Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin
- 29 December 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (1), 297-301
- https://doi.org/10.1073/pnas.0912952107
Abstract
Blood coagulation in humans requires the activity of vitamin K epoxide reductase (VKOR), the target of the anticoagulant warfarin (Coumadin). Bacterial homologs of VKOR were recently found to participate in a pathway leading to disulfide bond formation in secreted proteins of many bacteria. Here we show that the VKOR homolog from the bacterium Mycobacterium tuberculosis, the causative agent of human tuberculosis, is inhibited by warfarin and that warfarin-resistant mutations of mycobacterial VKOR appear in similar locations to mutations found in human patients who require higher doses of warfarin. Deletion of VKOR results in a severe growth defect in mycobacteria, and the growth of M. tuberculosis is inhibited by warfarin. The bacterial VKOR homolog may represent a target for antibiotics and a model for genetic studies of human VKOR. We present a simple assay in Escherichia coli, based on a disulfide-sensitive beta-galactosidase, which can be used to screen for stronger inhibitors of the M. tuberculosis VKOR homolog.Keywords
This publication has 30 references indexed in Scilit:
- Bacterial species exhibit diversity in their mechanisms and capacity for protein disulfide bond formationProceedings of the National Academy of Sciences of the United States of America, 2008
- Identification of an Atypical Membrane Protein Involved in the Formation of Protein Disulfide Bonds in Oxygenic Photosynthetic OrganismsPublished by Elsevier BV ,2008
- Prediction of membrane-protein topology from first principlesProceedings of the National Academy of Sciences of the United States of America, 2008
- VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individualsBlood, 2008
- Clustal W and Clustal X version 2.0Bioinformatics, 2007
- Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2Proceedings of the National Academy of Sciences of the United States of America, 2006
- Effect ofVKORC1Haplotypes on Transcriptional Regulation and Warfarin DoseNew England Journal of Medicine, 2005
- Protein Disulfide Bond Formation in ProkaryotesAnnual Review of Biochemistry, 2003
- Identification of a protein required for disulfide bond formation in vivoCell, 1991
- Tightly regulated tac promoter vectors useful for the expression of unfused and fused proteins in Escherichia coliGene, 1988