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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The specific function of Human ornithine aminotransferase (hOAT) is that of an enzyme. It can be found in humans, as well as mice and pigs. It helps transfer L-ornithine’s δ-amino group to α-ketoglutarate (α-KG). [3] There is a lack of understanding in regards to hOAT's catalytic mechanism, even though it is a key component of human metabolism. As noted in the article, hOAT operates on a "Bi-Bi, Ping-Pong" kinetic mechanism resulting in the first part of the reaction undergoing a conversion of PLP -> PMP and L-Orn -> L-GSA. Then PMP's amino group is catalyzed by hOAT creating an α-KG.
DABA
The binding affinities of GABA and AVA were higher and resulted in slower turnovers. This raised the question that AVA and GABA would be good drug targets, rather than specifically hOAT.
Biological relevance and broader implications
hOAT is important because it is heavily involved in the urea cycle. In mammals, it dictates a large portion of the development of neonates. The research on this protein is relevant to science as a whole because it could directly impact cancer research and lead to the creation of cancer management in humans. There has been overexpression of hOAT within Hepatocellular carcinoma (HCC) cells, therefore there is reason to believe that the overexpression of hOAT is an indication of chronic liver diseases and cancer of the liver. The inhibitors include: y-aminobutyric acid (GABA), 5-aminovaleric acid (AVA), and L-2,4-diaminobutyric acid (DABA). The highest affinity of binding with hOAT is GABA. It also has a higher percentage of return in the reverse reaction. The more that hOAT is understood and researched, the more inactivators can be designed to combat the overexpression of hOAT that is found in conjunction to HCC.
Important amino acids
The ligand of hOAT is Pyridoxal-5'-Phosphate (PLP). The role of the catalytic amino acids in an enzyme is to bind to a substrate, changing the structure, causing bonds to break and new bonds to be formed. When there is a difficult reaction, the triad of amino acids works in tandem to facilitate the reaction. A Glu 235-Arg 413salt bridge was found on AVA, but not on GABA. In regards to GABA, the salt bridge was disrupted in 30% of the monomers.
The crystal soaking experiments created an opportunity to decipher the reaction intermediates of the structures. While GABA linked to PLP covalently, PLP and catalytic Lys 292 were linked by AVA.
Space filling view of PLPSpace filling view of ''h''OAT is relevant because it shows the space that the atoms of the structure take up.
5-aminovaleric acid (AVA) lacking α-amino group does not impact the initial binding of the substrate and enzyme.
↑Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:https://dx.doi.org/10.1002/ijch.201300024
↑Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
Butrin, A., Butrin, A., Wawrzak, Z., Moran, G. R., & Liu, D. (2022). Determination of the ph dependence, substrate specificity, and turnovers of alternative substrates for human ornithine aminotransferase. Journal of Biological Chemistry, 298(6), 101969. https://doi.org/10.1016/j.jbc.2022.101969
