Alkamines reveal a hidden layer of steroid and drug metabolism
Agongo, J.; Panga, S. R.; Xing, S.; Charron-Lamoureux, V.; Gouda, H.; El Abiead, Y.; Nelson, M. R.; Patan, A.; Carrillo Terrazas, M.; Kvitne, K. E.; Seo, J. I.; Rajkumar, P.; Giddings, S.; Mannochio-Russo, H.; Zemlin, J.; Mohanty, I.; Sala-Climent, M.; Hu, Z.; Deleray, V.; Yeboah, S.; Zhao, H. N.; Caraballo Rodriguez, A. M.; Williams, C. E.; Williams, C. L.; Goncalves Nunes, W. D.; Dorrestein, K.; Cao, J.; Shepherd, I.; Bock, R.; Roethler, N.; Jinich, A.; Burnett, L. A.; Carver, J.; Devine, R. N.; Arnatt, C. K.; Murray, I. A.; Knight, R.; Guma, M.; Hagey, L. R.; Perdew, G.; Bandeira, N.; Wang,
Show abstract
Biomedical research overlooks most genes in favor of a well-studied minority, yet whether analogous blind spots exist in metabolomics remains unknown. We show that reductive amination, forming secondary amines from aldehydes or ketones and amines, generates a previously hidden class of metabolites we term alkamines. Multiplexed synthesis of 8,475 alkamines combined with MS/MS searches across 1.7 billion spectra identified 1,626 candidates across multiple species and organs. Of these, 56 were confirmed in biological samples, including 27 steroid- and 12 drug-derived alkamines matching prescription patterns. Notably, 77% of synthesized alkamines are absent from PubChem. This combinatorial logic likely explains why alkamines have evaded detection and suggests drug metabolism frameworks substantially underestimate drug-derived metabolite diversity. Reductive amination is an overlooked route modifying steroids, bile acids, and xenobiotics.
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