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S-thiolation of tyrosine hydroxylase by reactive nitrogen species in the presence of cysteine or glutathione.

Research paper by Mahdieh M Sadidi, Timothy J TJ Geddes, Donald M DM Kuhn

Indexed on: 07 Jul '05Published on: 07 Jul '05Published in: Antioxidants & redox signaling



Abstract

Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter dopamine. Peroxynitrite (ONOO-) and nitrogen dioxide (NO2) inhibit TH catalytic function and cause nitration of protein tyrosine residues. Exposure of TH to either ONOO- or NO2 in the presence of cysteine (or glutathione) prevents tyrosine nitration and results in S-thiolation instead. TH catalytic activity is suppressed by S-thiolation. Dithiothreitol prevents and reverses the modification of TH by S-thiolation, and returns enzyme activity to control levels. S-Nitrosothiols, which are known to S-thiolate proteins, can be formed in the reaction of cysteine or glutathione with reactive nitrogen species. Therefore, S-nitrosoglutathione (GSNO) was tested for its ability to modify TH. Fresh solutions of GSNO did not modify TH, whereas decomposed GSNO resulted in extensive S-thiolation of the protein. Dimedone, a sulfenic acid trap, prevents S-thiolation of TH when included with GSNO during its decomposition. Taken together, these results show that TH is S-thiolated by ONOO- or NO2 in the presence of cysteine. S-Thiolation occurs at the expense of tyrosine nitration. Glutathione disulfide S-oxide, which forms spontaneously in the decomposition of GSNO and which is found in tissue undergoing oxidative stress, may be the species that S-thiolates TH.