The phospholipids that make up most of the lipid component of the plasma and internal cellular mem branes serve as substrates for several types of phospholipases, as depicted in Figure 1A, depending on where the cleavage of the phospholipid takes place. Phospholipases C and D are involved in cell signaling events that require the polar head group (such as inositol triphosphate, IP3). The two types of phospholipase A cleave the fatty acid from either the sn-1 or sn-2 position, the latter being the position in which arachidonic acid or another polyunsaturated 20-carbon fatty acid is found. Subtypes of PLA2 include the 14 kDa secreted forms of PLA2 (sPLA2), such as those found in venoms of snakes and other creatures as well as mammalian pancreatic enzymes; these enzymes are dependent on high (millimolar) concentrations of Ca2+. A second sub type, Group IV, are the cytosolic PLA2s (cPLA2) that are dependent on micromolar concentrations of Ca2+. Member A of this group is the 85kDa protein that catalyzes the release of arachidonic acid from intracellular membrane phospholipids for eicosanoid synthesis. This enzyme is sometimes referred to as GIVA PLA2 as recognition of its place in the classification scheme, but here it will continue to be referred to as PLA2.

Fig1. Phospholipase A2. In panel A, a glycerophospholipid is shown in which R1 and R2 are long chain fatty acids. R1 is generally a 16 or 18 carbon saturated fatty acid while R2 is usually an 18 or 20 carbon polyunsaturated fatty acid, such as arachidonic acid. R3 is a polar head group such as choline. The catalytic activities of different types of phospholipases on this molecule are shown. Phospholipase A2 releases the long polyunsaturated fatty acid from the second position of the glycerophospholipid. B. When activated, phospholipase A2 moves to the phospholipid bilayer of the nuclear envelope or endoplasmic reticulum and removes a molecule of arachidonic acid from a molecule of, in this illustration, phosphatidyl choline. The nearby enzymes of eicosanoid biosynthesis convert arachidonic acid to the appropriate ones for the cell.

As shown in Figure 1B, the reaction that PLA2 catalyzes takes place at intracellular membranes, notably those of the nuclear envelope and the endoplasmic reticulum. The products of the reaction are arachidonic acid and lysophospholipid. Like many proteins that move from the cytoplasm to a membrane and as depicted in Figure 2, PLA2 has a Ca2+ phospholipid binding domain. Studies have shown that this domain functions in targeting the enzyme to the membrane area that contains the cyclooxygenase and lipoxygenase. The exact site and how the targeting occurs remain to be determined. Phosphorylation of specific serine residues increases PLA2 catalytic activity. Thus, these two intracellular messages, which can be stimulated by any one of a number of extracellular signals, bring about the maximal activation of phospholipase A2, initiating the eicosanoid cascade in a particular cell. Part of the anti-inflammatory action of glucocorticoids is due to inhibition of phospholipase A2, shutting off substrate availability for either cyclooxygenase or lipoxygenase.

Fig2. Activation of phospholipase A2. In this schematic diagram of a cell, the contributors to activation of cPLA2 (cytosol phospholipase A2) are shown. Two events bring about the movement of cPLA2 to internal membranes, such as the nuclear envelope or the endoplasmic reticulum (ER) and are required for the maximum stimulation of PLA2 activity. These are the phosphorylation (circle) of specific serine residues in the catalytic domain (light blue) and the binding of Ca2+ (box) to specific binding sites (dark blue) on the protein. External signals can initiate these events through ligand-receptor stimulation of intracellular signaling pathways. The one illustrated involves phospholipase C (PLC) which generates both an increase in intracellular Ca2+ through inositol triphosphate (IP3) and activation of a phosphorylation pathway through diacylglycerol (DAG). Intracellular Ca2+ can also be increased through the activation of calcium channels. COX, cyclooxygenase; MAPK, mitogen-activated protein kinase; PKC, protein kinase C.

The ability of a cell to produce a given prostanoid depends on the availability of the substrate, e.g., arachidonic acid, as well as that of cyclooxygenase and the specific synthase required. Part of the anti- inflammatory action of glucocorticoids is due to inhibition of phospholipase A2, shutting off substrate availability for either cyclooxygenase or lipoxygenase.

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مواضيع ذات صلة

Overview of Eicosanoid Synthesis

Structure and Nomenclature of Eicosanoids

Water is an Excellent Nucleophile

Interaction with Water Influences the Structure of Biomolecules

Fibrin Clots Are Dissolved by Plasmin

The Activity of Antithrombin, an Inhibitor of Thrombin, Is Increased by Heparin

Conversion of Fibrinogen to Fibrin Is Catalyzed by Thrombin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices

Lipid Composition Is Different in the Exoplasmic and Cytosolic Leaflets

Lipid Composition Influences the Physical Properties of Membranes

The Intrinsic Pathway Also Leads to Activation of Factor X