page_title: Lysophosphatidic acid phosphatase type 6
section_title: Structure
hierarchical_section_title: Lysophosphatidic acid phosphatase type 6 / Structure
caption_attribution_description: English: Active site showing residues that have polar interactions with the substrate
context_page_description: Lysophosphatidic acid phosphatase type 6 is an acid phosphatase enzyme that is encoded in humans by the ACP6 gene.
  It acts as a phosphomonoesterase at low pHs. It is responsible for the hydrolysis of Lysophosphatidic acids to their respective monoacylglycerols and the release a free phosphate group in the process. The enzyme has higher activity for myristate-LPA, oleate-LPA, laurate-LPA or palmitate-LPA. When the substrate is stearate-LPA, the enzyme has reduced activity. 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.
  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.
context_section_description: 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. The space between the two domains serves as a large substrate pocket, as well as a channel through which water molecules can move through.  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.
  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. 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.
caption: The active site of the enzyme shows the polar contacts between the residues in the pocket and the substrate. Image generated from 4JOC.[14]
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