SpringerLink
Log in

Molecule dynamics and combined QM/MM study on one-carbon unit transfer reaction catalyzed by GAR transformylase

  • Published:
Central European Journal of Chemistry

Abstract

Both a molecule dynamic study and a combined quantum mechanics and molecule mechanics (QM/MM) study on Glycinamide ribonucleotide transformylase (GAR Tfase) catalytic mechanism are presented. The results indicate a direct one-carbon unit transfer process but not a stepwise mechanism in this reaction. The residues near the active center can fix the cofactor (N10-formyltetrahydrofolate) and GAR in proper relative positions by a H-bond network. The transition state and the minimum energy pathway are located on the potential energy surface. After all the residues (including H2O molecules) are removed from the system the activation energy has increased from 145.1 kJ/mol to 243.3 kJ/mol, and the formly transfer reaction is very hard to achieve. The interactions between coenzyme, GAR and residues near the reactive center are discussed as well.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. J. Aimi, H. Qiu, J. Williams, H. Zalkin and J. E. Dixon: “De novo purine nucleotide biosynthesis: cloning of human and avian cDNAs encoding the trifunctional glycinamide ribonucleotide synthetase- aminoimidazole ribonucleotide synthetase-glycinamide ribonucleotide transformylase by functional complementation in E. coli”, Nucl. Acids. Res., Vol. 18, (1990), pp. 6665.

    CAS  Google Scholar 

  2. P. Chen, U. Schulz-Gahmen, E. A. Stura, J. Inglese, D. L. Johnson, A. Marolewski, S. J. Benkovic and I. A. Wilson: “Crystal Structure of Glycinamide Ribonucleotide Transformylase from Escherichia coli at 3.0 Å Resolution”, J. Mol. Biol., Vol. 227, (1992), pp. 283.

    Article  CAS  Google Scholar 

  3. R. J. Almassy, C. A. Janson, C. Kan and Z. Hostomska: “Structures of Apo and Complexed Escherichia coli Glycinamide Ribonucleotide Transformylase”, Proc. Natl. Acad. Sci., U.S.A., Vol. 89, (1992), pp. 6114.

    Article  CAS  Google Scholar 

  4. C. Klein, P. Chen, J. H. Arevalo, E. A. Stura, A. Marolewski, M. S. Warren, S. J. Benkovic and I. A. Wilson: “Towards Structure-based Drug Design: Crystal Structure of a Multisubstrate Adduct Complex of Glycinamide Ribonucleotide Transformylase at 1.96 Å Resolution”, J. Mol. Biol., Vol. 249(1), (1995), pp. 153.

    Article  CAS  Google Scholar 

  5. M. S. Warren, A. E. Marolewski and S. J. Benkovic: “A Rapid Screen of Active Site Mutants in Glycinamide Ribonucleotide Transformylase”, Biochemistry, Vol. 35, (1996), pp. 8855.

    Article  CAS  Google Scholar 

  6. J. H. Shim and S. J. Benkovic: “Catalytic Mechanism of Escherichia coli Glycinamide Ribonucleotide Transformylase Probed by Site-Directed Mutagenesis and pH-Dependent Studies”, Biochemistry, Vol. 38, (1999), pp. 10024.

    Article  CAS  Google Scholar 

  7. K. S. Gary, M. W. Thomas, J. S. Lawrence, W. D. Charles and J. B. Stephen: “Direct transfer of one-carbon units in the transformylations of de novo purine biosynthesis”, Biochemistry, Vol. 21, (1982), pp. 2870.

    Article  Google Scholar 

  8. Q. A. Qiao, Zh. T. Cai, D. C. Feng and Y. S. Jiang: “A quantum chemical study of the water-assisted mechanism in one-carbon unit transfer reaction catalyzed by glycinamide ribonucleotide transformylase”, Biophys. Chem., Vol. 110, (2004), pp. 259.

    Article  CAS  Google Scholar 

  9. J. Inglese, J. M. Smith and S. J. Benkovic: “Active-Site Map** and Site-Specific Mutagenesis of Glycinamide Ribonucleotide Transformylase from Escherichia coli”, Biochemistry, Vol. 29, (1990), pp. 6678.

    Article  CAS  Google Scholar 

  10. Q. A. Qiao, Zh. T. Cai and D. C. Feng: “Quantum study on a new mechanism in onecarbon unit transfer reaction: the water-assisted mechanism”, Chin. J. Chem., Vol. 22(6), (2004), pp. 505.

    Article  CAS  Google Scholar 

  11. P. L. Nagy, A. Marolewski, S. J. Benkovic and H. Zalkin: “Formyltetrahydrofolate Hydrolase, a Regulatory Enzyme That Functions To Balance Pools of Tetrahydrofolate and One-Carbon Tetrahydrofolate Adducts in Escherichia coli”, J. Bacteriology, Vol. 177(5), (1995), pp. 1292.

    CAS  Google Scholar 

  12. S. E. Greasley, M. M. Yamashita, H. Cai, S. J. Benkovic, D. L. Boger and I. A. Wilson: “New Insights into Inhibitor Design from the Crystal Structure and NMR Studies of Escherichia coli GAR Transformylase in Complex with β-GAR and 10-Formyl-5, 8, 10-trideazafolic Acid”, Biochemistry, Vol. 38, (1999), pp. 16783.

    Article  CAS  Google Scholar 

  13. Research Collaboratory for Structural Bioinformatics (RCSB), URL: http://www.rcsb.org.

  14. W. L. Jorgensen, J. Chandrasekhar, J. D. Madura, R. W. Impey and M. L. J. Klein: “Comparison of simple potential functions for simulating liquid water”, J. Chem. Phys., Vol. 79, (1983), pp. 926.

    Article  CAS  Google Scholar 

  15. J. R. Maple, M.-J. Hwang, K.J. Jalkanen, T. P. Stockfisch and A. T. Hagler: “Derivation of class II force fields: V. Quantum force field for amides, peptides, and related compounds”, J. Comp. Chem., Vol. 19, (1998), pp. 430 and references therein.

    Article  CAS  Google Scholar 

  16. Cerius 2, version 4.6, Accelrys Software Inc. 2001–2005.

  17. E. Dyguda, B. Szefczyk and W. A. Sokalski: “The mechanism of phosphoryl transfer reaction and the role of active site residues on the basis of ribokinase-like kinases”, Int. J. Mol. Sci., Vol. 5, (2004), pp. 141.

    Article  CAS  Google Scholar 

  18. A. D. Becke: “A new mixing of Hartree-Fock and local density-functional theories”, J. Chem. Phys., Vol. 98, (1993), pp. 1372.

    Article  CAS  Google Scholar 

  19. G. A. Petersson and M. A. Al-Laham: “A complete basis set model chemistry. II. Open-shell systems and the total energyes of the first-row atoms”, J. Chem. Phys., Vol. 94, (1991), pp. 6081.

    Article  CAS  Google Scholar 

  20. S. L. Mayo, B. D. Olafson and W. A. Goddard: “DREIDING: a generic force field for molecular simulations”, J. Phys. Chem., Vol. 94, (1990), pp. 8897.

    Article  CAS  Google Scholar 

  21. H. Fahmi and P. E. M. Siegbahn: “Catalytic Mechanism of Glyoxalase I: A Theoretical Study”, J. Am. Chem. Soc., Vol. 123(48), (2001), pp. 10280.

    Google Scholar 

  22. P. L. Cummins and J. E. Gready: “Energetically Most Likely Substrate and Active-Site Protonation Sites and Pathways in the Catalytic Mechanism of Dihydrofolate Reductase”, J. Am. Chem. Soc., Vol. 123, (2001), pp. 3418.

    Article  CAS  Google Scholar 

  23. Gaussian 03, Revision B03, Gaussian, Inc., Pittsburgh PA, 2003.

  24. P. Y. Ayala and H. B. Schlegel: “A combined method for determining reaction paths, minima and transition state geometries”, J. Chem. Phys., Vol. 107, (1997), pp. 375.

    Article  CAS  Google Scholar 

  25. M. S. Warren, K. M. Mattia, A. E. Marolewski and S. J. Benkovic: “The Transformylase Enzymes of de novo Purine Biosynthesis”, Pure & Appl. Chem., Vol. 68(11), (1996), pp. 2029.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry and Materials Science, Yantai Normal University, 264025, Yantai, China

    Qing-An Qiao & Rongjun Qu

  2. Library of Yantai Normal University, 264025, Yantai, China

    Yueqing **

  3. Institute of Theoretical Chemistry, Shandong University, 250100, **an, China

    Zhengting Cai

  4. Department of Physics, Yantai Normal University, 264025, Yantai, China

    Chuanlu Yang & Meishan Wang

Authors
  1. Qing-An Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yueqing **
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengting Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rongjun Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chuanlu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meishan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Qiao, QA., **, Y., Cai, Z. et al. Molecule dynamics and combined QM/MM study on one-carbon unit transfer reaction catalyzed by GAR transformylase. cent.eur.j.chem. 3, 674–682 (2005). https://doi.org/10.2478/BF02475196

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.2478/BF02475196

Key words

Search

Navigation