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Function of your protein
The protein Ornithinine Aminotransferase (OAT), in humans (hOAT), is an enzyme that catalyzes the reaction between carbamoyl phosphate and orthinine to form citrulline and phosphate. Its ligand is pyridoxal-5'phosphate (PLP) which is a cofactor of the reaction. An amino group from L-Orn is transferred to PLP which turns it into pyridoxine phosphate (PMP) and L-Orn is converted to L glutamate-y-semialdehyde. PLP is regenerated when the amino group PMP is transferred to alpha-KG. It has 3 ligands pyridoxal-5' phosphate (PLP) which is a cofactor in the reaction. An amino group from L-Ornithinine is transferred to PLP which converts it to pyridoxamine phosphate (PMP) and L-Orn is converted to L-glutamate-y-semialdehyde. PLP is regenerated when PMP is transferred to alpha-KG.
Biological relevance and broader implications
hOAT is a ubiquitous enzyme found in almost all organisms and has been found to be overexpressed in hepatocellular carcinoma cells (HCC), which is a type of liver cancer. It is found predominantly in the liver and kidney. The liver, where it is an integral part of the urea cycle, and the intestine, where it synthesizes citrulline for export and plays a major role in amino acid homeostasis, particularly of L-glutamine and L-arginine. Studying this protein could be a potential drug to target cancer as a different therapy and radiation. hOAT has been a target mechanism-based inactivator (MBIs) in drug design efforts. HCC has diagnosed an advanced type of cancer which makes it more resistant to chemotherapy. hOAT inhibitors were created as fragmented-sized alternative substances such as GABA and 5-aminovaleric acid (AVA). hOAT was soaked with GABA and AVA and the new substrates prevented original interactions with catalytic amino acids and the ligand (PLP) which creates a tighter to hOAT instead of L-ornithine. GABA and AVA had a stronger binding affinity and slower turnovers which makes them potential drug targets for hOAT.
Important amino acids
Amino Acids in PLP binding site are ,Lys 292</scene> Asp 263, Phe 177 and Arg 180</scene>.[3]. They are essential to the active site. PLP is covalently bonded to the amino acid lysine. The phosphate group interacts with the positively charged nitrogen of the arginine side chain. There is also a pi-stacking interaction between its ring and the ring of PLP.
Structural highlights
hOAT is a protein with a consisting of mainly alpha-helices but it also has parallel and anti-parallel beta-sheets and random coil. It's a polymer with a that has three subunits held together by non-covalent interactions such as hydrogen bonds and salt bridges hidden in the protein. The has a phosphate group surrounded by polar amino acids, and carbons are surrounded by non-polar amino acids to satisfy the needs of the ligand and active site. Interactions like hydrogen bonding and pi-stacking stabilize and bind the ligand in the active site. The binding pocket of PLP is semi-exposed to the surrounding. The binding pockets can help competitive substrates to bind to the active site and inhibit the enzyme. The PLP ligand has a phosphate group that is surrounded by other polar amino acids and the carbons are surrounded by other non-polar acids which makes it favorable for the ligand and active site. The polar (hydrophilic) portions of the would-be unstable if they tried to interact with the non-polar (hydrophobic) surrounding. Interactions like hydrogen bonding and pi-stacking stabilize and bind the ligand to the active site.
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