• editor.aipublications@gmail.com
  • Track Your Paper
  • Contact Us
  • ISSN: 2456-866X

International Journal Of Chemistry, Mathematics And Physics(IJCMP)

Quantitative In silico analysis of mammalian serine racemase activity

Toshihiko Hanai

International Journal of Chemistry, Mathematics And Physics(IJCMP), Vol-2,Issue-6, November - December 2018, Pages 53-58 , 10.22161/ijcmp.2.6.1

Download | Downloads : 9 | Total View : 984


Serine racemase (SR) is a pyridoxal 5’-phosphate (PLP)-dependent enzyme catalyzing the racemization of S-serine to R-serine, and also oxidizes R-serine to pyruvate; however, the enzymatic racemization reaction is not fully understood. Therefore, quantitative in silico analysis of mammalian SR was performed followed byD-amino acid oxidase (DAO) analysis.The downloaded stereo structures of Rattus norvegicus (PBD ID: 3hmk) and mammalian (PDB ID: 3l6r and 3l6b) SR were optimized using molecular mechanic (MM2) calculation. Furthermore, the stereo structure of mammalian SR was constructed using 3hmk and the amino acid sequence data. The atomic partial charge (apc) of the target atoms was calculated using MOPAC-PM5. The atomic distances, bond angles, and apc of the mutants were used to study the enzyme reaction mechanism.The serine carboxyl group contacted lysine-56, where its amino group contacted the oxygen molecules of PLP aldehyde. The apc of C indicated that S-serine was selectively oxidized. Manganese located at another side of PLP is directly involved in the serine racemization by forming bonding with the hydroxyl group of serine. The enzyme racemization activity was quantitatively related to the bond angle of the substituted serine rather than to that of alanine. However, 316r and 316b lack several amino acid residues; therefore, the selective oxidation of S84 mutants was not clearly demonstrated.

Mammalian serine racemase, Quantitative analysis, Enzyme activity, in silico.

[1] A. Hashimoto, T. Nishikawa, T. Hayashi, N. Fujii, K. Harada, T. Oka, K. Takahashi, The presence of free D-serine in rat brain. FWBS Let. 1992, 296, 33-36, Doi: 10.1016/0014-5793(92)80397-Y.
[2] H. Wolosker, K.N. Sheth, M. Takahashi, J.P. Mothet, R.O.Jr. Brady, C.D. Ferris, S.H. Snyder, Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc. Natl. Acad. Sci. U S A.1999b, 96, 721–725.
[3] M.A. Smith, V. Mach, A. Ebneth, O. Moraes, B. Felicetti, M. Wood, D. Schonfeld, O. Mather, A. Cesura, J. Barker, The structure of mammalian serine racemase, Evidence for conformational changes upon inhibitor binding, J. Bio. Chem., 2010, 285, 12873-12881. Doi: 10.1074/jbcM109.050062.
[4] W. Wang, S.W. Barger, Roles of quaternary structure and cysteine residues in the activity of human serine racermase, BMC Biochem. 2011, 12, 63. Doi: 10.1186/1471-2091-12-63.
[5] L. Pollegioni, L. Piubelli, G. Molla, E. Rosini,D-amino acid oxidase-pLG72 interaction and D-serine modulation, Front. Mol. Biosci., 2018, 5, 1-12. Doi: 10.3389/fmolb.2018.00003.
[6] N.R. Kondori, P. Paul, J.P. Robbins, K. Liu, J.C.W. Hilyard, D.J. Wells, J.S. De Belleroche, Focus on the role of D-serine and D-amino acid oxidase in Amyotrophic Lateral Sclerosis/motor neuron disease (ALC), Front. Mol. Biosci., 2018, 5, 1-7. Doi: 10.3389/fmolb.2018.00008.
[7] N. Nitoker, D.T. Major, Understanding the reaction mechanisms and intermediate stabilization in mammalian serine racemase using multiscale quantum-classical simulation, Biochem., 2015, 52(2), 516-527.
[8] T. Hanai, Quantitative in silico analysis of D-amino acid oxidase reactivity and inhibition, Current Bioactive Compounds, 2017, 13, 312-317. Doi:10.2174/1573407212666161014133246
[9] T. Hanai, Basic properties of a molecular mechanics program and the generation of unknown stereo structures of proteins for quantitative analysis of enzyme reactions, In: Watkins, P. (Ed.), Molecular Mechanics and Modeling. Nova Science: New York, 2015, Chapter 2, 25-48. (ISBN: 978-1-63483-388-2)
[10] T. Hanai, Quantitative in silico analysis of enzyme reactions: comparison of D-amino acid oxidase and monoamine oxidase. Am. Biotechnol. Lab.2007, 25, 8-13.
[11] T. Hanai, Quantitative in silico analysis of alanine racemase reactivity, In Watkins, P. (Ed.), Molecular Mechanics and Modeling. Nova Science: New York, 2015, Chapter 3, 49-71. (ISBN: 978-1-63483-388-2)
[12] RCSB, Protein Data Bank, www.rcsb.org/pdb/.
[13]D.L.Nelson, G.A. Applegate, M.L. Beio, D.L. Graham, D.V. Berkowitz, Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position-84 as a hotspot for -elimination function, J. Biol. Chem., published on July 10, 2017, 1-35. Doi:10.1074/jbc.M117.777904.
[14]H. Wu, Y.B. Qi, J. Kong, F. Kou, F. Jia, X.F. Dan, Y. Wang, A seven-coordinate manganese (II) complex formed with the tripodal tetradentate ligand tris(N-methylbenzimidazol-2-ylmethyl)amine,Z.Naturforsch. 2010, 65b, 1097-1100.
[15] D.E. Metzler, E.E. Snell, Deamination of serine: 1. Catalystic deamination of serine and cysteine by pyridoxal and metal salts, J. Biol. Chem., 1952, 198, 353-361.
[16]L. Gorgannezhad, G. Dehghan, S.Y. Ebrahimipour, A. Nasen, J.E.N. Dolatabadi, Complex of manganese (II) with curcumin: Spectroscopic characterization, DFT study, model-based analysis and antiradical activity, J. Mol. Struc.,2016, 1109, 139-145. Doi:org/10.1016/jmoistruc.2015.12.051.
[17]K.Islam, Manganese complex of ethylenediamine-tetraacetic acid (EDTA)-benzothiazole aniline (BTA) conjugate as a potential liver-targeting MRI contrast agent, J. Med. Chem., 2017, 60(7), 2993-3001. Doi: 10.1021/acs.jmedchem.6b01799.
[18]D.W. Gohara, E.D. Cera, Molecular mechanisms of enzyme activation by monovalent cations, J. Biol. Chem. 2016, 291(40),20840-20848.Doi: 10.1074/jbc.R116.737833.