Phospholipase A2 biochemistry

Abstract

The phospholipase A(2) (PLA(2)) superfamily consists of many different groups of enzymes that catalyze the hydrolysis of the sn-2 ester bond in a variety of different phospholipids. The products of this reaction, a free fatty acid, and lysophospholipid have many different important physiological roles. There are five main types of PLA(2): the secreted sPLA(2)'s, the cytosolic cPLA(2)'s, the Ca(2+)independent iPLA(2)'s, the PAF acetylhydrolases, and the lysosomal PLA(2)'s. This review focuses on the superfamily of PLA(2) enzymes, and then uses three specific examples of these enzymes to examine the differing biochemistry of the three main types of these enzymes. These three examples are the GIA cobra venom PLA(2), the GIVA cytosolic cPLA(2), and the GVIA Ca(2+)-independent iPLA(2).

Figure 1

Reaction catalyzed by the PLA₂ superfamily of enzymes. Phospholipid on the left is hydrolyzed at the sn-2 position to yield lysophospholipid and free fatty acid on the right.

Figure 2

Group IA PLA₂ with phospholipid substrate modeled in the active site based on crystal structure by Fremont et al. [39], along with NOE measurements [52] using amide pseudo-substrate inhibitor [53]. The active site residues His-48 and Asp-93 and the bound Ca²⁺ is 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; of special interest are the aromatic residues on the interfacial binding surface Tyr-3, Trp-19, Trp 61, and Phe 64. Adapted from Dennis [3]

Figure 3

Group IVA PLA₂ crystal structure as determined by Dessen et. Al. [74]. The C2 domain is shown in orange, with two bound Ca²⁺ ions shown in light yellow. The catalytic domain is shown on the right with the cap region colored yellow, and the lid region 415–432 colored magenta. The active site residues Ser-228, Asp-549 and Arg-200 are shown in stick form colored red. The PIP₂ binding site is shown in dark blue, and the C1P binding site is shown in cyan.