| Phosphatidate phosphatase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 3.1.3.4 | ||||||||
| CAS no. | 9025-77-8 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
The enzymephosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatoryenzyme in lipid metabolism,catalyzing the conversion ofphosphatidate todiacylglycerol:[1][2]
The reverse conversion is catalyzed by the enzymediacylglycerol kinase, which replaces the hydroxyl group on diacylgylcerol with a phosphate fromATP, generatingADP in the process.
In yeast, the forward direction is Mg2+-dependent, while the reverse process is Ca2+-dependent.[3] PAP1, a cytosolic phosphatidate phosphatase found in the lung, is also Mg2+-dependent, but PAP2, a six-transmembrane-domain integral protein found in the plasma membrane, is not.[4][5]
Phosphatidate phosphatase regulates lipid metabolism in several ways. In short, it is a key player in controlling the overall flux oftriacylglycerols tophospholipids and vice versa, also exerting control through the generation and degradation of lipid-signaling molecules related to phosphatidate.[4] When the phosphatase is active,diacylglycerols formed by it can go on to form any of several products, includingphosphatidylethanolamine,phosphatidylcholine,phosphatidylserine, andtriacylglycerol.[6] Phospholipids can be formed from diacylglycerol through reaction with activatedalcohols, and triacylglycerols can be formed from diacylglycerols through reaction with fatty acyl CoA molecules. When phosphatidate phosphatase is inactive, diacylglycerol kinase catalyzes the reverse conversion, allowing phosphatidate to accumulate as it brings down diacylglycerol levels. Phosphatidate can then be converted into an activated form, CDP-diacylglycerol by liberation of apyrophosphate from a CTP molecule, or intocardiolipin. This is a principal precursor used by the body in phospholipid synthesis. Furthermore, because both phosphatidate and diacylglycerol function assecondary messengers, phosphatidate phosphatase is able to exert extensive and intricate control of lipid metabolism far beyond its local effect on phopshatidate and diacylglycerol concentrations and the resulting effect on the direction of lipid flux as outlined above.[7]
Phosphatidate phosphatase is up-regulated by CDP-diacylglycerol,phosphatidylinositol (formed from reaction of CDP-diacylglycerol withinositol), andcardiolipin. It is down-regulated bysphingosine anddihydrosphingosine. This makes sense in the context of the discussion above. Namely, a build up of products that are formed from phosphatidate serves to up-regulate the phosphatase, the enzyme that consumes phosphatidate, thereby acting as a signal that phosphatidate is in abundance and causing its consumption. At the same time, a build up of products that are formed from DAG serves to down regulate the enzyme that forms diacylglycerol, thereby acting as a signal that this is in abundance and its production should be slowed.[7]
PAP belongs to the family of enzymes known ashydrolases, and more specifically to the hydrolases that act on phosphoricmonoester bonds. This enzyme participates in 4metabolic pathways:glycerolipid,glycerophospholipid,ether lipid, andsphingolipid metabolism.
Thesystematic name isdiacylglycerol-3-phosphate phosphohydrolase.[8] Other names in common use include:
There are several different genes that code for phosphatidate phosphatases. They fall into one of two types (type I and type II), depending on their cellular localization and substrate specificity.[9]
Type I phosphatidate phosphatases are soluble enzymes that can associate to membranes. They are found mainly in the cytosol and the nucleus. Encoded for by a group of genes namedLipin, they are substrate specific only to phosphatidate. There are speculated to be involved in thede novo synthesis of glycerolipids.
Each of the 3Lipin proteins found in mammals—Lipin1, Lipin2, andLipin3—has unique tissue expression motifs and distinct physiological functions.[10]
Regulation of mammalianLipin PAP enzymes occurs at the transcriptional level. For example,Lipin1 is induced byglucocorticoids during adipocyte differentiation as well as in cells that are experiencing proliferation of theendoplasmic reticulum (ER).Lipin2, on the other hand, is repressed during adipocyte differentiation.[3]
Lipin is phosphorylated in response to insulin in skeletal muscle and adipocytes, linking the physiologic action of insulin to fat cell differentiation. Lipin phosphorylation is inhibited by treatment with rapamycin, suggesting that mTOR controls signal transduction feeding into lipin and may partially explain dyslipidemia resulting from rapamycin therapy.[11]
Type II phosphatidate phosphatases are transmembrane enzymes found mainly in the plasma membrane. They can dephosphorylate other substrates besides phosphatidate, and therefore are also known aslipid phosphate phosphatases. Their main role is in lipid signaling and in phospholipid head-group remodeling.
One example of a type II phosphatidate phosphatase is PgpB (PDBe: 5jwy).[12][13] PgpB is one of three integral membrane phosphatases inEscherichia coli that catalyzes the dephosphorylation of phosphatidylglycerol phosphate (PGP) to PG (phosphatidylglycerol).[14] The other two are PgpA and PgpC. While all three catalyze the reaction from PGP to PG, their amino acid sequences are dissimilar and it is predicted that their active sites open to different sides of the cytoplasmic membrane. PG accounts for approximately 20% of the total membrane lipid composition in the inner membrane of bacteria. PgpB is competitively inhibited byphosphatidylethanolamine (PE), a phospholipid formed from DAG. This is therefore an example ofnegative feedback regulation. The enzyme active site contains a catalytic triadAsp-211,His-207, andHis-163 that establishes a charge relay system. However, this catalytic triad is essential for the dephosphorylation oflysophosphatidic acid,phosphatidic acid, andsphingosine-1-phosphate, but is not essential in its entirety for the enzyme's native substrate, phosphatidylglycerol phosphate; His-207 alone is sufficient to hydrolyze PGP.[14]
In the cartoon depiction of PgpB below, one can see its six transmembranealpha helices, which are here shown horizontally. Of the three PGP phosphatases discussed above, PgpB is the only to have multiple transmembrane alpha helices.[14]
Human genes that encode phosphatidate phosphatases include:
Lipin-1 deficiency in mice results inlipodystrophy,insulin resistance, andneuropathy. In humans, variations inLipin-1 expression levels can result ininsulin sensitivity,hypertension, and risk formetabolic syndrome. Serious mutations inLipin-2 lead to aninflammatory disorder in humans.[10]
