The Experts below are selected from a list of 909 Experts worldwide ranked by ideXlab platform
Eveline Lescrinier - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Evaluation of 5-Substituted 2′-Deoxyuridine Monophosphate Analogues As Inhibitors of Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis
Journal of medicinal chemistry, 2011Co-Authors: Martin Kögler, Bart Vanderhoydonck, Steven De Jonghe, Jef Rozenski, Kristien Van Belle, Jean Herman, Thierry Louat, Anastasia Parchina, Carol Hopkins Sibley, Eveline LescrinierAbstract:A series of 5-substituted 2′-Deoxyuridine Monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
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synthesis and evaluation of 5 substituted 2 Deoxyuridine Monophosphate analogues as inhibitors of flavin dependent thymidylate synthase in mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2011Co-Authors: Martin Kögler, Bart Vanderhoydonck, Steven De Jonghe, Jef Rozenski, Kristien Van Belle, Jean Herman, Thierry Louat, Anastasia Parchina, Carol Hopkins Sibley, Eveline LescrinierAbstract:A series of 5-substituted 2′-Deoxyuridine Monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
Martin Kögler - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Evaluation of 5-Substituted 2′-Deoxyuridine Monophosphate Analogues As Inhibitors of Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis
Journal of medicinal chemistry, 2011Co-Authors: Martin Kögler, Bart Vanderhoydonck, Steven De Jonghe, Jef Rozenski, Kristien Van Belle, Jean Herman, Thierry Louat, Anastasia Parchina, Carol Hopkins Sibley, Eveline LescrinierAbstract:A series of 5-substituted 2′-Deoxyuridine Monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
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synthesis and evaluation of 5 substituted 2 Deoxyuridine Monophosphate analogues as inhibitors of flavin dependent thymidylate synthase in mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2011Co-Authors: Martin Kögler, Bart Vanderhoydonck, Steven De Jonghe, Jef Rozenski, Kristien Van Belle, Jean Herman, Thierry Louat, Anastasia Parchina, Carol Hopkins Sibley, Eveline LescrinierAbstract:A series of 5-substituted 2′-Deoxyuridine Monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
Zeefen Chang - One of the best experts on this subject based on the ideXlab platform.
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the ca loop in thymidylate kinase is critical for growth and contributes to pyrimidine drug sensitivity of candida albicans
Journal of Biological Chemistry, 2019Co-Authors: Changyu Huang, Yeechun Chen, Betty A Wuhsieh, Jimmin Fang, Zeefen ChangAbstract:The yeast Candida albicans is the most prevalent opportunistic fungal pathogen in humans. Drug resistance among C. albicans isolates poses a common challenge, and overcoming this resistance represents an unmet need in managing this common pathogen. Here, we investigated CDC8, encoding thymidylate kinase (TMPK), as a potential drug target for the management of C. albicans infections. We found that the region spanning amino acids 106-123, namely the Ca-loop of C. albicans TMPK (CaTMPK), contributes to the hyperactivity of this enzyme compared with the human enzyme (hTMPK) and to the utilization of Deoxyuridine Monophosphate (dUMP)/deoxy-5-fluorouridine Monophosphate (5-FdUMP) as a substrate. Notably, expression of CaTMPK, but not of hTMPK, produced dUTP/5-FdUTP-mediated DNA toxicity in budding yeast (Saccharomyces cerevisiae). CRISPR-mediated deletion of this Ca-loop in C. albicans revealed that the Ca-loop is critical for fungal growth and susceptibility to 5-fluorouridine (5-FUrd). Of note, pathogenic and drug-resistant C. albicans clones were similarly sensitive to 5-FUrd, and we also found that CaTMPK is essential for the growth of C. albicans In conclusion, these findings not only identified a target site for the development of CaTMPK-selective drugs, but also revealed that 5-FUrd may have potential utility as drug for managing C. albicans infections.
Ryoji Masui - One of the best experts on this subject based on the ideXlab platform.
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Crystal structure of family 5 uracil-DNA glycosylase bound to DNA.
Journal of molecular biology, 2007Co-Authors: Hiromichi Kosaka, Jun Hoseki, Noriko Nakagawa, Seiki Kuramitsu, Ryoji MasuiAbstract:Uracil-DNA glycosylase (UDG) removes uracil generated by the deamination of cytosine or misincorporation of Deoxyuridine Monophosphate. Within the UDG superfamily, a fifth UDG family lacks a polar residue in the active-site motif, which mediates the hydrolysis of the glycosidic bond by activation of a water molecule in UDG families 1-4. We have determined the crystal structure of a novel family 5 UDG from Thermus thermophilus HB8 complexed with DNA containing an abasic site. The active-site structure suggests this enzyme uses both steric force and water activation for its excision reaction. A conserved asparagine residue acts as a ligand to the catalytic water molecule. The structure also implies that another water molecule acts as a barrier during substrate recognition. Based on no significant open-closed conformational change upon binding to DNA, we propose a "slide-in" mechanism for initial damage recognition.
Dileep Vasudevan - One of the best experts on this subject based on the ideXlab platform.
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Structure analysis of thymidylate synthase from white spot syndrome virus reveals WSSV-specific structural elements.
International journal of biological macromolecules, 2020Co-Authors: Vipul Panchal, Sushil Kumar, Nausad Hossain, Dileep VasudevanAbstract:Abstract White spot syndrome virus (WSSV), the causative agent of white spot disease (WSD) severely affecting crustacean life forms, is highly contagious and forms the principal cause of massive economic losses in the shrimp aquaculture industry. Previous studies have demonstrated thymidylate synthase as a successful anti-cancer therapeutic drug target, leading to various anti-cancer drugs. The differential utilization of nucleotide precursors between white spot syndrome virus and shrimp encouraged us to analyze WSSV-thymidylate synthase (wTS). Here, we report the crystal structures of wTS in its apo-form and as a ternary complex with Deoxyuridine Monophosphate (dUMP) and methotrexate at a resolution of 2.35 A and 2.6 A, respectively. wTS possesses a fold characteristic to known thymidylate synthase (TS) structures. Like other TS structures, the apo-form of wTS displays an open conformation, whereas the wTS ternary complex attains a closed conformation. While the C-terminal loop maintains a typical distance from methotrexate, the Sγ atom of the catalytic Cys is positioned farther from the C6 atom of dUMP. Altogether, we report the first TS structure from a crustacean virus and highlight its distinction from shrimp and other TS structures.