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Phospholipase C (PLC) is a class of membrane-associated
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s that cleave phospholipids just before the
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...
group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cell
physiology Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemic ...
, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of
phosphatidylinositol 4,5-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PIP2) into diacyl glycerol (DAG) and
inositol 1,4,5-trisphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
(IP3), which serve as
second messengers Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first m ...
. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids. There are thirteen kinds of mammalian phospholipase C that are classified into six isotypes (β, γ, δ, ε, ζ, η) according to structure. Each PLC has unique and overlapping controls over expression and subcellular distribution.


Variants


Mammalian variants

The extensive number of functions exerted by the PLC reaction requires that it be strictly regulated and able to respond to multiple extra- and intracellular inputs with appropriate kinetics. This need has guided the evolution of six isotypes of PLC in animals, each with a distinct mode of regulation. The pre-mRNA of PLC can also be subject to differential splicing such that a mammal may have up to 30 PLC enzymes. * beta: PLCB1, PLCB2,
PLCB3 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-3 is an enzyme that in humans is encoded by the ''PLCB3'' gene. The gene codes for the enzyme phospholipase C β3. The enzyme catalyzes the formation of inositol 1,4,5-trisphosphate an ...
,
PLCB4 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-4 is an enzyme that in humans is encoded by the ''PLCB4'' gene. Function The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol ...
* gamma: PLCG1, PLCG2 * delta:
PLCD1 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-1 is an enzyme that in humans is encoded by the ''PLCD1'' gene. PLCd1 is essential to maintain homeostasis of the skin. See also Phospholipase C Phospholipase C (PLC) is a class of ...
,
PLCD3 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-3 is an enzyme that in humans is encoded by the ''PLCD3'' gene. Function This gene encodes a member of the phospholipase C family, which catalyze the hydrolysis of phosphatidylino ...
,
PLCD4 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-4 is an enzyme that in humans is encoded by the ''PLCD4'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of ...
* epsilon:
PLCE1 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) is an enzyme that in humans is encoded by the ''PLCE1'' gene. This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bi ...
* eta: PLCH1,
PLCH2 PLCH may stand for: * Plch, a municipality in the Czech Republic * The Public Library of Cincinnati and Hamilton County, a public library system in Cincinnati, Ohio, United States * Pulmonary Langerhans' cell histiocytosis Langerhans cell histioc ...
* zeta: PLCZ1 * phospholipase C-like: PLCL1,
PLCL2 PLCL may refer to: * Park Lane College Leeds, a former British further education college, now part of Leeds City College * ''Parker Lewis Can't Lose ''Parker Lewis Can't Lose'' is an American teen sitcom that originally aired on Fox from Sept ...


Bacterial variants

Most of the bacterial variants of phospholipase C are characterized into one of four groups of structurally related proteins. The toxic phospholipases C are capable of interacting with eukaryotic cell membranes and hydrolyzing phosphatidylcholine and sphingomyelin, ultimately leading to cell lysis. *Zinc-metallophospholipases C: '' Clostridium perfringens'' alpha-toxin, '' Bacillus cereus'' PLC (BC-PLC) *Sphingomyelinases: ''B. cereus'', '' Staphylococcus aureus'' *Phosphatidylinositol-hydrolyzing enzymes: ''B. cereus'', '' B. thuringiensis'', '' L. monocytogenes'' (PLC-A) *Pseudomonad phospholipases C: ''
Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic– facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. a ...
'' (PLC-H and PLC-N)


Enzyme structure

In mammals, PLCs share a conserved core structure and differ in other domains specific for each family. The core enzyme includes a split triosephosphate isomerase (TIM) barrel, pleckstrin homology (PH) domain, four tandem EF hand domains, and a C2 domain. The TIM barrel contains the active site, all catalytic residues, and a Ca2+ binding site. It has an autoinhibitory insert that interrupts its activity called an X-Y linker. The X-Y linker has been shown to occlude the active site, and with its removal PLC is activated. The genes encoding alpha-toxin (''Clostridium perfringens''), '' Bacillus cereus'' PLC (BC-PLC), and PLCs from '' Clostridium bifermentans'' and '' Listeria monocytogenes'' have been isolated and nucleotides sequenced. There is significant homology of the sequences, approximately 250 residues, from the N-terminus. Alpha-toxin has an additional 120 residues in the C-terminus. The C-terminus of the alpha-toxin has been reported as a “C2-like” domain, referencing the C2 domain found in eukaryotes that are involved in signal transduction and present in mammalian phosphoinositide phospholipase C.


Enzyme mechanism

The primary catalyzed reaction of PLC occurs on an insoluble substrate at a lipid-water interface. The residues in the active site are conserved in all PLC isotypes. In animals, PLC selectively catalyzes the hydrolysis of the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) on the glycerol side of the phosphodiester bond. There is the formation of a weakly enzyme-bound intermediate, inositol 1,2-cyclic phosphodiester, and release of diacylglycerol (DAG). The intermediate is then hydrolyzed to inositol 1,4,5-trisphosphate (IP3). Thus the two end products are DAG and IP3. The acid/base catalysis requires two conserved histidine residues and a Ca2+ ion is needed for PIP2 hydrolysis. It has been observed that the active-site Ca2+ coordinates with four acidic residues and if any of the residues are mutated then a greater Ca2+ concentration is needed for catalysis.


Regulation


Activation

Receptors that activate this pathway are mainly
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s coupled to the Gαq subunit, including: * 5-HT2 serotonergic receptors * α1 (Alpha-1)
adrenergic receptors The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...
Page 104 * Calcitonin receptors * H1
histamine receptors The histamine receptors are a class of G protein–coupled receptors which bind histamine as their primary endogenous ligand. There are four known histamine receptors: * H1 receptor * H2 receptor * H3 receptor * H4 receptor Comparison There ...
* Metabotropic glutamate receptors, Group I * M1, M3, and M5 muscarinic receptors * Thyroid-Releasing Hormone receptor in anterior pituitary gland Other, minor, activators than Gαq are: * MAP kinase. Activators of this pathway include PDGF and FGF. * βγ-complex of heterotrimeric G-proteins, as in a minor pathway of
growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
release by growth hormone-releasing hormone.GeneGlobe -> GHRH Signaling
Retrieved on May 31, 2009
* Cannabinoid receptors


Inhibition

*Small molecule U73122: aminosteroid, putative PLC inhibitor. However, the specificity of U73122 has been questioned. It has been reported that U73122 activates the phospholipase activity of purified PLCs. * Edelfosine: lipid-like, anti-neoplastic agent (ET-18-OCH3) *Autoinhibition of X-Y linker in mammalian cells: It is proposed that the X-Y linker consists of long stretches of acidic amino acids that form dense areas of negative charge. These areas could be repelled by the negatively charged membrane upon binding of the PLC to membrane lipids. The combination of repulsion and steric constraints is thought to remove the X-Y linker from near the active site and relieve auto-inhibition. *Compounds containing the morpholinobenzoic acid scaffold belong to a class of drug-like phosphatidylcholine-specific PLC inhibitors. *''o''-phenanthroline: heterocyclic organic compound, known to inhibit zinc-metalloenzymes *EDTA: molecule that chelates Zn2+ ions and effectively inactivates PLC, known to inhibit zinc-metalloenzymes


Biological function

PLC cleaves the phospholipid
phosphatidylinositol 4,5-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PIP2) into diacyl glycerol (DAG) and
inositol 1,4,5-trisphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
(IP3). Thus PLC has a profound impact on the depletion of PIP2, which acts as a membrane anchor or allosteric regulator and an agonist for many lipid-gated ion channels. PIP2 also acts as the substrate for synthesis of the rarer lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is responsible for signaling in multiple reactions. Therefore, PIP2 depletion by the PLC reaction is critical to the regulation of local PIP3 concentrations both in the plasma membrane and the nuclear membrane. The two products of the PLC catalyzed reaction, DAG and IP3, are important second messengers that control diverse cellular processes and are substrates for synthesis of other important signaling molecules. When PIP2 is cleaved, DAG remains bound to the membrane, and IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol to bind to IP3 receptors, particularly
calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables e ...
s in the smooth endoplasmic reticulum (ER). This causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity. In addition, calcium and DAG together work to activate protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. End-effects include taste, tumor promotion, as well as vesicle exocytosis, superoxide production from NADPH oxidase, and JNK activation. Both DAG and IP3 are substrates for the synthesis of regulatory molecules. DAG is the substrate for the synthesis of phosphatidic acid, a regulatory molecule. IP3 is the rate-limiting substrate for the synthesis of inositol polyphosphates, which stimulate multiple protein kinases, transcription, and mRNA processing. Regulation of PLC activity is thus vital to the coordination and regulation of other enzymes of pathways that are central to the control of cellular physiology. Additionally, phospholipase C plays an important role in the inflammation pathway. The binding of agonists such as thrombin, epinephrine, or
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
, to platelet surface receptors can trigger the activation of phospholipase C to catalyze the release of
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''ara ...
from two major membrane phospholipids,
phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
and phosphatidylcholine. Arachidonic acid can then go on into the cyclooxygenase pathway (producing prostoglandins (PGE1, PGE2, PGF2),
prostacyclins Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosteno ...
(PGI2), or thromboxanes (TXA2)), and the lipoxygenase pathway (producing leukotrienes (LTB4, LTC4, LTD4, LTE4)). The bacterial variant ''Clostridium perfringens'' type A produces alpha-toxin. The toxin has phospholipase C activity, and causes
hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing ( lysis) of red blood cells (erythrocytes) and the release of their contents ( cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in viv ...
, lethality, and dermonecrosis. At high concentrations, alpha-toxin induces massive degradation of phosphatidylcholine and sphingomyelin, producing diacylglycerol and ceramide, respectively. These molecules then participate in signal transduction pathways. It has been reported that the toxin activates the arachidonic acid cascade in isolated rat aorta. The toxin-induced contraction was related to generation of thromboxane A2 from arachidonic acid. Thus it is likely the bacterial PLC mimics the actions of endogenous PLC in eukaryotic cell membranes.


See also

* Glycosylphosphatidylinositol diacylglycerol-lyase A trypanosomal enzyme. * Phosphatidylinositol diacylglycerol-lyase Another related bacterial enzyme * Phosphoinositide phospholipase C The main form found in eukaryotes, especially mammals. * Zinc-dependent phospholipase C family of bacterial enzymes that includes the alpha toxins of '' C. perfringens'' (also known as lecithinase), '' P. aeruginosa'', and '' S. aureus''.


References

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