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Function
The protein Orthinine Aminotransferase (OAT) [3]. and hOAT in humans is an enzyme that catalyzes the transfer of an amino acid group L-orthinine from L-orthinine to an alpha-ketoglutarate. Its ligand pyrodixal-5-phosphate (PLP) is a cofactor in the reaction. An amino group from L-orthinine is transferred to PLP which converts it to pyridoxamine phosphate (PMP) and L-orthinine is converted to L-glutamate-y-semialdehyde. PLP is regenerated when PMP is transferred to alpha-KG.
Bilogical relavance and broader implications
hOAT is an enzyme that is found in almost all tissues but predominately in the liver and kidney. There is an overexpression of hOAT in cancer cells so understanding it can help the proliferation of cancer cells, especially hepatocellular carcinoma (HCC) which is a type of liver cell. hOAT has been a target mechanism-based inactivator (MBIs) in an attempt to create drugs. HCC is generally diagnosed in advanced stages which makes cancer more resistant to chemotherapy. hOAT inhibitors were created as fragmented-sized alternative substrates such as y-aminobutyric acid (GABA) and 5-aminovaleric acid (AVA). GABA is covalently bonded to PLP. While AVA is covalently attached to PLP by lysine 292, which is a catalytic enzyme in the binding pocket. GABA and AVA have strong binding affinity but slow turnovers.
Important amino acids
The amino acids in the PLP binding site are , , , and . They are essential in the active site because of their interaction with PLP. PLP is covalently bonded to the amino acid lysine. The nitrogen in the ring of PLP interacts with the negatively charged oxygen in the aspartate side chain. The phosphate interacts with the positively charged nitrogen of the arginine side chain. And Phe 177 has a pi- stacking interaction between its ring and the ring of PLP
Structural highlights
hOAT is a protein with a that is mainly made of alpha helices but also has parallel and anti-parallel beta sheets and random coil. Its a polymer with a that has three subunits held by non-cavantly interactions like hydrogen bond and salt bridges between the side chains and amino acids. The binding pocket is semi-exposed which makes helps competitive substrates bind to the active site. The PLP has a phosphate groups surrounded by polar amino acids and the carbons are surrounded by non-polar amino acids which makes it favorable for the ligand and active site. PLP has polar (hydrophilic) portions that are exposed to the surrounding and non-polar (hydophobic) protions that are hidden within the protein making it stable. Hydrogen bonding and pi-stacking stabilize the and the active site.
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