Positive charge intrinsic to Arg37-Arg38 is critical for dopamine inhibition of the catalytic activity of human tyrosine hydroxylase type 1

Akira Nakashima, Nobuhiro Hayashi, Keiji Mori, Yoko S. Kaneko, Toshiharu Nagatsu, Akira Ota

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13 Citations (Scopus)


Tyrosine hydroxylase (TH), which converts L-tyrosine to L-3,4-dihydroxyphenylalanine, is a rate-limiting enzyme in the biosynthesis of catecholamines; its activity is regulated by the feedback inhibition of the catecholamine products including dopamine. To rationalize the significant role of the N-terminal sequence Arg37-Arg38 of human TH type 1 (hTH1) in determining the efficiency of feedback inhibition, we produced mutants of which the positively charged Arg37-Arg38 site was replaced by electrically neutral Gly and/or negatively charged Glu and analyzed the degree of inhibition of these mutant enzymes by dopamine. The replacement of Arg by Gly reduced the inhibitory effect of dopamine on the catalytic activity measured in the basic pH range and the replacement of Arg by Glu was enough to abolish the inhibitory effect, although these mutations brought no significant changes to the circular dichroism spectrum. The prediction of the secondary structure of N-terminal residues 1-60 by computer software specified the location of the Arg37-Arg38 sequence in the turn intervening between the two α-helices (residues 16-29 and residues 41-59). These results suggest that the positive charge of the amino acid residues at positions 37 and 38 is one of the main factors that maintains the characteristic of the turn and is responsible for the enzyme inhibition by dopamine. Copyright (C) 2000 Federation of European Biochemical Societies.

Original languageEnglish
Pages (from-to)59-63
Number of pages5
JournalFEBS Letters
Issue number1
Publication statusPublished - 07-01-2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology


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