Lysophosphatidic acid phosphatase type 6

Last updated

ACP6
Crystal Sctructure Lysophosphatidic Acid Phosphatase with Malonate in Active Site.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ACP6 , ACPL1, LPAP, PACPL1, acid phosphatase 6, lysophosphatidic
External IDs OMIM: 611471 MGI: 1931010 HomoloGene: 41128 GeneCards: ACP6
Orthologs
SpeciesHumanMouse
Entrez

51205

66659

Ensembl

ENSG00000162836

ENSMUSG00000028093

UniProt

Q9NPH0

Q8BP40

RefSeq (mRNA)

NM_016361
NM_001323625

NM_019800

RefSeq (protein)

NP_001310554
NP_057445

NP_062774

Location (UCSC) Chr 1: 147.63 – 147.67 Mb Chr 3: 97.07 – 97.08 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Lysophosphatidic acid phosphatase type 6 is an acid phosphatase enzyme that is encoded in humans by the ACP6 gene. [5] [6]

Contents

It acts as a phosphomonoesterase at low pHs. [7] It is responsible for the hydrolysis of Lysophosphatidic acids (LPAs) to their respective monoacylglycerols and the release a free phosphate group in the process. [8] The enzyme has higher activity for myristate-LPA (14 carbon chain), oleate-LPA (18 carbon chain and one unsaturated carbon-carbon bond), laurate-LPA (12 carbon chain) or palmitate-LPA (16 carbon chain). When the substrate is stearate-LPA (18 carbon chain), the enzyme has reduced activity. [9] Phosphatidic acids can also be hydrolyzed by lysophosphatidic acid phosphatase, but at a significantly lower rate. The addition of the second fatty chain makes fitting into the active site much harder. [10]

LPAs are necessary for healthy cell growth, survival and pro-angiogenic factors for both in vivo and in vitro cells. Unbalanced concentrations of lysophosphatidic acid phosphatase can frequently lead to unbalanced LPA concentrations, which can cause metabolic disorders, and lead to ovarian cancer in women. [11] [12] [13]

Structure

Space-filling model of lysophosphatidic acid phosphatase depicting the filled solvent channel. Image generated from 4JOC. Space filling representation for ACP 6.png
Space-filling model of lysophosphatidic acid phosphatase depicting the filled solvent channel. Image generated from 4JOC.

Lysophosphatidic acid phosphatase is a monomer composed of two domains. One domain functions as a cap on the enzyme, while the second comprises the body of the enzyme. The enzyme has two (α) alpha helices on one side, seven (β) beta sheets in the middle, and two more α helices on the opposite side. [14] The space between the two domains serves as a large substrate pocket, as well as a channel through which water molecules can move through. [14] This channel is lined with hydrophilic residues that lead the water molecule to the active site, where the terminal water molecule interacts with Asp-335 residue and is then activated. This catalyzes the bond formation to the phosphate group. Lysophosphatidic acid phosphatase also has two disulfide bridges. One that binds α12 and α4 together, and the other that binds a turn at the edge of β7 strand. Analysis of the pocket shows that the active site pocket has space for one long fatty acid chain, but not for two fatty chains, furthermore supporting that this enzyme has strong preference for LPAs. [14]

The active site of the enzyme shows the polar contacts between the residues in the pocket and the substrate. Image generated from 4JOC. Active site with residues that interact with lysophosphatidic acid.png
The active site of the enzyme shows the polar contacts between the residues in the pocket and the substrate. Image generated from 4JOC.

The active site of lysophosphatidic acid phosphatase has six main residues required to stabilize the phosphate group and the hydroxyl. These residues are Arg-58, His-59, Arg-62, Arg-168, His-334, Asp-335. Though there are no crystal structures with a LPA molecule in the substrate pocket, the crystal structure with malonate shows the hydrogen bonding between the enzyme residues and the carbonyl groups that would stabilize the phosphate and hydroxyl groups on the LPA. In the active site, the phosphate group is stabilized by Arg-58, Arg-62, Arg-168 and His-334. The guanidinium groups and hydrogen on the protonated imidazole ring from the histidine residue. [14] When any of these residues were mutated to alanine, the catalytic activity of the enzyme was greatly reduced. This is evidence that the active site requires this "claw" to hold on to the phosphate group, the aspartic acid residue to activate a water molecule, and the histidine residue to provide a proton to form the alcohol. When the residues at the entrance to the water channel were mutated to bulkier residues, such as Leucine, Phenylalanine or Tryptophan, the enzyme was no longer capable of hydrolyzing the LPA. This further supports the proposed mechanism in which water, supplied from the solvent through the channel, acts as a nucleophile in the active site. [14]

Mechanism

Proposed Mechanism for the Hydrolysis of LPAs by Lysophosphatidic Acid Phosphatase ACP 6 2 hydrolysis mechanism.png
Proposed Mechanism for the Hydrolysis of LPAs by Lysophosphatidic Acid Phosphatase

Lysophosphatidic acid phosphatase has a very similar reaction mechanism to those of other phosphomonoesterases. One significant difference is this enzymes ability to perform the desired hydrolysis most effectively at low pHs. [15] At low pHs, all the arginines and histidines are found in their protonated states. This ensures that Arg58, Arg62, Arg168 and His334 will be able to stabilize the phosphate group and hydroxyl group in the active site. The aspartic acid side chain has a pKa of approximately 4. In an acidic environment, this residue will readily give up its proton, but will also take a proton away from water if the side chain is deprotonized, thus catalyzing the hydroxyl attack on the phosphate group. Soon after the deprotonation of the histidine residue and the protonation of the aspartic acid residue, the histidine residue will deprotonate the aspartic acid residue, preparing the enzyme to hydrolyze an LPA again. [14]

Function

Lysophosphatidic acid phosphatase has several roles. Although lysophosphatidic acid phosphatase is found ubiquitously throughout the body with higher levels in the kidney, heart, small intestine, muscles and the liver, evidence suggests that this enzyme is regulates lipid metabolism in the mitochondria. [16]

Another function is to control the concentration of LPAs that serve as messengers for G protein-coupled receptors in the cell. These LPAs are responsible for the signaling of cell growth, proliferation, muscle contractions, and wound healing, among many other roles. [17] Due to this role, an imbalance in the concentrations of lysophosphatidic acid phosphatase can frequently lead to several metabolic diseases. [8]

Lysophosphatidic acid phosphatase is also responsible for the digestion of lysophosphatidic acids when the cell enters a state of phosphate starvation. These enzymes break down LPAs and release phosphate groups. This stops the production of phospholipids and phosphatidic acids to signal the end of a cell's proliferation process. [18]

Disease relevance

Two examples of disorders caused by irregular LPA levels and show increased enzyme activity are ovarian cancer and Gaucher's Disease.

Ovarian cancer

Lysophosphatidic acid phosphatase activity is used to detect and to quantify irregular levels of LPAs on a cell's surface. [12] LPAs are receptor-active mediators that promote cell motility, cell growth and cell survival. [11] [13] There is clear evidence that cancerous ovarian cells have an increased level of LPA concentrations on their cell surfaces. These LPAs leak from the cell surface into the blood stream. The high levels of LPAs in the blood are used as tumor markers. In these cell clusters, lysophosphatidic acid phosphatase activity is higher than it is in regular cells. This can be attributed to the significantly increased levels of LPA that are secreted and synthesized by the ovarian cancer cells. This helps explain the cancerous cell's radical behavior and uncontrollable proliferation caused by the imbalance of enzyme and substrate concentrations, therefore leading to the inability to turn off the LPA cascade signalling effectively. [11] [19] One possible way to address and treat ovarian cancer cell proliferation would be to increase the concentration of lysophosphatidic acid phosphatase on the cell's surface, thus decreasing the amount of LPAs available to signal the cell to proceed with its radical behavior. [20]

Gaucher's Disease

Gaucher's Disease is another disorder in which lysophosphatidic acid phosphatase is found in irregular concentrations. Increased concentration levels of lysophosphatidic acid phosphatase and enzyme activity in a patient's blood are used in order to aid in the diagnosis of Gaucher's Disease. The increased activity can be attributed to the excess of LPAs in the serum. Gaucher's Disease is caused by an accumulation of glucosphingolipids in the body tissues and bone marrow. LPAs are a precursor of sphingolipids, so although lysophosphatidic acid phosphatase is not directly responsible for the imbalance that leads to Gaucher's Disease, its activity can be used to support the diagnosis of the disease. It is important to note that even though the increased activity of the enzyme has been found in patients with Gaucher's Disease, there has been no clear relation between the enzyme and the progression of the disease. [21]

Interactions

ACP6 has been shown to interact with Integrin-linked kinase. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Phosphofructokinase 1</span> Class of enzymes

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell's energy requirements. For example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.

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<span class="mw-page-title-main">Glucose 6-phosphatase</span> Enzyme

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<span class="mw-page-title-main">Glucocerebrosidase</span> Mammalian protein found in humans

β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism that is abundant in cell membranes. It is localized in the lysosome, where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

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<span class="mw-page-title-main">Phosphoenolpyruvate carboxylase</span> Class of enzymes

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<span class="mw-page-title-main">Phosphoglycerate mutase</span> Class of enzymes

Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis - the internal transfer of a phosphate group from C-3 to C-2 which results in the conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG) through a 2,3-bisphosphoglycerate intermediate. These enzymes are categorized into the two distinct classes of either cofactor-dependent (dPGM) or cofactor-independent (iPGM). The dPGM enzyme is composed of approximately 250 amino acids and is found in all vertebrates as well as in some invertebrates, fungi, and bacteria. The iPGM class is found in all plants and algae as well as in some invertebrate, fungi, and Gram-positive bacteria. This class of PGM enzyme shares the same superfamily as alkaline phosphatase.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

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<span class="mw-page-title-main">Lysophosphatidic acid</span> Chemical compound

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<span class="mw-page-title-main">Autotaxin</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

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<span class="mw-page-title-main">LPAR2</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 2 also known as LPA2 is a protein that in humans is encoded by the LPAR2 gene. LPA2 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">PPAP2A</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PPAP2B</span> Protein-coding gene in the species Homo sapiens

Lipid phosphate phosphohydrolase 3 (LPP3), also known as phospholipid phosphatase 3 (PLPP3) and phosphatidic acid phosphatase type 2B, is an enzyme that in humans is encoded by the PPAP2B gene on chromosome 1. It is ubiquitously expressed in many tissues and cell types. LPP3 is a cell-surface glycoprotein that hydrolyzes extracellular lysophosphatidic acid (LPA) and short-chain phosphatidic acid. Its function allows it to regulate vascular and embryonic development by inhibiting LPA signaling, which is associated with a wide range of human diseases, including cardiovascular disease and cancer, as well as developmental defects. The PPAP2B gene also contains one of 27 loci associated with increased risk of coronary artery disease.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162836 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028093 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Takayama I, Daigo Y, Ward SM, Sanders KM, Walker RL, Horowitz B, Yamanaka T, Fujino MA (June 2002). "Novel human and mouse genes encoding an acid phosphatase family member and its downregulation in W/W(V) mouse jejunum". Gut. 50 (6): 790–6. doi:10.1136/gut.50.6.790. PMC   1773242 . PMID   12010880.
  6. ↑ "Entrez Gene: ACP6 acid phosphatase 6, lysophosphatidic".
  7. ↑ "Acid Phosphotase". National Institutes of Health. Retrieved 24 February 2015.
  8. 1 2 Ando T, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, Sugito N, Tomoda K, Mori R, Takashima N, Ogawa R, Fujii Y (June 2006). "Expression of ACP6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma". Oncology Reports. 15 (6): 1551–1555. doi: 10.3892/or.15.6.1551 . PMID   16685394.
  9. ↑ Reddy VS, Rao DK, Rajasekharan R (April 2010). "Functional characterization of lysophosphatidic acid phosphatase from Arabidopsis thaliana". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1801 (4): 455–461. doi:10.1016/j.bbalip.2009.12.005. PMID   20045079.
  10. ↑ Hiroyama M, Takenawa T (December 1998). "Purification and characterization of a lysophosphatidic acid-specific phosphatase". The Biochemical Journal. 336 (Pt 2): 483–9. doi:10.1042/bj3360483. PMC   1219894 . PMID   9820827.
  11. 1 2 3 Fang X, Schummer M, Mao M, Yu S, Tabassam FH, Swaby R, Hasegawa Y, Tanyi JL, LaPushin R, Eder A, Jaffe R, Erickson J, Mills GB (2002). "Lysophosphatidic acid is a bioactive mediator in ovarian cancer". Biochim. Biophys. Acta. 1582 (1–3): 257–64. doi:10.1016/S1388-1981(02)00179-8. PMID   12069836.
  12. 1 2 Luquain C, Singh A, Wang L, Natarajan V, Morris AJ (October 2003). "Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells". Journal of Lipid Research. 44 (10): 1963–1975. doi: 10.1194/jlr.M300188-JLR200 . PMID   12837850.
  13. 1 2 Luquain C, Sciorra VA, Morris AJ (July 2003). "Lysophosphatidic acid signaling: how a small lipid does big things". Trends in Biochemical Sciences. 28 (7): 377–383. doi: 10.1016/S0968-0004(03)00139-7 . PMID   12878005.
  14. 1 2 3 4 5 6 7 8 9 PDB: 4JOC ​; Li J, Dong Y, Lü X, Wang L, Peng W, Zhang XC, Rao Z (July 2013). "Crystal structures and biochemical studies of human lysophosphatidic acid phosphatase type 6". Protein & Cell. 4 (7): 548–61. doi:10.1007/s13238-013-3031-z. PMC   4875511 . PMID   23807634.
  15. ↑ Makowska W (May 2001). "[Cytological evaluation of punctates from neck cysts in the records of the Department of Otorhinolaryngology, Medical Academy, Warsaw]". Otolaryngologia Polska. The Polish Otolaryngology. 29 (5): 66–72. PMID   1187150.
  16. ↑ Hiroyama M, Takenawa T (October 1999). "Isolation of a cDNA encoding human lysophosphatidic acid phosphatase that is involved in the regulation of mitochondrial lipid biosynthesis". The Journal of Biological Chemistry. 274 (41): 29172–29180. doi: 10.1074/jbc.274.41.29172 . PMID   10506173.
  17. ↑ Mills GB, Moolenaar WH (August 2003). "The emerging role of lysophosphatidic acid in cancer". Nature Reviews. Cancer. 3 (8): 582–91. doi:10.1038/nrc1143. PMID   12894246. S2CID   29079135.
  18. ↑ Reddy VS, Singh AK, Rajasekharan R (April 2008). "The Saccharomyces cerevisiae PHM8 gene encodes a soluble magnesium-dependent lysophosphatidic acid phosphatase". The Journal of Biological Chemistry. 283 (14): 8846–8854. doi: 10.1074/jbc.M706752200 . PMID   18234677.
  19. ↑ Tanyi JL, Hasegawa Y, Lapushin R, Morris AJ, Wolf JK, Berchuck A, Lu K, Smith DI, Kalli K, Hartmann LC, McCune K, Fishman D, Broaddus R, Cheng KW, Atkinson EN, Yamal JM, Bast RC, Felix EA, Newman RA, Mills GB (September 2003). "Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer". Clinical Cancer Research. 9 (10 Pt 1): 3534–3545. PMID   14506139.
  20. ↑ Imai A, Furui T, Tamaya T, Mills GB (September 2000). "A gonadotropin-releasing hormone-responsive phosphatase hydrolyses lysophosphatidic acid within the plasma membrane of ovarian cancer cells". The Journal of Clinical Endocrinology and Metabolism. 85 (9): 3370–3375. doi: 10.1210/jcem.85.9.6793 . PMID   10999836.
  21. ↑ Robinson DB, Glew RH (March 1980). "Acid phosphatase in Gaucher's disease" (PDF). Clinical Chemistry. 26 (3): 371–382. doi:10.1093/clinchem/26.3.371. PMID   6988111.
  22. ↑ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.
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