@article{dc5341c96b0947a98d5c022b300d994d,
title = "Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1",
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.",
keywords = "assay development, crystal structure, enzymology, glutaric aciduria, inborn errors of metabolism, lysine metabolism",
author = "Jo{\~a}o Leandro and Susmita Khamrui and Chalada Suebsuwong and Chen, {Peng Jen} and Cody Secor and Tetyana Dodatko and Chunli Yu and Roberto Sanchez and Devita, {Robert J.} and Houten, {Sander M.} and Lazarus, {Michael B.}",
note = "Funding Information: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers R21HD102745 (to S.M.H. and R.J.D.) and R35GM124838 (to M.B.L.). This research used resources of the National Synchrotron Light Source II, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory, under Contract No. DESC0012704. The Life Science Biomedical Technology Research resource is primarily supported by the NIH, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant (No. P41GM111244), and by the DOE Office of Biological and Environmental Research (No. KP1605010). This work used the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504. Acknowledgements Publisher Copyright: {\textcopyright} ",
year = "2022",
month = sep,
day = "21",
doi = "10.1098/rsob.220179",
language = "English",
volume = "12",
journal = "Open Biology",
issn = "2046-2441",
publisher = "The Royal Society",
number = "9",
}