Levalbuterol lowers the feedback inhibition by dopamine and delays misfolding and aggregation in tyrosine hydroxylase.

Autor: Flydal MI; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway. Electronic address: marte.flydal@uib.no., Kråkenes TA; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway., Tai MDS; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway., Tran MPA; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway., Teigen K; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway., Martinez A; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway. Electronic address: aurora.martinez@uib.no.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2021 Apr; Vol. 183, pp. 126-132. Date of Electronic Publication: 2020 Dec 10.
DOI: 10.1016/j.biochi.2020.12.002
Abstrakt: Tyrosine hydroxylase (TH) catalyses the (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)-dependent conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-Dopa), which is the rate-limiting step in the synthesis of dopamine and other catecholamine neurotransmitters and hormones. Dysfunctional mutant TH causes tyrosine hydroxylase deficiency (THD), characterized by symptoms ranging from mild l-Dopa responsive dystonia to severe neuropathy. THD-associated mutations often present misfolding and a propensity to aggregate, characteristics that can also be manifested by dysregulated wild-type TH. TH - and subsequently dopamine - is also reduced in Parkinson's disease (PD) due to the selective death of dopaminergic neurons. Thus, TH is a target for stabilizing small molecular weight compounds that can function as pharmacological chaperones, restoring enzyme folding and function. In this work we carried out a screening of a compound library with 1280 approved drugs and we identified levalbuterol, a beta2-adrenergic agonist that is broadly used in asthma treatment, as an interesting validated binder of human TH. Levalbuterol stabilized TH with reduced affinity compared to dopamine, the end-product and regulatory feedback inhibitor of TH, but without compromising enzymatic activity. Moreover, levalbuterol also delays the formation of TH aggregates and makes the enzyme less sensitive to dopamine, effects that could contribute to ameliorate disorders related to TH, such as THD and PD.
(Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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