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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 substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s that cleave
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids ty ...
s 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. Bact ...
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 Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. 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 phosphatidyl ...
,
PLCD4 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-4 is an enzyme that in humans is encoded by the ''PLCD4'' gene. References Further reading * * * * * * * * * * * * * * * * EC 3.1.4 EF-hand-containing proteins {{ge ...
* epsilon: PLCE1 * 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, a type of interstitial ...
* 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'', a 1990s television series {{disambiguation ...


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 ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, rod-shaped, anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present in nature an ...
'' alpha-toxin, ''
Bacillus cereus ''Bacillus cereus'' is a Gram-positive rod-shaped bacterium commonly found in soil, food, and marine sponges. The specific name, ''cereus'', meaning "waxy" in Latin, refers to the appearance of colonies grown on blood agar. Some strains are ...
'' PLC (BC-PLC) *Sphingomyelinases: ''B. cereus'', ''
Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posit ...
'' *Phosphatidylinositol-hydrolyzing enzymes: ''B. cereus'', '' B. thuringiensis'', ''
L. monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a Facultative anaerobic organism, facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can gro ...
'' (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. aer ...
'' (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 ''Bacillus cereus'' is a Gram-positive rod-shaped bacterium commonly found in soil, food, and marine sponges. The specific name, ''cereus'', meaning "waxy" in Latin, refers to the appearance of colonies grown on blood agar. Some strains are ...
'' PLC (BC-PLC), and PLCs from ''
Clostridium bifermentans ''Paraclostridium bifermentans'', formerly known as ''Clostridium bifermentans'' and abbreviated CLOBI, is an anaerobic, motile, gram-positive bacterium. Toxins and mosquito larvae A certain subspecies, ''Clostridium bifermentans'' subsp. Malays ...
'' 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 Page 104 * Calcitonin receptors * H1 histamine receptors * 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 The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanosine nucleotide-binding proteins, ...
of
heterotrimeric G-protein Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structura ...
s, 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 receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recep ...
s


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 Edelfosine (ET-18-O-CH3; 1-octadecyl-2-''O''-methyl-glycero-3-phosphocholine) is a synthetic alkyl-lysophospholipid (ALP). It has antineoplastic (anti-cancer) effects. Like all ALPs, it incorporates into the cell membrane and does not target t ...
: 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 Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids ty ...
phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. 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 ...
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, to platelet surface receptors can trigger the activation of phospholipase C to catalyze the release of arachidonic acid from two major membrane phospholipids, phosphatidylinositol and
phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or so ...
. Arachidonic acid can then go on into the cyclooxygenase pathway (producing
prostoglandins The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deriv ...
(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, lethality, and dermonecrosis. At high concentrations, alpha-toxin induces massive degradation of
phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or so ...
and
sphingomyelin Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a ethano ...
, 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 The enzyme glycosylphosphatidylinositol diacylglycerol-lyase (EC 4.6.1.14) catalyzes the reaction :6-(α-D-glucosaminyl)-1-phosphatidyl-1D-''myo''-inositol = 6-(α-D-glucosaminyl)-1D-''myo''-inositol 1,2-cyclic phosphate + 1,2-diacyl-''sn''-glyce ...
A trypanosomal enzyme. *
Phosphatidylinositol diacylglycerol-lyase The enzyme phosphatidylinositol diacylglycerol-lyase (EC 4.6.1.13) catalyzes the following reaction: :1-phosphatidyl-1D-''myo''-inositol = 1D-''myo''-inositol 1,2-cyclic phosphate + 1,2-diacyl-''sn''-glycerol This enzyme belongs to the family ...
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

{{Portal bar, Biology, border=no EC 3.1.4