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Review
. 2011 Oct 12;111(10):6130-85.
doi: 10.1021/cr200085w. Epub 2011 Sep 12.

Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention

Edward A Dennis  1 , Jian Cao, Yuan-Hao Hsu, Victoria Magrioti, George Kokotos
Affiliations
Review

Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention

Edward A Dennis et al. Chem Rev. .
No abstract available

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Figures

Figure 1
Figure 1
The specific reaction catalyzed by phospholipase A2 at the sn-2 position of the glycerol backbone is shown. X, any of a number of polar headgroups; R1, fatty acids, or alkyl, or alkenyl groups and R2, fatty acids or acyl moieties.
Figure 2
Figure 2
Illustration of the application of “surface dilution kinetics” to the phospholipase A2-catalyzed hydrolysis of phospholipids contained in mixed micelles with nonionic surfactants such as Triton X-100. Two possibilities are shown: top, the “surface binding model” whereby the enzyme first associates nonspecifically with the micelle surface; and bottom, the “phospholipid binding model” whereby the enzyme first associates specifically with phospholipid in the micelle surface. In both cases, in a subsequent step, the enzyme associated with the micelle binds a phospholipid substrate molecule in the micelle in its catalytic site and carries out hydrolysis producing as products a lysophospholipid and a fatty acid, which may be released to solution or be retained in the micelle surface. Phospholipid molecules are depicted in red, detergent molecules in gold, and enzyme in blue. Adapted from Ref.
Figure 3
Figure 3
Schematic presentation of secreted PLA2s. Calcium binding loops, active sites (red squares), N and C-terminal extension residues are shown.
Figure 4
Figure 4
A. Overall structure of Group IA sPLA2. Helices are in magenta, β-strands are in green, calcium is shown as a red sphere and disulfide bonds are shown as yellow sticks. (PDB entry: 1PSH) B. The Group IA sPLA2 with phospholipid substrate modeled in the active site as a space filling model. The active site residues His-48 and Asp-93 and the bound Ca2+ are shown in purple. Ca2+ is bound by Asp-49 as well as the carbonyl oxygens of Tyr-28, Gly-30, and Gly-32. Aromatic residues are shown in white. Adapted from Dennis.
Figure 5
Figure 5
Model of the lipid surface binding of the Group IA sPLA2 is shown with residues on the interfacial binding surface Tyr-3, Trp-19, Trp-61, and Phe-64 shown in blue stick form. Adapted from Burke et al.
Figure 6
Figure 6
Schematic presentation of Group IV cPLA2s. Calcium binding loops (CBL), active sites (red squares), and the 242 residue- and 120 residue-inserts of GIVB PLA2 are shown.
Figure 7
Figure 7
Features of the Group IVA cPLA2 crystal structure. The C2 domain is in orange, the α/β hydrolase domain is in green, the cap region is yellow, and the lid is in pink. The C1P binding site is in magenta, the PIP2 binding site is in blue and the active site residues are in red. Adapted from Ref.
Figure 8
Figure 8
Model of the lipid-binding surface of Group IVA cPLA2. Residues interacting with the lipid membrane are based on the experiments of hydrogen/deuterium exchange in the presence of phospholipid vesicles. Adapted from Burke et al.
Figure 9
Figure 9
A. Group IVA cPLA2 residues involved in binding pyrrophenone. B. Group IVA cPLA2 residues involved in binding oxoamide AX007. The residues that have contact with pyrrophenone or AX007 greater than 90% of the time in the molecular dynamics simulation are represented as red sticks and labeled in the figure. The inhibitor is shown in the licorice representation, with carbon, hydrogen, oxygen, nitrogen, and phosphorus atoms colored cyan, white, red, blue, and yellow, respectively. Adapted from Ref.
Figure 10
Figure 10
Schematic presentation of Group VI iPLA2. Ankyrin repeats (ANK), nucleotide phosphate binding domain (cNMP), active site residues in red squares, and patatin-like lipase domains are indicated in green.
Figure 11
Figure 11
Features of Group VIA PLA2 homology models. The domains and binding sites are differentiated by colors. Adapted from Ref.
Figure 12
Figure 12
Phospholipid binding of the Group VIA iPLA2. A. Phospholipid membrane binding effects on H/D exchange of the Group VIA iPLA2 mapped onto the catalytic domain model. B. Model of the lipid-binding surface of the Group VIA iPLA2 based on interactions with lipid membrane. Adapted from Ref.
Figure 13
Figure 13
A. The α/β hydrolase fold of the Group VIIA PLA2 (PAF-AH/Lp-PLA2) crystal structure (PDB entry:3D59). Helixes are shown in purple, β strands in green and loops in light gray. The predicted LDL (residues 114–126) and HDL(residues 362–369) binding surface are shown as indicated. B. Hypothetical model of Lp-PLA2 association with the DMPC lipid membrane surface. The Lp-PLA2 region implicated for Lp-PLA2/liposome association (residues 113–120), is shown in blue and the proposed key residues for Lp-PLA2/liposome association, Trp-115 and Leu-116 are shown in red, as are the catalytic triad residues, Ser-273, Asp-296 and His-351.
Figure 14
Figure 14
The crystal structure of Group VIII PLA2 (PAF-AH IB) α1 subunit (PDB entry 1WAB). Helixes are shown in light orange, β strands in purple and loops in light gray. The catalytic triad residues Ser-47, Asp-192 and His-195 are shown in red sticks. The specific pocket is comprised of residues Leu-48, Thr-103 and Leu-194, which defines the enzyme substrate specificity, are shown in blue sticks.
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References

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