Researchers discover unknown enzyme activity towards human endogenous substrates

At SciLifeLab and Uppsala University, scientists have identified an enzymatic activity towards common drugs as well as significant human endogenous substrates, that was previously not known, while analyzing the powerful metabolic detoxification process that is accountable for eliminating toxic drugs and compounds.

Researchers discover unknown enzyme activity towards human endogenous substrates
Image Credit: SciLifeLab.

The latest study focused on the investigation of one of the key metabolizing enzymes called N-arylamine acetyltransferase 2 (NAT2). It was published in the Angewandte Chemie International Edition journal.

A wide range of enzymes is present in the human body, converting molecules that are not part of an individual’s metabolism, like food-derived substances and drugs. Enzymes like these have evolved to alter particular groups of molecules and have been actively analyzed due to their effects on drug clearance.

The current research made an unexpected finding that significant endogenous metabolites of the human metabolism are also acetylated by the NAT2 enzyme.

Among the most significantly upregulated metabolites, we identified the polyamines spermidine, which has been identified as a key metabolite in aging and longevity.”

Daniel Globisch, Study Co-Lead, SciLifeLab

Globisch also works at Uppsala University.

It is known that the NAT2 enzyme acetylates arylamine-containing substrates; however, spermidine contains only aliphatic amines. Researchers discovered more endogenous polyamine containing substrates, implying an unidentified regulatory function of the NAT2 enzyme.

The regioselective acetylation of spermidine by the NAT2 enzyme provides an answer to a long-held question relating to the metabolism of polyamine, as researchers were unaware of the enzymatic source of diacetylspermidine formation.

In addition, many commonly used drugs comprising aliphatic amines with several hundred millions of yearly prescriptions were also demonstrated to be converted by the NAT2 enzyme. Around 10% of the prescribed drugs exhibit an aliphatic amine moiety and are promising substrates of the NAT2 enzyme.

The outcomes show that acetylation by the NAT2 enzyme may play a more crucial role in the efficacy, metabolism, and elimination of common drugs than previously believed.

Our findings have great potential to help tailoring the dosage of drugs to individual patient needs to achieve personalized medicine.”

Tobias Sjöblom, Study Co-Lead, SciLifeLab

Sjöblom also works at Uppsala University.

Source:
Journal reference:

Conway, L. P., et al. (2020) Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2. Angewandte Chemie International Edition. doi.org/10.1002/anie.202005915.

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