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Phospholipase A2

Phospholipase A2 (PLA2) designates a class of enzymes that hydrolyze the sn-2 ester of glycerophospholipids to produce a fatty acid and a lysophospholipid. It has become clear that some of these enzymes liberate arachidonic acid in mammalian cells for the biosynthesis of eicosanoids, and thus there has been considerable interest in developing PLA2 inhibitors. Based on amino acid sequences, there are now more than 12 distinct groups of mammalian PLA2s, as well as many non-mammalian forms, all of which have been classified into 14 distinct groups with many subgroups.

Since naturally occurring phospholipids have virtually no solubility in water, PLA2 must bind to the lipid-water interface to access its substrate, and it is clear that catalysis occurs at the interface (interfacial catalysis). One has to be careful with the interpretation of kinetic data including inhibition data, and in fact many of the previously reported PLA2 inhibitors work by non-specific mechanisms. One of the problems is that the substrate forms an interface, and the inhibitor can potentially partition into the membrane phase. Thus, inhibition of a PLA2 by micromolar amounts of a compound using micromolar amounts of substrate may occur because a large fraction of the interface could be occupied by inhibitor. This may change the physical nature of the interface, causing the enzyme to desorb from the membrane into the aqueous phase, resulting in non-specific inhibition. Inhibitors that work by this non-specific mechanism are clearly not useful for studying the role of PLA2s in complex cellular processes. Among those inhibitors that bind tightly to the active site of PLA2s, and thus operate by a specific mechanism, the issue of PLA2 group specificity is important.

To date, 10 groups of mammalian secreted PLA2s, known as s-PLA2s, have been identified. Group IB PLA2, also known as pancreatic PLA2, is found not only as part of the digestive fluid where it functions to hydrolyze dietary phospholipids, but also in non-digestive tissues including spleen where it has unknown functions. Group IIA PLA2 was the first non-pancreatic mammalian PLA2 to be identified as a component of synovial fluid and platelets. This enzyme is pro-inflammatory, displays potent bactericial properties and is a target for the development of anti-inflammatory agents including anti-sepsis agents. Groups IIC, IID, IIE, IIF, III, X, XIIA and XIIB secreted PLA2 were discovered by recombinant DNA techniques. The group IIC gene is functional in mice but occurs as a pseudogene in humans. Group XIIB is best designated as a secreted PLA2-like protein since it has a natural mutation of a key catalytic residue that renders this protein devoid of phospholipase activity. The function of these recently discovered secreted PLA2s are unknown. Group V PLA2, also discovered at the DNA level, is an active enzyme secreted from macrophages and probably a variety of other cells. Recent gene disruption studies implicate a role of this enzyme in arachidonic acid release in stimulated macrophages. All of these secreted PLA2s have similar size, three-dimensional structure, and active site residues (except for group XIIB as noted above). They require submillimolar amounts of calcium for catalytic activity.

Mammalian cells also contain two intracellular enzymes that act on long-chain phospholipids. Group IVA PLA2 translocates from the cytosol to internal membranes in response to micromolar calcium, and shows specificity for arachidonyl-containing phospholipids. A wide variety of studies have shown that this enzyme, also known as cPLA2a, releases arachidonic acid from membrane phospholipids for the biosynthesis of eicosanoids. Recent paralogs of cPLA2a have been identified in the genome, but their functions are not known. It has been proposed that the calcium-independent group VI PLA2 may be involved in phospholipid remodeling, insulin secretion from b cells and in stores-operated calcium entry. Groups VII and VIII PLA2s are highly specific for phospholipids with short sn-2 chains and are thought to terminate the action of platelet activation factor by hydrolyzing the sn-2 ester and to act on oxidized phospholipids.

Table 1 and Table 2 contain Accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Table 1.Accepted modulators and additional information
Table 2.Accepted modulators and additional information

Footnotes

a) Not included in the table are a variety of other PLA2s from non-mammalian sources including PLA2s in snake and insect venoms, for example the group IA enzymes in cobra and krait venoms (P7778), rattlesnakes and bee venom (P9279).

b) The species and tissue distribution is only a partial listing.

c) Only those inhibitors that have been shown to bind specifically to the active site of the PLA2s have been listed (see text for more discussion); and the list is not necessarily comprehensive.

d) The list of physiological functions and disease relevance is only partial as the functions of PLA2s is under active investigation and is still unresolved in many cases.

e) See, Singer et al., J Biol. Chem., 277, 48535-49 (2002).

f) See, Smart, B.P., et al., Bioorg. Med. Chem., 12, 1737-1749 (2004).

Abbreviations

AACH(OH)CF3: 2-Hydroxy-1,1,1,-trifluoro-6,9,12,15-heneicosatetraene
AACOCF3: 2-oxo-1,1,1-Trifluoro-6,9-12,15-heneicosatetraene
AACOCH3: 2-oxo-6,9,12,15-Heneicosatetetraene
BEL: (E)-6-(Bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one
MAFP: 4,7,10,13-Nonadecatetraenyl fluorophosphonic acid methyl ester
SB-222657: N-[6-(4-Chlorophenyl)hexyl]-2-oxo-4-[(S)-(phenylmethyl)sulfinyl]-1-azetidineacetamide
SB-223777: N-[6-(4-Chlorophenyl)hexyl]-2-oxo-4-[(R)-(phenylmethyl)sulfinyl]-1-azetidineacetamide

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