ArticleNucleic acids research2004
Pyridoxal 5'-phosphate inactivates DNA topoisomerase IB by modifying the lysine general acid.
Article in Nucleic acids research, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 26 citations in OpenAlex.
- Genetic Analysis Using Vitamin BJournal of bacteriology · 2022Article
- Loss of YggS (COG0325) impacts aspartate metabolism in Salmonella enterica.Molecular microbiology · 2021Article
- The Role of YggS in Vitamin BJournal of bacteriology · 2020Article
- A Survey of Pyridoxal 5'-Phosphate-Dependent Proteins in the Gram-Positive Model BacteriumFrontiers in molecular biosciences · 2019Review
- Inactivation of NEIL2 DNA glycosylase by pyridoxal phosphate reveals a loop important for substrate binding.Biochemical and biophysical research communications · 2010Article
- The modulation of topoisomerase I-mediated DNA cleavage and the induction of DNA-topoisomerase I crosslinks by crotonaldehyde-derived DNA adducts.Nucleic acids research · 2008Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The present results demonstrate that pyridoxal, pyridoxal 5'-phosphate (PLP) and pyridoxal 5'-diphospho-5'-adenosine (PLP-AMP) inhibit Candida guilliermondii and human DNA topoisomerases I in forming an aldimine with the epsilon-amino group of an active site lysine. PLP acts as a competitive inhibitor of C.guilliermondii topoisomerase I (K(i) = 40 microM) that blocks the cleavable complex formation. Chemical reduction of PLP-treated enzyme reveals incorporation of 1 mol of PLP per mol of protein. The limited trypsic proteolysis releases a 17 residue peptide bearing a lysine-bound PLP (KPPNTVIFDFLGK*DSIR). Targeted lysine (K*) in C.guilliermondii topoisomerase I corresponds to that found in topoisomerase I of Homo sapiens (K532), Candida albicans (K468), Saccharomyces cerevisiae (K458) and Schizosaccharomyces pombe (K505). In the human enzyme, K532, belonging to the active site acts as a general acid catalyst and is therefore essential for activity. The spatial orientation of K532-PLP within the active site was approached by molecular modeling using available crystallographic data. The PLP moiety was found at close proximity of several active residues. PLP could be involved in the cellular control of topoisomerases IB. It constitutes an efficient tool to explore topoisomerase IB dynamics during catalysis and is also a lead for new drugs that trap the lysine general acid.
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Registered trials
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