Skip to main content
SpringerLink
Log in

Role of water coordination at zinc binding site and its catalytic pathway of dizinc creatininase: insights from quantum cluster approach

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Creatininase is a key enzyme of creatinine-metabolizing pathway in mammals, and has a great potential for diagnostic application. It catalyzes the reversible conversion of creatinine to creatine. Here, we investigated its reaction mechanism with density functional theory in conjunction with the quantum cluster approach. Three reaction pathways in which several possible proton transfers assisted by either His178 or a water ligand to Zn1 (Wat2) or both were considered. DFT calculations reveal, depending on Wat2 coordination mode at Zn1, two competitive ring-opening pathways where His178 playing a central role as a proton shuttle or both His178 and Wat2 serving as a dual catalytic role as a base and an acid, respectively. Three elementary steps were proposed for the reaction: the first involves nucleophilic attack by a bridging hydroxide to the substrate and forms a gem-diolate intermediate, followed by a proton transfer from the gem-diolate to His178 (His178 protonation is a required step for efficient proton transfers). Finally, the second proton transfer from the protonated His178 or Wat2 to the amide of substrate leads to the ring opening. The first proton transfer is the rate-limiting step of the whole reaction, in consistent with previous experimental and computational studies. A detailed understanding of the reaction mechanism of the creatininase enzyme family will also be helpful for developing a biosensor for kidney function.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

All data generated or analysed during this study are included in this published article (and its supplementary information files).

References

  1. Szulmajster J (1958) Bacterial degradation of creatinine. II. Creatinine desimidase. Biochim Biophys Acta 30(1):154

    Article  CAS  Google Scholar 

  2. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80(3):1107

    Article  CAS  Google Scholar 

  3. Kaplan A, Szabo LL (1974) Creatinine hydrolase and creatine amidinohydrolase. II. Partial purification and properties. Mol Cell Biochem 3:17

    Article  CAS  Google Scholar 

  4. Tsuru D, Oka I, Yoshimoto T (1976) Creatinine decomposing enzymes in Pseudomonas putida. Agric Biol Chem 40:1011

    CAS  Google Scholar 

  5. Rikitake K, Oka I, Ando M, Yoshimoto T, Tsuru D (1979) Creatinine amidohydrolase (creatininase) from Pseudomonas putida. Purification and some properties. J Biochem 86:1109

    Article  CAS  Google Scholar 

  6. Tang TY, Wen CJ (2000) Expression of the creatininase gene from Pseudomonas putida RS65 in Escherichia coli. J Ind Microbiol 24:2

    CAS  Google Scholar 

  7. Yoshimoto T, Oka I, Tsuru D (1976) Creatine amidinohydrolase of Pseudomonas putida: Crystallization and some properties. Arch Biochem Biophys 177(2):508

    Article  CAS  Google Scholar 

  8. Schumann J, Böhm G, Schumacher G, Rudolph R, Jaenicke R (1993) Stabilization of creatinase from Pseudomonas putida by random mutagenesis. Protein Sci 2(10):1612

    Article  CAS  Google Scholar 

  9. Yamamoto K, Oka M (1995) Cloning of the creatinine amidohydrolase gene from Pseudomonas sp. PS-7. Biosci Biotechnol Biochem 59:1331

    Article  CAS  Google Scholar 

  10. Beuth B, Niefind K, Schomburg D (2002) Crystallization and preliminary crystallographic analysis of creatininase from Pseudomonas putida. Acta Crystallogr D Biol Crystallogr 58(8):1356

    Article  Google Scholar 

  11. Beuth B, Niefind K, Schomburg D (2003) Crystal structure of creatininase from Pseudomonas putida: a novel fold and a case of convergent evolution. J Mol Biol 332(1):287

    Article  CAS  Google Scholar 

  12. Ito K, Kanada N, Inoue T, Furukawa K, Yamashita K, Tanaka N, Nakamura KT, Nishiya Y, Sogabe A, Yoshimoto T (2002) Preliminary crystallographic studies of the creatinine amidohydrolase from Pseudomonas putida. Acta Crystallogr Sect D 58:2180

    Article  Google Scholar 

  13. Yamashita K, Nakajima Y, Matsushita H, Nishiya Y, Yamazawa R, Wu YF, Matsubara F, Oyama H, Ito K, Yoshimoto T (2010) Substitution of Glu122 by glutamine revealed the function of the second water molecule as a proton donor in the binuclear metal enzyme creatininase. J Mol Biol 396(4):1081

    Article  CAS  Google Scholar 

  14. Yoshimoto T, Tanaka N, Kanada N, Inoue T, Nakajima Y, Haratake M, Nakamura KT, Xu Y, Ito K (2004) Crystal structures of creatininase reveal the substrate binding site and provide an insight into the catalytic mechanism. J Mol Biol 337(2):399

    Article  CAS  Google Scholar 

  15. Jitonnom J, Mujika JI, van der Kamp MW, Mulholland AJ (2017) Quantum mechanics/molecular mechanics simulations identify the ring-opening mechanism of creatininase. Biochemistry 56(48):6377

    Article  CAS  Google Scholar 

  16. Seibert CM, Raushel FM (2005) Structural and catalytic diversity within the amidohydrolase superfamily. Biochemistry 44(17):6383

    Article  CAS  Google Scholar 

  17. Liao R-Z, Yu J-G, Frank M, Raushel, Himo F (2008) Theoretical investigation of the reaction mechanism of the dinuclear zinc enzyme dihydroorotase. Chem Eur J 14:4287

    Article  CAS  Google Scholar 

  18. Liao R-Z, Himo F, Yu J-G, Liu R-Z (2010) Dipeptide hydrolysis by the dinuclear zinc enzyme human renal dipeptidase: Mechanistic insights from DFT calculations. J Inorg Biochem 104(1):37

    Article  CAS  Google Scholar 

  19. Liao R-Z, Yu J-G, Himo F (2009) Reaction Mechanism of the Dinuclear Zinc Enzyme N-Acyl-l-homoserine Lactone Hydrolase: A Quantum Chemical Study. Inorg Chem 48(4):1442

    Article  CAS  Google Scholar 

  20. Krivitskaya AV, Khrenova MG, Nemukhin AV (2021) Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase. Molecules 26(20):6280

    Article  CAS  Google Scholar 

  21. Reidl CT, Mascarenhas R, Mohammad TSH, Lutz MR Jr, Thomas PW, Fast W, Liu D, Becker DP (2021) Cyclobutanone Inhibitor of Cobalt-Functionalized Metallo-γ-Lactonase AiiA with Cyclobutanone Ring Opening in the Active Site. ACS omega 6(21):13567

    Article  CAS  Google Scholar 

  22. Liao R-Z, Yu J-G, Himo F (2010) Reaction Mechanism of the Trinuclear Zinc Enzyme Phospholipase C: A Density Functional Theory Study. J Phys Chem B 114(7):2533

    Article  CAS  Google Scholar 

  23. Zhu X, Barman A, Ozbil M, Zhang T, Li S, Prabhakar R (2012) Mechanism of peptide hydrolysis by co-catalytic metal centers containing leucine aminopeptidase enzyme: a DFT approach. J Biol Inorg Chem 17(2):209

    Article  CAS  Google Scholar 

  24. Manta B, Raushel FM, Himo F (2014) Reaction mechanism of zinc-dependent cytosine deaminase from Escherichia coli: a quantum-chemical study. J Phys Chem B 118(21):5644

    Article  CAS  Google Scholar 

  25. Jitonnom J, Sattayanon C, Kungwan N, Hannongbua S (2015) A DFT study of the unusual substrate-assisted mechanism of Serratia marcescens chitinase B reveals the role of solvent and mutational effect on catalysis. J Mol Graph Model 56:53

    Article  CAS  Google Scholar 

  26. Jitonnom J, Hannongbua S (2018) Theoretical study of the arabinan hydrolysis by an inverting GH43 arabinanase. Mol Simul 44(8):631

    Article  CAS  Google Scholar 

  27. Fernandes HS, Teixeira CSS, Sousa SF, Cerqueira NMFSA (2019) Formation of unstable and very reactive chemical species catalyzed by metalloenzymes: a mechanistic overview.Molecules24(13)

  28. Jitonnom J, Lee VS, Nimmanpipug P, Rowlands HA, Mulholland AJ (2011) Quantum mechanics/molecular mechanics modeling of substrate-assisted catalysis in family 18 chitinases: conformational changes and the role of Asp142 in catalysis in ChiB. Biochemistry 50(21):4697

    Article  CAS  Google Scholar 

  29. Himo F (2017) Recent Trends in Quantum Chemical Modeling of Enzymatic Reactions. J Am Chem Soc 139(20):6780

    Article  CAS  Google Scholar 

  30. Siegbahn PEM, Himo F (2011) The quantum chemical cluster approach for modeling enzyme reactions. Wiley Interdisciplinary Reviews: Computational Molecular Science 1(3):323

    CAS  Google Scholar 

  31. Siegbahn PE, Himo F (2009) Recent developments of the quantum chemical cluster approach for modeling enzyme reactions. J Biol Inorg Chem 14(5):643

    Article  CAS  Google Scholar 

  32. Ahmadi S, Barrios Herrera L, Chehelamirani M, Hostaš J, Jalife S, Salahub DR (2018) Multiscale modeling of enzymes: QM-cluster, QM/MM, and QM/MM/MD: A tutorial review. Int J Quantum Chem 118(9):e25558

    Article  Google Scholar 

  33. Mulliken RS (1955) Electronic population analysis on LCAO–MO molecular wave functions. I J Chem Phys 23(10):1833

    Article  CAS  Google Scholar 

  34. Cossi M, Rega N, Scalmani G, Barone V (2003) Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J Comput Chem 24(6):669

    Article  CAS  Google Scholar 

  35. Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132(15):154104

    Article  Google Scholar 

  36. Grimme S, Ehrlich S, Goerigk L (2011) Effect of the damping function in dispersion corrected density functional theory. J Comput Chem 32(7):1456

    Article  CAS  Google Scholar 

  37. Brás NF, Fernandes PA, Ramos MJ (2014) QM/MM study and MD simulations on the hypertension regulator angiotensin-converting enzyme. ACS Catal 4(8):2587

    Article  Google Scholar 

  38. Lonsdale R, Harvey JN, Mulholland AJ (2010) Inclusion of dispersion effects significantly improves accuracy of calculated reaction barriers for cytochrome P450 catalyzed reactions. J Phys Chem Lett 1(21):3232

    Article  CAS  Google Scholar 

  39. Lonsdale R, Harvey JN, Mulholland AJ (2012) Effects of dispersion in density functional based quantum mechanical/molecular mechanical calculations on cytochrome P450 catalyzed reactions. J Chem Theory Comput 8(11):4637

    Article  CAS  Google Scholar 

  40. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2009) Gaussian 09 Rev. A.02. Wallingford, CT;

  41. Kim H, Lipscomb WN (1993) Differentiation and identification of the two catalytic metal binding sites in bovine lens leucine aminopeptidase by x-ray crystallography. Proc Natl Acad Sci USA 90(11):5006

    Article  CAS  Google Scholar 

  42. Rowlett RS, Tu C, McKay MM, Preiss JR, Loomis RJ, Hicks KA, Marchione RJ, Strong JA, Donovan GS Jr, Chamberlin JE (2002) Kinetic characterization of wild-type and proton transfer-impaired variants of beta-carbonic anhydrase from Arabidopsis thaliana. Arch Biochem Biophys 404(2):197

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Financial supports by the Thailand Research Fund and the University of Phayao (Grants RSA6280104 and FF64-RIB002) are gratefully acknowledged. The School of Science, University of Phayao (Grant PBTSC65006) is also acknowledged. The authors acknowledge National e-Science Infrastructure Consortium for providing computing resources that have partly contributed to the research results reported within this paper (www.e-science.in.th).

Author information

Authors and Affiliations

  1. Demonstration School University of Phayao, 56000, Phayao, Thailand

    Wijitra Meelua

  2. Division of Chemistry, School of Science, University of Phayao, 56000, Phayao, Thailand

    Wijitra Meelua & Jitrayut Jitonnom

  3. Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Gellért tér 4, H-1111, Budapest, Hungary

    Julianna Oláh

Authors
  1. Wijitra Meelua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julianna Oláh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jitrayut Jitonnom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jitrayut Jitonnom.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meelua, W., Oláh, J. & Jitonnom, J. Role of water coordination at zinc binding site and its catalytic pathway of dizinc creatininase: insights from quantum cluster approach. J Comput Aided Mol Des 36, 279–289 (2022). https://doi.org/10.1007/s10822-022-00451-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-022-00451-8

Keywords

Search

Navigation