8E8V

Structure of the short LOR domain of human AASS bound to N-ethylsuccinimide

Summary for 8E8V

• Entry DOI: 10.2210/pdb8e8v/pdb
• Descriptor: Alpha-aminoadipic semialdehyde synthase, mitochondrial, 1-ETHYL-PYRROLIDINE-2,5-DIONE (2 entities in total)
• Functional Keywords: lysine metabolism, ketoglutarate, mitochondrial, reductase, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 193897.11

Authors

Khamrui, S.,Lazarus, M.B. (deposition date: 2022-08-25, release date: 2022-10-05, Last modification date: 2024-11-06)

Primary citation

Leandro, J.,Khamrui, S.,Suebsuwong, C.,Chen, P.J.,Secor, C.,Dodatko, T.,Yu, C.,Sanchez, R.,DeVita, R.J.,Houten, S.M.,Lazarus, M.B.
Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1.
Open Biology, 12:220179-220179, 2022

PubMed 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.

PubMed: 36128717
DOI: 10.1098/rsob.220179

Experimental method

X-RAY DIFFRACTION (2.45 Å)