phospholipids having long-chain fatty acyl hydroperoxides at sn-2 position and protect against potential accumulation of these oxylipins in the vascular wall. Catalyzes the release from membrane phospholipids of F2-isoprostanes, lipid biomarkers of cellular oxidative damage.

Classification

Family (Pfam)

PF03403 PAF-AH_p_II

InterPro

AB_hydrolase_fold, PAF_acetylhydro_eukaryote

Functional cluster

Zinc-Finger & Ubiquitination Proteins

Experimental structures · PDB · 33

• 3D59 X-ray 1.50A
• 3D5E X-ray 2.10A
• 3F96 X-ray 2.10A
• 3F97 X-ray 1.70A
• 3F98 X-ray 1.70A
• 3F9C X-ray 2.30A
• 5I8P X-ray 2.37A
• 5I9I X-ray 2.70A
• 5JAD X-ray 2.05A
• 5JAH X-ray 2.06A
• 5JAL X-ray 2.06A
• 5JAN X-ray 2.12A
• … and 21 more

A predicted model is available from AlphaFold.

Gene Ontology · 16

• GO:0005576 extracellular region
• GO:0034364 high-density lipoprotein particle
• GO:0034362 low-density lipoprotein particle
• GO:0003847 1-alkyl-2-acetylglycerophosphocholine esterase activity
• GO:0004623 A2-type glycerophospholipase activity
• GO:0016788 hydrolase activity, acting on ester bonds
• GO:0005543 phospholipid binding
• GO:0034440 lipid oxidation
• GO:0034374 low-density lipoprotein particle remodeling
• GO:0016486 peptide hormone processing
• GO:0034638 phosphatidylcholine catabolic process
• GO:0034441 plasma lipoprotein particle oxidation
• GO:0062234 platelet activating factor catabolic process
• GO:0046469 platelet activating factor metabolic process
• GO:0050729 positive regulation of inflammatory response
• GO:0090026 positive regulation of monocyte chemotaxis

Disease associations

• platelet-activating factor acetylhydrolase deficiency MONDO:0013663

Drugs targeting this protein · 2

• DARAPLADIB inhibitor
• RILAPLADIB inhibitor

Related proteins · sequence + function similarity

• Platelet-activating factor acetylhydrolase 0.93
• Platelet-activating factor acetylhydrolase 0.92
• Platelet-activating factor acetylhydrolase 0.90
• Platelet-activating factor acetylhydrolase 0.86
• Platelet-activating factor acetylhydrolase 0.82
• Platelet-activating factor acetylhydrolase 2, cytoplasmic 0.75
• Platelet-activating factor acetylhydrolase 2, cytoplasmic 0.71
• Platelet-activating factor acetylhydrolase 2, cytoplasmic 0.68
• Platelet-activating factor acetylhydrolase 2, cytoplasmic 0.68
• Platelet-activating factor acetylhydrolase homolog 2 0.65
• Lysophosphatidylserine lipase ABHD12 0.56
• Arylacetamide deacetylase-like 4 family member 1 0.53

Co-cited proteins · studied together in the literature

• Platelet-activating factor acetylhydrolase 3 shared papers
• Platelet-activating factor acetylhydrolase 1 shared papers
• Platelet-activating factor acetylhydrolase 1 shared papers
• Platelet-activating factor acetylhydrolase 1 shared papers

Literature · 21 cited papers

• Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes. Biochem. Pharmacol. · 2009
• Crystal structure of human plasma platelet-activating factor acetylhydrolase: structural implication to lipoprotein binding and catalysis. J. Biol. Chem. · 2008
• Identification of a domain that mediates association of platelet-activating factor acetylhydrolase with high density lipoprotein. J. Biol. Chem. · 2008
• Phospholipase action of platelet-activating factor acetylhydrolase, but not paraoxonase-1, on long fatty acyl chain phospholipid hydroperoxides. J. Biol. Chem. · 2007
• Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases. J. Biol. Chem. · 2006
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• The DNA sequence and analysis of human chromosome 6. Nature · 2003
• Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction. Circulation · 2003
• N-linked glycosylation of macrophage-derived PAF-AH is a major determinant of enzyme association with plasma HDL. J. Lipid Res. · 2001
• The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am. J. Hum. Genet. · 2000
• Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry · 1999
• Molecular basis of the interaction between plasma platelet-activating factor acetylhydrolase and low density lipoprotein. J. Biol. Chem. · 1999
• … and 9 more in the literature graph