Ketohexokinase (KHK), in an adenosine triphosphate (ATP) dependent reaction, catalyzes the first reaction in fructose metabolism, which converts the furanose form of D-fructose into fructose-1-phosphate. This enzyme has become a target for pharmacological development against fatty liver and metabolic syndrome. KHK exists in two isoforms, A and C, which differs by alternative splicing of exon 3 which encodes 45 out of 298 amino acids. Normally KHK exists as a homodimer and is comprised of an alpha/beta domain interlocking with a β-clasp domain. For KHK-C, there appear to be at least two conformations of the β-clasp domain. Previous work on KHK-A reveals it does not adopt the same conformations. A structure of the mouse KHK-A in its unliganded form is solved and shows that these two conformations also exist for KHK-A. Furthermore, this property is conserved across species. While crystals of human KHK-A in its unliganded form were grown, a structure was not achieved. However, unpublished structures of human KHK-A in its unliganded form also shows different conformations in β-clasp domain when in juxtaposition with the same enzyme complex with ligands. Defining the role of conformational changes in KHK-A is important, because this isozyme has been reported to have a role in cancer metastasis.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46349 |
| Date | 14 June 2023 |
| Creators | Bae, So Young |
| Contributors | Tolan, Dean R., Allen, Karen N. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nd/4.0/ |
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