4wjx › Citations

New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM.

Fadel F, Zhao Y, Cachau R, Cousido-Siah A, Ruiz FX, Harlos K, Howard E, Mitschler A, Podjarny A
Acta Crystallogr D Biol Crystallogr 71 1455-70 (2015)
Related entries: 4wk9, 4wka, 4wkf, 4wkh

Cited: 12 times
EuropePMC logo PMID: 26143917

Abstract

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, an N-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 Å (PDB entry 1waw) to 0.95-1.10 Å for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities.

Articles - 4wjx mentioned but not cited (2)

  1. X-Ray Crystal Structure of the Full Length Human Chitotriosidase (CHIT1) Reveals Features of Its Chitin Binding Domain. Fadel F, Zhao Y, Cousido-Siah A, Ruiz FX, Mitschler A, Podjarny A. PLoS One 11 e0154190 (2016)
  2. The oxygen-oxygen distance of water in crystallographic data sets. Palese LL. Data Brief 28 105076 (2020)


Reviews citing this publication (4)

  1. Immunomodulatory Effects of Chitotriosidase Enzyme. Elmonem MA, van den Heuvel LP, Levtchenko EN. Enzyme Res 2016 2682680 (2016)
  2. Chitinases and Chitinase-Like Proteins as Therapeutic Targets in Inflammatory Diseases, with a Special Focus on Inflammatory Bowel Diseases. Mazur M, Zielińska A, Grzybowski MM, Olczak J, Fichna J. Int J Mol Sci 22 6966 (2021)
  3. Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding. Peach ML, Cachau RE, Nicklaus MC. J Mol Recognit 30 (2017)
  4. Structural insights into the mechanisms and specificities of IgG-active endoglycosidases. Du JJ, Klontz EH, Guerin ME, Trastoy B, Sundberg EJ. Glycobiology 30 268-279 (2020)

Articles citing this publication (6)

  1. A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death. Yokoyama S, Cai Y, Murata M, Tomita T, Yoneda M, Xu L, Pilon AL, Cachau RE, Kimura S. Elife 7 e37854 (2018)
  2. Molecular Basis of Broad Spectrum N-Glycan Specificity and Processing of Therapeutic IgG Monoclonal Antibodies by Endoglycosidase S2. Klontz EH, Trastoy B, Deredge D, Fields JK, Li C, Orwenyo J, Marina A, Beadenkopf R, Günther S, Flores J, Wintrode PL, Wang LX, Guerin ME, Sundberg EJ. ACS Cent Sci 5 524-538 (2019)
  3. GH18 endo-β-N-acetylglucosaminidases use distinct mechanisms to process hybrid-type N-linked glycans. Trastoy B, Du JJ, Li C, García-Alija M, Klontz EH, Roberts BR, Donahue TC, Wang LX, Sundberg EJ, Guerin ME. J Biol Chem 297 101011 (2021)
  4. Structural dissection reveals a general mechanistic principle for group II chitinase (ChtII) inhibition. Chen W, Zhou Y, Yang Q. J Biol Chem 294 9358-9364 (2019)
  5. Crystal structures of the GH18 domain of the bifunctional peroxiredoxin-chitinase CotE from Clostridium difficile. Whittingham JL, Hanai S, Brannigan JA, Ferreira WT, Dodson EJ, Turkenburg JP, Cartwright J, Cutting SM, Wilkinson AJ. Acta Crystallogr F Struct Biol Commun 76 241-249 (2020)
  6. Discovery and Optimization of a Novel Macrocyclic Amidinourea Series Active as Acidic Mammalian Chitinase Inhibitors. Balestri LJI, Trivisani CI, Orofino F, Fiorucci D, Truglio GI, D'Agostino I, Poggialini F, Botta L, Docquier JD, Dreassi E. ACS Med Chem Lett 14 417-424 (2023)


Quick links