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Br J Pharmacol. 2013 Jun;169(4):922-32. doi: 10.1111/bph.12171.

Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE).

Author information

1
Department of Pharmacy, Laboratory of Molecular Pharmacology, University of Patras, Patras, Greece.

Abstract

BACKGROUND AND PURPOSE:

Hydrogen sulfide (H₂S) is a signalling molecule that belongs to the gasotransmitter family. Two major sources for endogenous enzymatic production of H₂S are cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). In the present study, we examined the selectivity of commonly used pharmacological inhibitors of H₂S biosynthesis towards CSE and CBS.

EXPERIMENTAL APPROACH:

To address this question, human CSE or CBS enzymes were expressed and purified from Escherichia coli as fusion proteins with GSH-S-transferase. After purification, the activity of the recombinant enzymes was tested using the methylene blue method.

KEY RESULTS:

β-Cyanoalanine (BCA) was more potent in inhibiting CSE than propargylglycine (PAG) (IC₅₀ 14 ± 0.2 μM vs. 40 ± 8 μM respectively). Similar to PAG, L-aminoethoxyvinylglycine (AVG) only inhibited CSE, but did so at much lower concentrations. On the other hand, aminooxyacetic acid (AOAA), a frequently used CBS inhibitor, was more potent in inhibiting CSE compared with BCA and PAG (IC₅₀ 1.1 ± 0.1 μM); the IC₅₀ for AOAA for inhibiting CBS was 8.5 ± 0.7 μM. In line with our biochemical observations, relaxation to L-cysteine was blocked by AOAA in aortic rings that lacked CBS expression. Trifluoroalanine and hydroxylamine, two compounds that have also been used to block H₂S biosynthesis, blocked the activity of CBS and CSE. Trifluoroalanine had a fourfold lower IC₅₀ for CBS versus CSE, while hydroxylamine was 60-fold more selective against CSE.

CONCLUSIONS AND IMPLICATIONS:

In conclusion, although PAG, AVG and BCA exhibit selectivity in inhibiting CSE versus CBS, no selective pharmacological CBS inhibitor is currently available.

PMID:
23488457
PMCID:
PMC3687671
DOI:
10.1111/bph.12171
[Indexed for MEDLINE]
Free PMC Article

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