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

Levalbuterol lowers the feedback inhibition by dopamine and delays misfolding and aggregation in tyrosine hydroxylase. Biochimie. 2020 Dec 09;: Authors: Flydal MI, Kråkenes TA, Tai MDS, Tran MPA, Teigen K, Martinez A Abstract 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 beta-adrenergic antagonist 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 fe...
Source: Biochimie - Category: Biochemistry Authors: Tags: Biochimie Source Type: research