Phospholipase

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A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D.

Phospholipase A (PLA)

Phospholipases A2 (PLA2s) are a large family of enzymes that all hydrolyze a particular form of glycerophospholipids. Glycerophospholipids are relatively small lipid (fat) molecules that contain both hydrophilic and hydrophobic regions. The hydrophobic region of the molecule includes the fatty acids, and the hydrophilic portion includes the sugar alcohol backbone, glycerol. PLA2 enzymes specifically deacylate fatty acids from the 2nd carbon atom (sn2, thus PLA2) of the triglyceride backbone of phospholipids, producing a free fatty acid and a lyso-phospholipid.

There are many glycerophospholipids, since a large range of different fatty acids can be bound to the sn2 position of phospho-lipids, including arachidonic acid and eicosapentaenoic acid.

Arachidonic acid is both a signalling molecule and the precursor for other signalling molecules termed eicosanoids. These include leukotrienes and prostaglandins. Some eicosanoids are synthesized from diacylglycerol, released from the lipid bilayer by phospholipase C (see below).

Phospholipases A2 are ubiquitous enzymes, though the individual enzymes expression patterns differ dramatically. Initially, phospholipases A2 were named based on location of activity (e.g. pancreatic and secretory) or mode of activity (calcium dependent and calcium independent). A much more structured and accurate system has been developed based on genetic homology. For reference see (Six DA, Dennis EA. The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochimica et Biophysica Acta. 2000;1488(1-2):1-19).

Phospholipase B (PLB)

To be written

Phospholipase B is said to be a mixture of both PLA1 and PLA2. It generally acts on lysolecithin (which is formed by the action of PLA2 on lecithin). The action of Phospholipase B results in the cleaving of both fatty acid residues.

Phospholipase C (PLC)

To be expanded

Phospholipase C is a key enzyme in phosphatidylinositol (PIP2) metabolism and lipid signaling pathways. It is activated by either Gαq protein or Gβγ subunits (making it part of a G protein-coupled receptor signal transduction pathway) or by transmembrane receptors with intrinsic or associated tyrosine kinase activity.

It hydrolyzes PIP2, a phosphatidylinositol, into two second messagers, inositol triphosphate (IP3) and diacylglycerol, which then go on to modulate the activity of downstream proteins during cellular signalling, e.g. calcium channels in the endoplasmic reticulum of various cell types and protein kinase C, respectively.

The Phospholipase C family consists of 13 isozymes split between six subfamilies, PLC-δ, -β, -γ, -ε, -ζ, and the recently discovered -η isoform. The molecular weights of each being 85kDa for the δ form, 120-155kDa for both the β and γ forms, and 230-260kDa for the ε form. They all require calcium for catalytic activity, although the only isoform which is known to be inactive at basal intracellular calcium levels is the δ subfamily of enzymes.

  • PLC-δ is activated by high calcium levels and binding to PIP2 through its PH domain. It is also thought to be the archetypical PLC.
  • PLC-β is activated by G protein subunits.
  • PLC-γ is activated by receptor tyrosine kinases.
  • PLC-ε is activated by Ras.
  • PLC-ζ is thought to play an important role in vertebrate fertilization, although, its mode of activation is currently unclear.
  • PLC-η has been found to be important for proper neuronal functioning.

All members of the family contain X and Y catalytic domains, SH2 (phosphotyrosine binding) domains are only found in the γ form, and only the ε form contains the RA (Ras Associating) domain. The -β, -δ and -γ forms all contain PH domains at their N-termini, however, the -β subfamily is distinguished from the others by the presence of a long C-terminal extension which is required for activation by Gαq subunits.

Phospholipase D (PLD)

To be expanded

There are two isoforms of Phospholipase D in the mammalian cell: PLD1 and PLD2. PLD (Template:EC number), is located in the plasma membrane and catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid (PA), releasing the soluble choline headgroup into the cytosol. As choline is very abundant in the cell PLD activity does not significantly affect choline levels and choline is unlikely to play any role in signalling.

Phosphatidic acid is a signal molecule and acts to recruit sphingosine kinase 1 (SK1) to membranes [1]. PA is extremely short lived and is rapidly hydrolysed by the enzyme PA phosphohydrolase to form diacylglycerol (DAG). DAG may also be converted to PA by DAG kinase. Although PA and DAG are interconvertible, they do not act in the same pathways. Stimuli that activate PLD do not activate enzymes downstream of DAG and vice versa.

It is possible that, though PA and DAG are interconvertible, separate pools of signalling and non-signalling lipids may be maintained. Studies have suggested that DAG signalling is mediated by polyunsaturated DAG while PLD derived PA is monounsaturated or saturated. Thus functional saturated/monounsaturated PA can be degraded by hydrolysing it to form non-functional saturated/monounsaturated DAG while functional polyunsaturated DAG can be degraded by converting it into non-functional polyunsaturated PA [2]

References

  1. Christine Delon, Maria Manifava, Eleanor Wood, Dawn Thompson, Sonja Krugmann, Susan Pyne, and Nicholas T. Ktistakis (2004) Sphingosine Kinase 1 Is an Intracellular Effector of Phosphatidic Acid J. Biol. Chem. (279):44763-74
  2. Hodgkin MN, Pettitt TR, Martin A, Michell RH, Pemberton AJ, Wakelam MJ. (1998) Diacylglycerols and phosphatidates: which molecular species are intracellular messengers? Trends in Biochem. Sci. 23,200-204