Sandbox Reserved 1760

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This Sandbox is Reserved from November 4, 2022 through January 1, 2023 for use in the course CHEM 351 Biochemistry taught by Bonnie Hall at the Grand View University, Des Moines, USA. This reservation includes Sandbox Reserved 1755 through Sandbox Reserved 1764.

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Human Ornithine Aminotransferase

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia or to the article describing Jmol to the rescue. Function of your protein The function of hOAT is to catalyze the transfer of the amino group from L-ornithine to an α-ketoglutarate. Biological relevance and broader implications hOAT is found in most tissues in the body but predominates in the liver and kidney. There is a need to study the enzyme hOAT because the overexpression of this protein aids the proliferation of cancer cells, specifically Hepatocellular carcinoma (HCC), a common form of liver cancer. hOAT has been a target for mechanism-based inactivators (MBIs) in ongoing drug design efforts. HCC is normally diagnosed at advanced stages where the tumors tend to be resistant to radiotherapy and chemotherapy, making this type of cancer difficult to treat. In ongoing research, new hOAT inhibitors were created as fragmented-sized alternative substrates such as γ-aminobutyric acid (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 substrate PLP and provided a tighter binding to hOAT then L-ornithine. GABA covalently attached to PLP. While AVA covalently attached to PLP and Lysine 292, one of the catalytic enzymes in this binding pocket. GABA and AVA both displayed a stronger binding affinity and slower turnovers, making them strong demonstrators for potential drug targets of hOAT. Important amino acids Amino Acids in the PLP binding site are Lys 292, Asp 263, Arg 180. They are essential to the active site by providing certain interactions 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 group interacts with the positively charged nitrogen of the arginine side chain. Another interaction provided in this active site but not apart of the catalytic triad is the amino acid phenylalanine 177, there is a pi stacking interaction between its ring and the ring of the PLP. Structural highlights hOAT is a protein with secondary structures consisting of alpha helices, parallel and antiparallel beta sheets, and random coil. It's a polymer with a globular structure that has three subunits held together by non-covalent interactions like hydrogen bonds and salt bridges between the side chains of amino acids. The binding pocket of PLP are semi-exposed to the "outside world" but also slightly hidden into the protein. Having binding pockets only slightly exposed can help prevent other competitive substrates from binding and and inhibiting the enzyme. The substrate PLP has a phosphate group that is surrounded by other polar amino acids but the rest of the substrate, the carbons are surrounded by other non-polar amino acids to satisfy the needs of the substrate and active site. PLP would not be very stable if the polar/hydrophilic portions of the substrate were trying to interact with all surrounding non-polar/hydrophobic amino acids. This allows interactions such as hydrogen bonding and pi-stacking to stabilize and bind a substrate in an active site.