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Article

Advanced Spectroscopy and APBS Modeling for Determination of the Role of His190 and Trp103 in Mouse Thymidylate Synthase Interaction with Selected dUMP Analogues

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Inter-Faculty Interdisciplinary Doctoral Studies in Natural Sciences and Mathematics, MISMaP College, University of Warsaw, ul. Banacha 2C, 02-097 Warsaw, Poland
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Institute of Experimental Physics, Faculty of Physics, University of Warsaw, ul. Pasteura 5, 02-093 Warsaw, Poland
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Nencki Institute of Experimental Biology, ul. Pasteura 3, 02-093 Warsaw, Poland
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Nanoscale BioPhotonics Laboratory, School of Chemistry, National University of Ireland, University Road, H91 TK33 Galway, Ireland
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Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
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Faculty of Chemistry, Warsaw University of Technology, ul Noakowskiego 3, 00-664 Warsaw, Poland
*
Authors to whom correspondence should be addressed.
Academic Editor: Eugene S. Vysotski
Int. J. Mol. Sci. 2021, 22(5), 2661; https://doi.org/10.3390/ijms22052661
Received: 27 January 2021 / Revised: 26 February 2021 / Accepted: 2 March 2021 / Published: 6 March 2021
A homo-dimeric enzyme, thymidylate synthase (TS), has been a long-standing molecular target in chemotherapy. To further elucidate properties and interactions with ligands of wild-type mouse thymidylate synthase (mTS) and its two single mutants, H190A and W103G, spectroscopic and theoretical investigations have been employed. In these mutants, histidine at position 190 and tryptophan at position 103 are substituted with alanine and glycine, respectively. Several emission-based spectroscopy methods used in the paper demonstrate an especially important role for Trp 103 in TS ligands binding. In addition, the Advanced Poisson–Boltzmann Solver (APBS) results show considerable differences in the distribution of electrostatic potential around Trp 103, as compared to distributions observed for all remaining Trp residues in the mTS family of structures. Together, spectroscopic and APBS results reveal a possible interplay between Trp 103 and His190, which contributes to a reduction in enzymatic activity in the case of H190A mutation. Comparison of electrostatic potential for mTS complexes, and their mutants, with the substrate, dUMP, and inhibitors, FdUMP and N4-OH-dCMP, suggests its weaker influence on the enzyme–ligand interactions in N4OH-dCMP-mTS compared to dUMP-mTS and FdUMP-mTS complexes. This difference may be crucial for the explanation of the ”abortive reaction” inhibitory mechanism of N4OH-dCMP towards TS. In addition, based on structural analyses and the H190A mutant capacity to form a denaturation-resistant complex with N4-OH-dCMP in the mTHF-dependent reaction, His190 is apparently responsible for a strong preference of the enzyme active center for the anti rotamer of the imino inhibitor form. View Full-Text
Keywords: mouse thymidylate synthase; spectroscopy; APBS modeling mouse thymidylate synthase; spectroscopy; APBS modeling
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MDPI and ACS Style

Prokopowicz, M.; Jarmuła, A.; Casamayou-Boucau, Y.; Gordon, F.; Ryder, A.; Sobich, J.; Maj, P.; Cieśla, J.; Zieliński, Z.; Fita, P.; Rode, W. Advanced Spectroscopy and APBS Modeling for Determination of the Role of His190 and Trp103 in Mouse Thymidylate Synthase Interaction with Selected dUMP Analogues. Int. J. Mol. Sci. 2021, 22, 2661. https://doi.org/10.3390/ijms22052661

AMA Style

Prokopowicz M, Jarmuła A, Casamayou-Boucau Y, Gordon F, Ryder A, Sobich J, Maj P, Cieśla J, Zieliński Z, Fita P, Rode W. Advanced Spectroscopy and APBS Modeling for Determination of the Role of His190 and Trp103 in Mouse Thymidylate Synthase Interaction with Selected dUMP Analogues. International Journal of Molecular Sciences. 2021; 22(5):2661. https://doi.org/10.3390/ijms22052661

Chicago/Turabian Style

Prokopowicz, Małgorzata, Adam Jarmuła, Yannick Casamayou-Boucau, Fiona Gordon, Alan Ryder, Justyna Sobich, Piotr Maj, Joanna Cieśla, Zbigniew Zieliński, Piotr Fita, and Wojciech Rode. 2021. "Advanced Spectroscopy and APBS Modeling for Determination of the Role of His190 and Trp103 in Mouse Thymidylate Synthase Interaction with Selected dUMP Analogues" International Journal of Molecular Sciences 22, no. 5: 2661. https://doi.org/10.3390/ijms22052661

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