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Guanidino acid hydrolysis by the human enzyme annotated as agmatinase

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2022

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European Union (EU): 681777

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RiboDisc - Discovery of novel orphan riboswitch ligands
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Scientific Reports. Springer Nature. 2022, 12, 22088. eISSN 2045-2322. Available under: doi: 10.1038/s41598-022-26655-4

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Guanidino acids such as taurocyamine, guanidinobutyrate, guanidinopropionate, and guanidinoacetate have been detected in humans. However, except for guanidionacetate, which is a precursor of creatine, their metabolism and potential functions remain poorly understood. Agmatine has received considerable attention as a potential neurotransmitter and the human enzyme so far annotated as agmatinase (AGMAT) has been proposed as an important modulator of agmatine levels. However, conclusive evidence for the assigned enzymatic activity is lacking. Here we show that AGMAT hydrolyzed a range of linear guanidino acids but was virtually inactive with agmatine. Structural modelling and direct biochemical assays indicated that two naturally occurring variants differ in their substrate preferences. A negatively charged group in the substrate at the end opposing the guanidine moiety was essential for efficient catalysis, explaining why agmatine was not hydrolyzed. We suggest to rename AGMAT as guanidino acid hydrolase (GDAH). Additionally, we demonstrate that the GDAH substrates taurocyamine, guanidinobutyrate and guanidinopropionate were produced by human glycine amidinotransferase (GATM). The presented findings show for the first time an enzymatic activity for GDAH/AGMAT. Since agmatine has frequently been proposed as an endogenous neurotransmitter, the current findings clarify important aspects of the metabolism of agmatine and guanidino acid derivatives in humans.

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ISO 690SINN, Malte, Marco STANOPPI, Franziskus HAUTH, Jennifer R. FLEMING, Dietmar FUNCK, Olga MAYANS, Jörg S. HARTIG, 2022. Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. In: Scientific Reports. Springer Nature. 2022, 12, 22088. eISSN 2045-2322. Available under: doi: 10.1038/s41598-022-26655-4
BibTex
@article{Sinn2022Guani-66196,
  year={2022},
  doi={10.1038/s41598-022-26655-4},
  title={Guanidino acid hydrolysis by the human enzyme annotated as agmatinase},
  volume={12},
  journal={Scientific Reports},
  author={Sinn, Malte and Stanoppi, Marco and Hauth, Franziskus and Fleming, Jennifer R. and Funck, Dietmar and Mayans, Olga and Hartig, Jörg S.},
  note={Article Number: 22088}
}
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