Abstract
ThyX, a flavin-dependent thymidylate synthase that is involved in the synthesis of dTMP from dUMP, is a promising target for the development of novel antibacterial drugs that aimed at blocking the biosynthesis of dTMP, one of the building blocks of DNA. This enzyme has been recently identified in some dsDNA viruses and pathogenic bacteria, including the gastric pathogen Helicobacter pylori. It shares neither sequence nor structural homology with the classical ThyA in humans and other organisms. Further more, ThyX and ThyA are the only source of dTMP in these organisms and other pathways cannot substitute for their function. Thus, ThyX-specific inhibitors could be effective antibacterial reagents while having no impact on human cells. Here we report the crystal structure of ThyX from Helicobacter pylori strain 26695 in complex with co-factor FAD and substrate dUMP at 2.5 Å resolution, which consists of a 1.5 tetramer of ThyX with a total of 1248 residues, six FAD and six dUMP molecules in an asymmetric unit. The structure revealed the key residues that are involved in co-factor FAD and substrate dUMP binding, site-directed mutagenesis were performed to analysis the importance of these residues on ThyX activity by genetic complementation and FAD binding assay.
Keywords: Crystal structure, dUMP, FAD, Flavin-dependent thymidylate synthase, Helicobacter pylori
Protein & Peptide Letters
Title:Crystal Structure of a Flavin-dependent Thymidylate Synthase from Helicobacter pylori strain 26695
Volume: 19 Issue: 11
Author(s): Xiaoli Zhang, Jinyong Zhang, Gang Guo, Xuhu Mao, Yonglin Hu and Quanming Zou
Affiliation:
Keywords: Crystal structure, dUMP, FAD, Flavin-dependent thymidylate synthase, Helicobacter pylori
Abstract: ThyX, a flavin-dependent thymidylate synthase that is involved in the synthesis of dTMP from dUMP, is a promising target for the development of novel antibacterial drugs that aimed at blocking the biosynthesis of dTMP, one of the building blocks of DNA. This enzyme has been recently identified in some dsDNA viruses and pathogenic bacteria, including the gastric pathogen Helicobacter pylori. It shares neither sequence nor structural homology with the classical ThyA in humans and other organisms. Further more, ThyX and ThyA are the only source of dTMP in these organisms and other pathways cannot substitute for their function. Thus, ThyX-specific inhibitors could be effective antibacterial reagents while having no impact on human cells. Here we report the crystal structure of ThyX from Helicobacter pylori strain 26695 in complex with co-factor FAD and substrate dUMP at 2.5 Å resolution, which consists of a 1.5 tetramer of ThyX with a total of 1248 residues, six FAD and six dUMP molecules in an asymmetric unit. The structure revealed the key residues that are involved in co-factor FAD and substrate dUMP binding, site-directed mutagenesis were performed to analysis the importance of these residues on ThyX activity by genetic complementation and FAD binding assay.
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Cite this article as:
Zhang Xiaoli, Zhang Jinyong, Guo Gang, Mao Xuhu, Hu Yonglin and Zou Quanming, Crystal Structure of a Flavin-dependent Thymidylate Synthase from Helicobacter pylori strain 26695, Protein & Peptide Letters 2012; 19 (11) . https://dx.doi.org/10.2174/092986612803217105
DOI https://dx.doi.org/10.2174/092986612803217105 |
Print ISSN 0929-8665 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5305 |
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