PMID:12885245
| Citation |
Weber, TP, Widger, WR and Kohn, H (2003) Metal-1,4-dithio-2,3-dihydroxybutane chelates: novel inhibitors of the Rho transcription termination factor. Biochemistry 42:9121-6 |
|---|---|
| Abstract |
Rho is an enzyme that is essential for the growth and survival of Escherichia coli, and bicyclomycin (1) is its only known selective inhibitor. We show that metal (Cd(2+), Ni(2+), and Zn(2+)) complexes of 1,4-dithio-2,3-dihydroxybutanes (2) serve as effective and potent rho inhibitors with I(50) values that can exceed that of 1. Maximal inhibition for ZnCl(2) and L-dithiothreitol (2a) corresponded to Zn(2):L-DTT stoichiometry. The I(50) value for the 2:1 Zn-L-DTT solution was 20 microM, which made it 3 times more potent than 1 (I(50) = 60 microM). Kinetic studies showed that a Zn-L-DTT solution functioned as a noncompetitive inhibitor with respect to ATP in the rho poly(C)-dependent ATPase assay and as a competitive inhibitor with respect to ribo(C)(10) in the poly(dC).ribo(C)(10)-stimulated ATPase assay. These findings demonstrated that both 1 and a Zn-L-DTT solution disrupted rho-mediated ATP hydrolysis but that they inhibit using different mechanisms. Substitution of L-DTT with 1,2-ethanedithiol in ZnCl(2) solutions led to a comparable loss of rho poly(C)-dependent ATPase activity, indicating that other metal chelates can serve as efficient inhibitors. The site and pathway of rho inhibition by the putative metal-1,4-dithio-2,3-dihydroxybutane chelates are discussed in light of the current data. |
| Links |
PubMed Online version:10.1021/bi030089w |
| Keywords |
Adenosine Triphosphatases/antagonists & inhibitors; Bicyclo Compounds, Heterocyclic/chemistry; Cadmium Chloride/chemistry; Chelating Agents/chemistry; Chlorides/chemistry; Dithiothreitol/chemistry; Enzyme Inhibitors/chemistry; Escherichia coli Proteins/antagonists & inhibitors; Escherichia coli Proteins/chemistry; Manganese Compounds/chemistry; Metals, Heavy/chemistry; Nickel/chemistry; Poly C/chemistry; Rho Factor/antagonists & inhibitors; Rho Factor/chemistry; Solutions; Zinc Compounds/chemistry |
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