Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases

Frontiers in Pharmacology
Mike PetrassiMatthew Thomas

Abstract

Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition. However, selectivity over non-pathogenic enzyme family members, TPH2, phenylalanine hydroxylase, and tyrosine hydroxylase has hampered therapeutic development. Here we describe the site/sequence, biochemical, and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases is achieved. We demonstrate the mechanism of action by which novel compounds selectively inhibit TPH1 using surface plasma resonance and enzyme competition assays with both tryptophan ligand and BH4 co-factor. We demonstrate 15-fo...Continue Reading

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Citations

Apr 18, 2018·Clinical Pharmacology and Therapeutics·Martine GehinJasper Dingemanse
Mar 22, 2020·International Journal of Molecular Sciences·Irina B DeryabinaKhalil L Gainutdinov
Oct 21, 2019·Pharmacology & Therapeutics·Michael Bader
Jun 3, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Adrian BekierKatarzyna Dzitko
Jul 13, 2021·Future Medicinal Chemistry·Nibal BetariJan Haavik

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Methods Mentioned

BETA
X-ray
size exclusion chromatography
Biosensor
chip
Assay
equilibrium dialysis
gene knockdown

Software Mentioned

Analyst
ARRIVE
BiaCore
Biaevaluation
Graphpad Prism
SigmaPlot
EMBL Cluster Omega
Molsoft
ICMPro
transcripome

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