Direct coordination of pterin to FeII enables neurotransmitter biosynthesis in the pterin-dependent hydroxylases

Shyam R. Iyer, Kasper D. Tidemand, Jeffrey T. Babicz, Ariel B. Jacobs, Leland B. Gee, Lærke T. Haahr, Yoshitaka Yoda, Masayuki Kurokuzu, Shinji Kitao, Makina Saito, Makoto Seto, Hans E.M. Christensen, Günther H.J. Peters, Edward I. Solomon

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6 Citations (Scopus)


The pterin-dependent nonheme iron enzymes hydroxylate aromatic amino acids to perform the biosynthesis of neurotransmitters to maintain proper brain function. These enzymes activate oxygen using a pterin cofactor and an aromatic amino acid substrate bound to the FeII active site to form a highly reactive FeIV = O species that initiates substrate oxidation. In this study, using tryptophan hydroxylase, we have kinetically generated a pre-FeIV = O intermediate and characterized its structure as a FeII-peroxy-pterin species using absorption, Mössbauer, resonance Raman, and nuclear resonance vibrational spectroscopies. From parallel characterization of the pterin cofactor and tryptophan substrate-bound ternary FeII active site before the O2 reaction (including magnetic circular dichroism spectroscopy), these studies both experimentally define the mechanism of FeIV = O formation and demonstrate that the carbonyl functional group on the pterin is directly coordinated to the FeII site in both the ternary complex and the peroxo intermediate. Reaction coordinate calculations predict a 14 kcal/mol reduction in the oxygen activation barrier due to the direct binding of the pterin carbonyl to the FeII site, as this interaction provides an orbital pathway for efficient electron transfer from the pterin cofactor to the iron center. This direct coordination of the pterin cofactor enables the biological function of the pterin-dependent hydroxylases and demonstrates a unified mechanism for oxygen activation by the cofactor-dependent nonheme iron enzymes.

Original languageEnglish
Article numbere2022379118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
Publication statusPublished - 2021 Apr 13


  • Cofactor-dependent metalloenzymes
  • Neurotransmitter biosynthesis
  • Oxygen activation


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