ArticleOpen biology2022
Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1.
Article in Open biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Structural and biochemical insight into allosteric regulation of the human 2-aminoadipic semialdehyde synthase, a bifunctional enzyme involved in lysine catabolism.Research square · 2026Article
- Interactome Quantitation Reveals Non-Energetic Mitochondrial Roles in Cell Type Specialization in Murine Kidney.Molecular & cellular proteomics : MCP · 2025Article
- Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Vitamin K as an add-on therapy in pyridoxine-dependent epilepsy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- LysineFrontiers in molecular neuroscience · 2025Review
- New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse.Brain communications · 2025Article
- Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.ACS chemical biology · 2024Article
- Intra-organ cell specific mitochondrial quantitative interactomics.bioRxiv : the preprint server for biology · 2024Article
- Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1.bioRxiv : the preprint server for biology · 2024Article
- MultifacetedProtDB: a database of human proteins with multiple functions.Nucleic acids research · 2024Article
- A case of hyperlysinemia identified by urine newborn screening.JIMD reports · 2023Article
- Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1.Open biology · 2022Article
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Authors and funding
11 authors.
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Abstract
In humans, a single enzyme 2-aminoadipic semialdehyde synthase (AASS) catalyses the initial two critical reactions in the lysine degradation pathway. This enzyme evolved to be a bifunctional enzyme with both lysine-2-oxoglutarate reductase (LOR) and saccharopine dehydrogenase domains (SDH). Moreover, AASS is a unique drug target for inborn errors of metabolism such as glutaric aciduria type 1 that arise from deficiencies downstream in the lysine degradation pathway. While work has been done to elucidate the SDH domain structurally and to develop inhibitors, neither has been done for the LOR domain. Here, we purify and characterize LOR and show that it is activated by alkylation of cysteine 414 by N-ethylmaleimide. We also provide evidence that AASS is rate-limiting upon high lysine exposure of mice. Finally, we present the crystal structure of the human LOR domain. Our combined work should enable future efforts to identify inhibitors of this novel drug target.
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