Journal:Acta Cryst F:S2053230X20002988
From Proteopedia
(Difference between revisions)
| Line 4: | Line 4: | ||
<hr/> | <hr/> | ||
<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | The human O-phosphoethanolamine phospho-lyase (hEtnppl) is an enzyme dependent on pyridoxal 5'-phosphate (PLP) that catalyzes the degradation of O-phosphoethanolamine (PEA) into acetaldehyde, phosphate and ammonia. Physiologically, the enzyme is involved in the phospholipid metabolism, since PEA is the precursor of phosphatidylethanolamine (PE), one of the four main membrane phospholipids, in the CDP-ethanolamine-Kennedy pathway. Indeed, it has been demonstrated that the knock-down of hEtnppl disrupts the normal synthesis of lipids in Hepatocellular carcinoma (HCC) and Cholangiocellular carcinoma (CCA) tissues, promoting an unusual activated lipogenesis ( | + | The human O-phosphoethanolamine phospho-lyase (hEtnppl) is an enzyme dependent on pyridoxal 5'-phosphate (PLP) that catalyzes the degradation of O-phosphoethanolamine (PEA) into acetaldehyde, phosphate and ammonia. Physiologically, the enzyme is involved in the phospholipid metabolism, since PEA is the precursor of phosphatidylethanolamine (PE), one of the four main membrane phospholipids, in the CDP-ethanolamine-Kennedy pathway. Indeed, it has been demonstrated that the knock-down of hEtnppl disrupts the normal synthesis of lipids in Hepatocellular carcinoma (HCC) and Cholangiocellular carcinoma (CCA) tissues, promoting an unusual activated lipogenesis (called ''de novo'' lipogenesis, DNL) that plays an essential role in supplying phospholipids during tumorigenesis. Moreover, the expression of the enzyme has been shown to decrease both in ovarian cancer and in breast cancer tissues and to increase in neuropsychiatric diseases such as schizophrenia and bipolar disorder. |
This enzyme was originally named AGXT2L1 (AGXT2-like 1) based on its homology to alanine glyoxylate aminotransferase 2 (AGXT2), a mitochondrial PLP-dependent enzyme that transaminates a variety of substrates while also acting as a lyase on L-cysteine conjugates. Unlike AGXT2, however, hEtnppl is almost completely inactive as a transaminase. Instead, it was shown to catalyze the irreversible 1,2-elimination of O-phosphophenanolamine (PEA) to produce acetaldehyde, phosphate and ammonia. | This enzyme was originally named AGXT2L1 (AGXT2-like 1) based on its homology to alanine glyoxylate aminotransferase 2 (AGXT2), a mitochondrial PLP-dependent enzyme that transaminates a variety of substrates while also acting as a lyase on L-cysteine conjugates. Unlike AGXT2, however, hEtnppl is almost completely inactive as a transaminase. Instead, it was shown to catalyze the irreversible 1,2-elimination of O-phosphophenanolamine (PEA) to produce acetaldehyde, phosphate and ammonia. | ||
The crystal structure of hEtnppl (determined at 2.05 ֳ… resolution) shows high similarity to the crystal structure of the phospho-lyase A1RDF1 from Arthrobacter aurescens TC1, which so far has been the only phospho-lyase structure reported in the literature. The active site of hEtnppl is located at the interface between the two subunits of the dimer, each subunit making crucial contributions to the active site. Most of the residues that line the catalytic pocket correspond to those found in the close structural homolog A1RDF1, strongly suggesting that these enzymes share a common mechanism. While confirming the presence of a cluster of positively charged residues for the recognition of the phosphate moiety of the substrate, the structure of the active site of hEtnppl suggests a striking mobility of the crucial catalytic residue K278. In hEtnppl, the cofactor binds essentially in the same position as in A1RDF1 in complex with PLP (internal aldimine) and PLP-PEA (external aldimine). However, in the crystal structure of hEtnppl, the cofactor does not covalently bind the ־µ-amino group of the adjacent K278 residue, suggesting that the cofactor captured in this structure is not PLP but PMP (pyridoxamine-5ג€²-phosphate), an intermediate in transamination reactions. | The crystal structure of hEtnppl (determined at 2.05 ֳ… resolution) shows high similarity to the crystal structure of the phospho-lyase A1RDF1 from Arthrobacter aurescens TC1, which so far has been the only phospho-lyase structure reported in the literature. The active site of hEtnppl is located at the interface between the two subunits of the dimer, each subunit making crucial contributions to the active site. Most of the residues that line the catalytic pocket correspond to those found in the close structural homolog A1RDF1, strongly suggesting that these enzymes share a common mechanism. While confirming the presence of a cluster of positively charged residues for the recognition of the phosphate moiety of the substrate, the structure of the active site of hEtnppl suggests a striking mobility of the crucial catalytic residue K278. In hEtnppl, the cofactor binds essentially in the same position as in A1RDF1 in complex with PLP (internal aldimine) and PLP-PEA (external aldimine). However, in the crystal structure of hEtnppl, the cofactor does not covalently bind the ־µ-amino group of the adjacent K278 residue, suggesting that the cofactor captured in this structure is not PLP but PMP (pyridoxamine-5ג€²-phosphate), an intermediate in transamination reactions. | ||
Revision as of 09:45, 5 March 2020
| |||||||||||
This page complements a publication in scientific journals and is one of the Proteopedia's Interactive 3D Complement pages. For aditional details please see I3DC.
