Human Chitinases: Structure, Function, and Inhibitor Discovery

  • Ashutosh Kumar
  • Kam Y. J. ZhangEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1142)


Chitinases are glycosyl hydrolases that hydrolyze the β-(1-4)-linkage of N-acetyl-D-glucosamine units present in chitin polymers. Chitinases are widely distributed enzymes and are present in a wide range of organisms including insects, plants, bacteria, fungi, and mammals. These enzymes play key roles in immunity, nutrition, pathogenicity, and arthropod molting. Humans express two chitinases, chitotriosidase 1 (CHIT1) and acid mammalian chitinase (AMCase) along with several chitinase-like proteins (CLPs). Human chitinases are reported to play a protective role against chitin-containing pathogens through their capability to degrade chitin present in the cell wall of pathogens. Now, human chitinases are gaining attention as the key players in innate immune response. Although the exact mechanism of their role in immune response is not known, studies in recent years begin to relate chitin recognition and degradation with the activation of signaling pathways involved in inflammation. The roles of both CHIT1 and AMCase in the development of various diseases have been revealed and several classes of inhibitors have been developed. However, a clear understanding could not be established due to complexities in the design of the right experiment for studying the role of human chitinase in various diseases. In this chapter, we will first outline the structural features of CHIT1 and AMcase. We will then review the progress in understanding the role of human chitinases in the development of various diseases. Finally, we will summarize the inhibitor discovery efforts targeting both CHIT1 and AMCase.


Chitin Chitinase Chitotriosidase 1 Acid mammalian chitinase Inflammation Inhibitors 


  1. Akagi K-I, Watanabe J, Hara M, Kezuka Y, Chikaishi E, Yamaguchi T, Akutsu H, Nonaka T, Watanabe T, Ikegami T (2006) Identification of the substrate interaction region of the chitin-binding domain of streptomyces griseus chitinase C. J Biochem 139:483–493CrossRefPubMedGoogle Scholar
  2. Alvarez F (2014) The effect of chitin size, shape, source and purification method on immune recognition. Molecules 19:4433CrossRefPubMedPubMedCentralGoogle Scholar
  3. Amarsaikhan N, Templeton SP (2015) Co-recognition of β-glucan and chitin and programming of adaptive immunity to Aspergillus fumigatus. Front Microbiol 6:344–344CrossRefPubMedPubMedCentralGoogle Scholar
  4. Arai N, Shiomi K, Iwai Y, Omura S (2000a) Argifin, a new chitinase inhibitor, produced by Gliocladium sp. FTD-0668. II. Isolation, physico-chemical properties, and structure elucidation. J Antibiot (Tokyo) 53:609–614CrossRefGoogle Scholar
  5. Arai N, Shiomi K, Yamaguchi Y, Masuma R, Iwai Y, Turberg A, Kolbl H, Omura S (2000b) Argadin, a new chitinase inhibitor, produced by clonostachys sp.FO-7314. Chem Pharm Bull 48:1442–1446CrossRefPubMedGoogle Scholar
  6. Arakane Y, Muthukrishnan S (2010) Insect chitinase and chitinase-like proteins. Cell Mol Life Sci 67:201–216CrossRefPubMedGoogle Scholar
  7. Bargagli E, Bennett D, Maggiorelli C, Di Sipio P, Margollicci M, Bianchi N, Rottoli P (2013) Human chitotriosidase: a sensitive biomarker of sarcoidosis. J Clin Immunol 33:264–270CrossRefPubMedGoogle Scholar
  8. Berecibar A, Grandjean C, Siriwardena A (1999) Synthesis and biological activity of natural aminocyclopentitol glycosidase inhibitors: mannostatins, trehazolin, allosamidins, and their analogues. Chem Rev 99:779–844CrossRefPubMedGoogle Scholar
  9. Bhattacharya D, Nagpure A, Gupta RK (2007) Bacterial chitinases: properties and potential. Crit Rev Biotechnol 27:21–28CrossRefPubMedGoogle Scholar
  10. Bierbaum S, Nickel R, Koch A, Lau S, Deichmann KA, Wahn U, Superti-Furga A, Heinzmann A (2005) Polymorphisms and haplotypes of acid mammalian chitinase are associated with bronchial asthma. Am J Respir Crit Care Med 172:1505–1509CrossRefPubMedPubMedCentralGoogle Scholar
  11. Boot RG, Blommaart EFC, Swart E, Ghauharali-Van Der Vlugt K, Bijl N, Moe C, Place A, Aerts JMFG (2001) Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem 276:6770–6778CrossRefPubMedGoogle Scholar
  12. Boot RG, Bussink AP, Verhoek M, de Boer PA, Moorman AF, Aerts JMFG (2005) Marked differences in tissue-specific expression of chitinases in mouse and man. J Histochem Cytochem 53:1283–1292Google Scholar
  13. Boot RG, Renkema GH, Strijland A, Van Zonneveld AJ, Aerts JMFG (1995) Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem 270:26252–26256CrossRefPubMedGoogle Scholar
  14. Bueter CL, Specht CA, Levitz SM (2013) Innate sensing of chitin and chitosan. PLoS Pathog 9:e1003080CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bussink AP, Speijer D, Aerts JMFG, Boot RG (2007) Evolution of mammalian chitinase(-Like) members of family 18 glycosyl hydrolases. Genetics 177:959–970CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cash HL, Whitham CV, Behrendt CL, Hooper LV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313:1126–1130CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chang N-CA, Hung S-I, Hwa K-Y, Kato I, Chen J-E, Liu C-H, Chang AC (2001) A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem 276:17497–17506CrossRefPubMedGoogle Scholar
  18. Chen L, Zhou Y, Qu M, Zhao Y, Yang Q (2014) Fully deacetylated chitooligosaccharides act as efficient glycoside hydrolase family 18 chitinase inhibitors. J Biol Chem 289:17932–17940CrossRefPubMedPubMedCentralGoogle Scholar
  19. Choi IK, Kim YH, Kim JS, Seo JH (2010) High serum YKL-40 is a poor prognostic marker in patients with advanced non-small cell lung cancer. Acta Oncol 49:861–864CrossRefPubMedGoogle Scholar
  20. Chou Y-T, Yao S, Czerwinski R, Fleming M, Krykbaev R, Xuan D, Zhou H, Brooks J, Fitz L, Strand J, Presman E, Lin L, Aulabaugh A, Huang X (2006) Kinetic characterization of recombinant human acidic mammalian chitinase. Biochemistry 45:4444–4454CrossRefPubMedGoogle Scholar
  21. Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, Dziura JD, Reed J, Coyle AJ, Kiener P, Cullen M, Grandsaigne M, Dombret M-C, Aubier M, Pretolani M, Elias JA (2007) A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 357:2016–2027CrossRefPubMedGoogle Scholar
  22. Cole DC, Olland AM, Jacob J, Brooks J, Bursavich MG, Czerwinski R, Declercq C, Johnson M, Joseph-Mccarthy D, Ellingboe JW, Lin L, Nowak P, Presman E, Strand J, Tam A, Williams CMM, Yao S, Tsao DHH, Fitz LJ (2010) Identification and characterization of acidic mammalian chitinase inhibitors. J Med Chem 53:6122–6128CrossRefPubMedGoogle Scholar
  23. Da Silva CA, Chalouni C, Williams A, Hartl D, Lee CG, Elias JA (2009) Chitin is a size-dependent regulator of macrophage TNF and IL-10 production. J Immunol 182:3573–3582CrossRefPubMedGoogle Scholar
  24. Da Silva CA, Hartl D, Liu W, Lee CG, Elias JA (2008) TLR-2 and IL-17A in Chitin-Induced macrophage activation and acute inflammation. J Immunol 181:4279–4286CrossRefPubMedPubMedCentralGoogle Scholar
  25. Davies GJ, Wilson KS, Henrissat B (1997) Nomenclature for sugar-binding subsites in glycosyl hydrolases. Biochem J 321:557–559CrossRefPubMedPubMedCentralGoogle Scholar
  26. Duan Y, Liu T, Zhou Y, Dou T, Yang Q (2018) Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine. J Biol ChemGoogle Scholar
  27. Elieh Ali Komi D, Sharma L, Dela Cruz CS (2018) Chitin and its effects on inflammatory and immune responses. Clin Rev Allergy Immunol 54:213–223Google Scholar
  28. Fadel F, Zhao Y, Cachau R, Cousido-Siah A, Ruiz FX, Harlos K, Howard E, Mitschler A, Podjarny A (2015) New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM. Acta Crystallograph Sect D 71:1455–1470CrossRefGoogle Scholar
  29. Fadel F, Zhao Y, Cousido-Siah A, Ruiz FX, Mitschler A, Podjarny A (2016) X-Ray crystal structure of the full length human chitotriosidase (CHIT1) reveals features of its chitin binding domain. PLoS One 11:e0154190CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fitz LJ, Declercq C, Brooks J, Kuang W, Bates B, Demers D, Winkler A, Nocka K, Jiao A, Greco RM, Mason LE, Fleming M, Quazi A, Wright J, Goldman S, Hubeau C, Williams CMM (2012) Acidic mammalian chitinase is not a critical target for allergic airway disease. Am J Respir Cell Mol Biol 46:71–79CrossRefPubMedGoogle Scholar
  31. Foster JM, Zhang Y, Kumar S, Carlow CKS (2005) Parasitic nematodes have two distinct chitin synthases. Mol Biochem Parasitol 142:126–132CrossRefPubMedGoogle Scholar
  32. Fuchs K, Gloria YC, Wolz OO, Herster F, Sharma L, Dillen CA, Täumer C, Dickhöfer S, Bittner Z, Dang TM, Singh A, Haischer D, Schlöffel MA, Koymans KJ, Sanmuganantham T, Krach M, Roger T, Le Roy D, Schilling NA, Frauhammer F, Miller LS, Nürnberger T, Leibundgut‐Landmann S, Gust AA, Macek B, Frank M, Gouttefangeas C, Dela Cruz CS, Hartl D, Weber AN (2018) The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size. EMBO RepGoogle Scholar
  33. Fukamizo F (2000) Chitinolytic enzymes: catalysis, substrate binding, and their application. Curr Protein Pept Sci 1:105–124CrossRefPubMedGoogle Scholar
  34. Furuhashi K, Suda T, Nakamura Y, Inui N, Hashimoto D, Miwa S, Hayakawa H, Kusagaya H, Nakano Y, Nakamura H, Chida K (2010) Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir Med 104:1204–1210CrossRefPubMedGoogle Scholar
  35. Fusetti F, Von Moeller H, Houston D, Rozeboom HJ, Dijkstra BW, Boot RG, Aerts JMFG, Van Aalten DMF (2002) Structure of human chitotriosidase: implications for specific inhibitor design and function of mammalian chitinase-like lectins. J Biol Chem 277:25537–25544CrossRefPubMedGoogle Scholar
  36. Gao J, Bauer MW, Shockley KR, Pysz MA, Kelly RM (2003) Growth of hyperthermophilic archaeon Pyrococcus furiosus on chitin involves two family 18 chitinases. Appl Environ Microbiol 69:3119–3128CrossRefPubMedPubMedCentralGoogle Scholar
  37. Gavala ML, Kelly EA, Esnault S, Kukreja S, Evans MD, Bertics PJ, Chupp GL, Jarjour NN (2013) Segmental allergen challenge enhances chitinase activity and levels of CCL18 in mild atopic asthma. Clin Experiment Allergy 43:187–197Google Scholar
  38. Giraud-Guille MM, Bouligand Y (1986) Chitin-protein molecular organization in arthropod. In: Muzzarelli R, Jeuniaux C, Gooday GW (eds.) Chitin in nature and technology, Boston, MA, Springer US, pp 29–35Google Scholar
  39. Glaser L, Brown DH (1957) The synthesis of chitin in cell-free extracts of neurospora crassa. J Biol Chem 228:729–742PubMedGoogle Scholar
  40. Goedken ER, O’Brien RF, Xiang T, Banach DL, Marchie SC, Barlow EH, Hubbard S, Mankovich JA, Jiang J, Richardson PL, Cuff CA, Cherniack AD (2011) Functional comparison of recombinant acidic mammalian chitinase with enzyme from murine bronchoalveolar lavage. Protein Expr Purificat 75:55–62Google Scholar
  41. Gonçalves IR, Brouillet S, Soulié M-C, Gribaldo S, Sirven C, Charron N, Boccara M, Choquer M (2016) Genome-wide analyses of chitin synthases identify horizontal gene transfers towards bacteria and allow a robust and unifying classification into fungi. BMC Evol Biol 16:252CrossRefPubMedPubMedCentralGoogle Scholar
  42. Gooday GW (1990) Physiology of microbial degradation of chitin and chitosan. Biodegradation 1:177–190CrossRefGoogle Scholar
  43. Grabowski GA (2012) Gaucher disease and other storage disorders. ASH Educat Prog Book 2012:13–18Google Scholar
  44. Grabowski GA, Zimran A, Ida H (2015) Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG gaucher registry. Am J Hematol 90:S12–S18CrossRefPubMedGoogle Scholar
  45. Grover A (2012) Plant chitinases: genetic diversity and physiological roles. Crit Rev Plant Sci 31:57–73CrossRefGoogle Scholar
  46. Hamid R, Khan MA, Ahmad M, Ahmad MM, Abdin MZ, Musarrat J, Javed S (2013) Chitinases: an update. J Pharm Bioallied Sci 5:21–29PubMedPubMedCentralGoogle Scholar
  47. Hellwig K, Kvartsberg H, Portelius E, Andreasson U, Oberstein TJ, Lewczuk P, Blennow K, Kornhuber J, Maler JM, Zetterberg H, Spitzer P (2015) Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer’s disease. Alzheimers Res Ther 7:74–74CrossRefPubMedPubMedCentralGoogle Scholar
  48. Henrissat B (1999) Classification of chitinases modulesGoogle Scholar
  49. Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16:358CrossRefPubMedGoogle Scholar
  50. Hollak CE, Van Weely S, Van Oers MH, Aerts JM (1994) Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Investig 93:1288–1292CrossRefPubMedGoogle Scholar
  51. Hong JY, Kim M, Sol IS, Kim KW, Lee C-M, Elias JA, Sohn MH, Lee CG (2018) Chitotriosidase inhibits allergic asthmatic airways via regulation of TGF-β expression and Foxp3 + Treg cells. Allergy 73:1686–1699CrossRefPubMedGoogle Scholar
  52. Houston DR, Eggleston I, Synstad BR, Eijsink VGH, Aalten DMFV (2002) The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate. Biochem J 368:23–27CrossRefPubMedPubMedCentralGoogle Scholar
  53. Houston DR, Recklies AD, Krupa JC, Van Aalten DMF (2003) Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes. J Biol Chem 278:30206–30212CrossRefPubMedGoogle Scholar
  54. Huang Q-S, Xie X-L, Liang G, Gong F, Wang Y, Wei X-Q, Wang Q, Ji Z-L, Chen Q-X (2012) The GH18 family of chitinases: Their domain architectures, functions and evolutions. Glycobiology 22:23–34CrossRefPubMedGoogle Scholar
  55. Hussain M, Wilson JB (2013) New paralogues and revised time line in the expansion of the vertebrate GH18 family. J Mol Evol 76:240–260CrossRefPubMedGoogle Scholar
  56. Ikegami T, Okada T, Hashimoto M, Seino S, Watanabe T, Shirakawa M (2000) Solution structure of the chitin-binding domain of bacillus circulans WL-12 chitinase A1. J Biol Chem 275:13654–13661CrossRefPubMedGoogle Scholar
  57. Imai T, Watanabe T, Yui T, Sugiyama J (2003) The directionality of chitin biosynthesis: a revisit. Biochem J 374:755–760CrossRefPubMedPubMedCentralGoogle Scholar
  58. Izumida H, Imamura N, Sano H (1996) A novel chitinase inhibitor from a marine bacterium, Pseudomonas sp. J Antibiot (Tokyo) 49:76–80CrossRefGoogle Scholar
  59. James AJ, Reinius LE, Verhoek M, Gomes A, Kupczyk M, Hammar U, Ono J, Ohta S, Izuhara K, Bel E, Kere J, Söderhäll C, Dahlén B, Boot RG, Dahlén S-E (2016) Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 193:131–142CrossRefPubMedGoogle Scholar
  60. Janelidze S, Hertze J, Zetterberg H, Landqvist Waldö M, Santillo A, Blennow K, Hansson O (2016) Cerebrospinal fluid neurogranin and YKL-40 as biomarkers of Alzheimer’s disease. Ann Clinic Transl Neurol 3:12–20CrossRefGoogle Scholar
  61. Jensen BV, Johansen JS, Price PA (2003) High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer. Clin Cancer Res 9:4423–4434PubMedGoogle Scholar
  62. Jiang X, Kumar A, Liu T, Zhang KYJ, Yang Q (2016) A novel scaffold for developing specific or broad-spectrum chitinase inhibitors. J Chem Inf Model 56:2413–2420CrossRefPubMedGoogle Scholar
  63. Johansen JS, Schultz NA, Jensen BV (2009) Plasma YKL-40: a potential new cancer biomarker? Fut Oncol 5:1065–1082CrossRefGoogle Scholar
  64. Kang M-J, Yoon CM, Nam M, Kim D-H, Choi J-M, Lee CG, Elias JA (2015) Role of chitinase 3–Like-1 in interleukin-18–induced pulmonary type 1, type 2, and type 17 inflammation; alveolar destruction; and airway fibrosis in the murine lung. Am J Respir Cell Mol Biol 53:863–871CrossRefPubMedPubMedCentralGoogle Scholar
  65. Kim KC, Yun J, Son DJ, Kim JY, Jung JK, Choi JS, Kim YR, Song JK, Kim SY, Kang SK, Shin DH, Roh YS, Han SB, Hong JT (2018) Suppression of metastasis through inhibition of chitinase 3-like 1 expression by miR-125a-3p-mediated up-regulation of USF1. Theranostics 8:4409–4428CrossRefPubMedPubMedCentralGoogle Scholar
  66. Kogiso M, Nishiyama A, Shinohara T, Nakamura M, Mizoguchi E, Misawa Y, Guinet E, Nouri-Shirazi M, Dorey CK, Henriksen RA, Shibata Y (2011) Chitin particles induce size-dependent but carbohydrate-independent innate eosinophilia. J Leukoc Biol 90:167–176CrossRefPubMedPubMedCentralGoogle Scholar
  67. Komi DEA, Kazemi T, Bussink AP (2016) New insights into the relationship between chitinase-3-like-1 and asthma. Curr Allerg Asthma Rep 16:57CrossRefGoogle Scholar
  68. Kramer KJ, Koga D (1986) Insect chitin: Physical state, synthesis, degradation and metabolic regulation. Ins Biochem 16:851–877CrossRefGoogle Scholar
  69. Kumar A, Zhang KYJ (2015) Hierarchical virtual screening approaches in small molecule drug discovery. Methods 71:26–37CrossRefPubMedGoogle Scholar
  70. Kuusk S, Sørlie M, Väljamäe P (2017) Human chitotriosidase is an endo-processive enzyme. PLoS One 12:e0171042–e0171042CrossRefPubMedPubMedCentralGoogle Scholar
  71. Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S (2006) Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 107:3221–3228CrossRefPubMedGoogle Scholar
  72. Langner T, Göhre V (2016) Fungal chitinases: function, regulation, and potential roles in plant/pathogen interactions. Curr Genet 62:243–254CrossRefPubMedGoogle Scholar
  73. Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, Sohn MH, Cohn L, Homer RJ, Kozhich AA, Humbles A, Kearley J, Coyle A, Chupp G, Reed J, Flavell RA, Elias JA (2009) Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis. J Exp Med 206:1149–1166CrossRefPubMedPubMedCentralGoogle Scholar
  74. Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, He CH, Takyar S, Elias JA (2011) Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol 73:479–501Google Scholar
  75. Lenardon MD, Munro CA, Gow NAR (2010) Chitin synthesis and fungal pathogenesis. Curr Opin Microbiol 13:416–423Google Scholar
  76. Létuvé S, Kozhich A, Humbles A, Brewah Y, Dombret M-C, Grandsaigne M, Adle H, Kolbeck R, Aubier M, Coyle AJ, Pretolani M (2010) Lung chitinolytic activity and chitotriosidase are elevated in chronic obstructive pulmonary disease and contribute to lung inflammation. Am J Pathol 176:638–649CrossRefPubMedPubMedCentralGoogle Scholar
  77. Li H, Greene LH (2010) Sequence and structural analysis of the chitinase insertion domain reveals two conserved motifs involved in chitin-binding. PLoS ONE 5:e8654CrossRefPubMedPubMedCentralGoogle Scholar
  78. Livnat G, Bar-Yoseph R, Mory A, Dagan E, Elias N, Gershoni R, Bentur L (2014) Duplication in CHIT1 gene and the risk for aspergillus lung disease in CF patients. Pediatr Pulmonol 49:21–27CrossRefPubMedGoogle Scholar
  79. Lombard V, Golaconda Ramulu H, Drula E, Coutinho PM, Henrissat B (2014) The carbohydrate-active enzymes database (CAZy) in 2013. Nucleic Acids Res 42:D490–D495CrossRefPubMedGoogle Scholar
  80. Ma B, Herzog EL, Lee CG, Peng X, Lee C-M, Chen X, Rockwell S, Koo JS, Kluger H, Herbst RS, Sznol M, Elias JA (2015) Role of chitinase 3–like-1 and semaphorin 7a in pulmonary melanoma metastasis. Can Res 75:487–496CrossRefGoogle Scholar
  81. Malaguarnera L, Di Rosa M, Zambito AM, Dell’ombra N, Nicoletti F, Malaguarnera M (2006) Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut 55:1313–1320CrossRefPubMedPubMedCentralGoogle Scholar
  82. Matsumoto T, Inoue H, Sato Y, Kita Y, Nakano T, Noda N, Eguchi-Tsuda M, Moriwaki A, Kan-O K, Matsumoto K, Shimizu T, Nagasawa H, Sakuda S, Nakanishi Y (2009) Demethylallosamidin, a chitinase inhibitor, suppresses airway inflammation and hyperresponsiveness. Biochem Biophys Res Commun 390:103–108CrossRefPubMedGoogle Scholar
  83. Mattsson N, Tabatabaei S, Johansson P, Hansson O, Andreasson U, Månsson J-E, Johansson J-O, Olsson B, Wallin A, Svensson J, Blennow K, Zetterberg H (2011) Cerebrospinal fluid microglial markers in Alzheimer’s disease: elevated chitotriosidase activity but lack of diagnostic utility. NeuroMol Med 13:151–159CrossRefGoogle Scholar
  84. Mazur M, Bartoszewicz A, Dymek B, Salamon M, Andryianau G, Kowalski M, Olejniczak S, Matyszewski K, Pluta E, Borek B, Stefaniak F, Zagozdzon A, Mazurkiewicz M, Koralewski R, Czestkowski W, Piotrowicz M, Niedziejko P, Gruza MM, Dzwonek K, Golebiowski A, Golab J, Olczak J (2018a) Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase. Bioorg Med Chem Lett 28:310–314CrossRefPubMedGoogle Scholar
  85. Mazur M, Olczak J, Olejniczak S, Koralewski R, Czestkowski W, Jedrzejczak A, Golab J, Dzwonek K, Dymek B, Sklepkiewicz PL, Zagozdzon A, Noonan T, Mahboubi K, Conway B, Sheeler R, Beckett P, Hungerford WM, Podjarny A, Mitschler A, Cousido-Siah A, Fadel F, Golebiowski A (2018b) Targeting acidic mammalian chitinase is effective in animal model of asthma. J Med Chem 61:695–710CrossRefPubMedGoogle Scholar
  86. Mccarter JD, Stephen Withers G (1994) Mechanisms of enzymatic glycoside hydrolysis. Curr Opin Struct Biol 4:885–892CrossRefPubMedGoogle Scholar
  87. Meng G, Zhao Y, Bai X, Liu Y, Green TJ, Luo M, Zheng X (2010) Structure of human Stabilin-1 interacting chitinase-like protein (SI-CLP) reveals a saccharide-binding cleft with lower sugar-binding selectivity. J Biol Chem 285:39898–39904CrossRefPubMedPubMedCentralGoogle Scholar
  88. Merzendorfer H (2006) Insect chitin synthases: a review. J Comp Physiol B 176:1–15CrossRefPubMedGoogle Scholar
  89. Merzendorfer H (2011) The cellular basis of chitin synthesis in fungi and insects: Common principles and differences. Eur J Cell Biol 90:759–769CrossRefPubMedGoogle Scholar
  90. Merzendorfer H, Zimoch L (2003) Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases. J Exp Biol 206:4393–4412CrossRefPubMedGoogle Scholar
  91. Monzingo AF, Marcotte EM, Hart PJ, Robertas JD (1996) Chitinases, chitosanases, and lysozymes can be divided into procaryotic and eucaryotic families sharing a conserved core. Nat Struct Biol 3:133CrossRefPubMedGoogle Scholar
  92. Mora-Montes HM, Netea MG, Ferwerda G, Lenardon MD, Brown GD, Mistry AR, Kullberg BJ, O’Callaghan CA, Sheth CC, Odds FC, Brown AJP, Munro CA, Gow NaR (2011) Recognition and blocking of innate immunity cells by candida albicans chitin. Infect Immun 79:1961–1970Google Scholar
  93. Morgan JLW, Strumillo J, Zimmer J (2012) Crystallographic snapshot of cellulose synthesis and membrane translocation. Nature 493:181CrossRefPubMedPubMedCentralGoogle Scholar
  94. Neville AC, Parry DA, Woodhead-Galloway J (1976) The chitin crystallite in arthropod cuticle. J Cell Sci 21:73PubMedGoogle Scholar
  95. Nikolov S, Petrov M, Lymperakis L, Friák M, Sachs C, Fabritius H-O, Raabe D, Neugebauer J (2010) Revealing the design principles of high-performance biological composites Using Ab initio and multiscale simulations: the example of lobster cuticle. Adv Mater 22:519–526CrossRefPubMedGoogle Scholar
  96. Nishimoto Y, Sakuda S, Takayama S, Yamada Y (1991) Isolation and characterization of new allosamidins. J Antibiot (Tokyo) 44:716–722CrossRefGoogle Scholar
  97. Ohno M, Togashi Y, Tsuda K, Okawa K, Kamaya M, Sakaguchi M, Sugahara Y, Oyama F (2013) Quantification of chitinase mRNA levels in human and mouse tissues by real-time PCR: species-specific expression of acidic mammalian chitinase in stomach tissues. PLoS ONE 8:e67399CrossRefPubMedPubMedCentralGoogle Scholar
  98. Ohno M, Tsuda K, Sakaguchi M, Sugahara Y, Oyama F (2012) Chitinase mRNA levels by quantitative PCR using the single standard DNA: acidic mammalian chitinase is a major transcript in the mouse stomach. PLoS ONE 7:e50381CrossRefPubMedPubMedCentralGoogle Scholar
  99. Ohno T, Armand S, Hata T, Nikaidou N, Henrissat B, Mitsutomi M, Watanabe T (1996) A modular family 19 chitinase found in the prokaryotic organism Streptomyces griseus HUT 6037. J Bacteriol 178:5065–5070CrossRefPubMedPubMedCentralGoogle Scholar
  100. Olland AM, Strand J, Presman E, Czerwinski R, Joseph-Mccarthy D, Krykbaev R, Schlingmann G, Chopra R, Lin L, Fleming M, Kriz R, Stahl M, Somers W, Fitz L, Mosyak L (2009) Triad of polar residues implicated in pH specificity of acidic mammalian chitinase. Protein Sci 18:569–578PubMedPubMedCentralGoogle Scholar
  101. Omura S, Arai N, Yamaguchi Y, Masuma R, Iwai Y, Namikoshi M, Turberg A, Kolbl H, Shiomi K (2000) Argifin, a new chitinase inhibitor, produced by Gliocladium sp. FTD-0668. I. Taxonomy, fermentation, and biological activities. J Antibiot (Tokyo) 53:603–608CrossRefGoogle Scholar
  102. Perrakis A, Tews I, Dauter Z, Oppenheim AB, Chet I, Wilson KS, Vorgias CE (1994) Crystal structure of a bacterial chitinase at 2.3 Å resolution. Structure 2:1169–1180CrossRefPubMedGoogle Scholar
  103. Ranok A, Wongsantichon J, Robinson RC, Suginta W (2015) Structural and thermodynamic insights into chitooligosaccharide binding to human cartilage chitinase 3-like protein 2 (CHI3L2 or YKL-39). J Biol Chem 290:2617–2629CrossRefPubMedGoogle Scholar
  104. Rao FV, Andersen OA, Vora KA, Demartino JA, Van Aalten DMF (2005a) Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes. Chem Biol 12:973–980CrossRefPubMedGoogle Scholar
  105. Rao FV, Houston DR, Boot RG, Aerts JM, Hodkinson M, Adams DJ, Shiomi K, van Aalten DMF (2005b) Specificity and affinity of natural product cyclopentapeptide inhibitors against A. fumigatus, human, and bacterial chitinases. Chem Biol 12:65–76Google Scholar
  106. Rao FV, Houston DR, Boot RG, Aerts JMFG, Sakuda S, Van Aalten DMF (2003) Crystal structures of allosamidin derivatives in complex with human macrophage chitinase. J Biol Chem 278:20110–20116CrossRefPubMedGoogle Scholar
  107. Reese TA, Liang H-E, Tager AM, Luster AD, Van Rooijen N, Voehringer D, Locksley RM (2007) Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447:92CrossRefPubMedPubMedCentralGoogle Scholar
  108. Renkema GH, Boot RG, Au FL, Donker-Koopman WE, Strijland A, Muijsers AO, Hrebicek M, Aerts JMFG (1998) Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem 251:504–509CrossRefPubMedGoogle Scholar
  109. Renkema GH, Boot RG, Muijsers AO, Donker-Koopman WE, Aerts JMFG (1995) Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins. J Biol Chem 270:2198–2202CrossRefPubMedGoogle Scholar
  110. Renkema GH, Boot RG, Strijland A, Donker-Koopman WE, Berg M, Muijsers AO, Aerts JMFG (1997) Synthesis, sorting, and processing into distinct isoforms of human macrophage chitotriosidase. Eur J Biochem 244:279–285CrossRefPubMedGoogle Scholar
  111. Rinaudo M (2006) Chitin and chitosan: properties and applications. Prog Polym Sci 31:603–632CrossRefGoogle Scholar
  112. Roy RM, Wüthrich M, Klein BS (2012) Chitin elicits CCL2 from airway epithelial cells and induces CCR112-dependent innate allergic inflammation in the lung. J Immunol 189:2545–2552CrossRefPubMedPubMedCentralGoogle Scholar
  113. Rudall KM, Kenchington W (1973) The chitin system. Biol Rev 48:597–633CrossRefGoogle Scholar
  114. Sakuda S, Isogai A, Makita T, Matsumoto S, Koseki K, Kodama H, Suzuki A (1987a) Structures of allosamidins, novel insect chitinase inhibitors, produced by actinomycetes. Agric Biol Chem 51:3251–3259Google Scholar
  115. Sakuda S, Isogai A, Matsumoto S, Suzuki A (1987b) Search for microbial insect growth-regulators. 2. Allosamidin, a novel insect chitinase inhibitor. J Antibiot 40:296–300CrossRefPubMedGoogle Scholar
  116. Sakuda S, Isogai A, Matsumoto S, Suzuki A, Koseki K (1986) The structure of allosamidin, a novel insect chitinase inhibitor, produced by streptomyces Sp. Tetrahedron Lett 27:2475–2478CrossRefGoogle Scholar
  117. Sakuda S, Isogai A, Matsumoto S, Suzuki A, Koseki K, Kodama H, Yamada Y (1988) Absolute configuration of allosamizoline, an aminocyclitol derivative of the chitinase inhibitor allosamidin. Agric Biol Chem 52:1615–1617Google Scholar
  118. Sakuda S, Isogai A, Suzuki A, Yamada Y (1993) Chemistry and biochemistry of the chitinase inhibitors, allosamidins. Actinomycetologica 7:50–57CrossRefGoogle Scholar
  119. Sakuda S, Sugiyama Y, Zhou Z-Y, Takao H, Ikeda H, Kakinuma K, Yamada Y, Nagasawa H (2001) biosynthetic studies on the cyclopentane ring formation of allosamizoline, an aminocyclitol component of the chitinase inhibitor allosamidin. J Organ Chem 66:3356–3361CrossRefGoogle Scholar
  120. Schimpl M, Rush CL, Betou M, Eggleston IM, Recklies AD, Van Aalten DM (2012) Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties. Biochem J 446:149–157Google Scholar
  121. Schüttelkopf AW, Andersen OA, Rao FV, Allwood M, Lloyd C, Eggleston IM, Van Aalten DMF (2006) Screening-based discovery and structural dissection of a novel family 18 chitinase inhibitor. J Biol Chem 281:27278–27285CrossRefPubMedGoogle Scholar
  122. Schüttelkopf AW, Andersen OA, Rao FV, Allwood M, Rush CL, Eggleston IM, Van Aalten DMF (2011) Bisdionin C—A rationally designed, submicromolar inhibitor of family 18 chitinases. ACS Med Chem Lett 2:428–432CrossRefPubMedPubMedCentralGoogle Scholar
  123. Seibold MA, Donnelly S, Solon M, Innes A, Woodruff PG, Boot RG, Burchard EG, Fahy JV (2008) Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit. J Allergy Clin Immunol 122:944–950.e943CrossRefPubMedPubMedCentralGoogle Scholar
  124. Semeňuk T, Krist P, Pavlíček J, Bezouška K, Kuzma M, Novák P, Křen V (2001) Synthesis of chitooligomer-based glycoconjugates and their binding to the rat natural killer cell activation receptor NKR-P1. Glycoconj J 18:817–826CrossRefPubMedGoogle Scholar
  125. Shen C-R, Juang H-H, Chen H-S, Yang C-J, Wu C-J, Lee M-H, Hwang Y-S, Kuo M-L, Chen Y-S, Chen J-K, Liu C-L (2015) The correlation between chitin and acidic mammalian chitinase in animal models of allergic asthma. Int J Mol Sci 16:27371–27377CrossRefPubMedPubMedCentralGoogle Scholar
  126. Shibata Y, Metzger WJ, Myrvik QN (1997) Chitin particle-induced cell-mediated immunity is inhibited by soluble mannan: mannose receptor-mediated phagocytosis initiates IL-12 production. J Immunol 159:2462–2467Google Scholar
  127. Shuhui L, Mok YK, Wong WSF (2009) Role of mammalian chitinases in asthma. Int Arch Allergy Immunol 149:369–377CrossRefPubMedGoogle Scholar
  128. Song H-M, Jang A-S, Ahn M-H, Takizawa H, Lee S-H, Kwon J-H, Lee Y-M, Rhim T, Park C-S (2008) Ym1 and Ym2 expression in a mouse model exposed to diesel exhaust particles. Environ Toxicol 23:110–116CrossRefPubMedGoogle Scholar
  129. Songsiriritthigul C, Pantoom S, Aguda AH, Robinson RC, Suginta W (2008) Crystal structures of Vibrio harveyi chitinase A complexed with chitooligosaccharides: Implications for the catalytic mechanism. J Struct Biol 162:491–499CrossRefPubMedGoogle Scholar
  130. Stam MR, Blanc E, Coutinho PM, Henrissat B (2005) Evolutionary and mechanistic relationships between glycosidases acting on α- and β-bonds. Carbohyd Res 340:2728–2734CrossRefGoogle Scholar
  131. Stefano S, Piras MR, Rita B, Giannina A, Fois ML, Giulio R, Salvatore M (2007) Chitotriosidase and Alzheimers disease. Curr Alzheimer Res 4:295–296CrossRefGoogle Scholar
  132. Sutherland TE (2018) Chitinase-like proteins as regulators of innate immunity and tissue repair: helpful lessons for asthma? Biochem Soc Trans 46:141–151CrossRefPubMedGoogle Scholar
  133. Sutherland TE, Andersen OA, Betou M, Eggleston IM, Maizels RM, van Aalten D, Allen JE (2011) Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chem Biol 18:569–579Google Scholar
  134. Terwisscha Van Scheltinga AC, Armand S, Kalk KH, Isogai A, Henrissat B, Dijkstra BW (1995) Stereochemistry of chitin hydrolysis by a plant chitinase/lysozyme and x-ray structure of a complex with allosamidin evidence for substrate assisted catalysis. Biochemistry 34:15619–15623CrossRefPubMedGoogle Scholar
  135. Tews I, Terwisscha Van Scheltinga AC, Perrakis A, Wilson KS, Dijkstra BW (1997) Substrate-assisted catalysis unifies two families of chitinolytic enzymes. J Am Chem Soc 119:7954–7959CrossRefGoogle Scholar
  136. Thomsen T, Schlosser A, Holmskov U, Sorensen GL (2011) Ficolins and FIBCD1: Soluble and membrane bound pattern recognition molecules with acetyl group selectivity. Mol Immunol 48:369–381CrossRefGoogle Scholar
  137. Tsai M-L, Liaw S-H, Chang N-C (2004) The crystal structure of Ym1 at 1.31Å resolution. J Struct Biol 148:290–296CrossRefPubMedGoogle Scholar
  138. Van Aalten DMF, Komander D, Synstad B, Gåseidnes S, Peter MG, Eijsink VGH (2001) Structural insights into the catalytic mechanism of a family 18 exo-chitinase. Proc Natl Acad Sci 98:8979–8984CrossRefPubMedGoogle Scholar
  139. Van Aalten DMF, Synstad B, Brurberg MB, Hough E, Riise BW, Eijsink VGH, Wierenga RK (2000) Structure of a two-domain chitotriosidase from Serratia marcescens at 1.9-Å resolution. Proc Natl Acad Sci 97:5842–5847CrossRefPubMedGoogle Scholar
  140. Van Dussen L, Hendriks EJ, Groener JEM, Boot RG, Hollak CEM, Aerts JMFG (2014) Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J Inherit Metab Dis 37:991–1001CrossRefPubMedGoogle Scholar
  141. Van Dyken SJ, Liang H-E, Naikawadi RP, Woodruff PG, Wolters PJ, Erle DJ, Locksley RM (2017) Spontaneous chitin accumulation in airways and age-related fibrotic lung disease. Cell 169:497–509.e413CrossRefPubMedPubMedCentralGoogle Scholar
  142. Van Dyken SJ, Mohapatra A, Nussbaum JC, Molofsky AB, Thornton EE, Ziegler SF, McKenzie AN, Krummel MF, Liang HE, Locksley RM (2014) Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40:414–424Google Scholar
  143. Vermeulen CA, Wessels JGH (1986) Chitin biosynthesis by a fungal membrane preparation. Eur J Biochem 158:411–415CrossRefPubMedGoogle Scholar
  144. Veronico P, Gray L, Jones J, Bazzicalupo P, Arbucci S, Cortese M, Di Vito M, De Giorgi C (2001) Nematode chitin synthases: gene structure, expression and function in Caenorhabditis elegans and the plant parasitic nematode Meloidogyne artiellia. Mol Genet Genom 266:28–34CrossRefGoogle Scholar
  145. Von Arnim C, Watabe-Rudolph M, Song Z, Schnack C, Begus-Nahrmann Y, Rolyan H, Otto M, Tumani H, Thal D, Attems J, Jellinger K, Kestler H, Rudolph K (2011) Chitinase enzyme activity in cerebral spinal fluid is strongly associated with Alzheimer’s Disease. Alzheimer’s Dementia 7:S288CrossRefGoogle Scholar
  146. Wajner A, Michelin K, Burin MG, Pires RF, Pereira MLS, Giugliani R, Coelho JC (2004) Biochemical characterization of chitotriosidase enzyme: comparison between normal individuals and patients with Gaucher and with Niemann-Pick diseases. Clin Biochem 37:893–897CrossRefPubMedGoogle Scholar
  147. Wakasugi M, Gouda H, Hirose T, Sugawara A, Yamamoto T, Shiomi K, Sunazuka T, Ōmura S, Hirono S (2013) Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening. Bioorg Med Chem 21:3214–3220CrossRefPubMedGoogle Scholar
  148. Wang X, Yu W, Fu X, Ke M, Xiao Q, Lü Y (2018) Chitotriosidase enhances TGFβ-Smad signaling and uptake of β-amyloid in N9 microglia. Neurosci Lett 687:99–103CrossRefPubMedGoogle Scholar
  149. Watabe-Rudolph M, Song Z, Lausser L, Schnack C, Begus-Nahrmann Y, Scheithauer M-O, Rettinger G, Otto M, Tumani H, Thal DR, Attems J, Jellinger KA, Kestler HA, Von Arnim CaF, Rudolph KL (2012) Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease. Neurology 78:569–577Google Scholar
  150. Yang C-J, Liu Y-K, Liu C-L, Shen C-N, Kuo M-L, Su C-C, Tseng C-P, Yen T-C, Shen C-R (2009) Inhibition of acidic mammalian chitinase by RNA interference suppresses ovalbumin-sensitized allergic asthma. Hum Gene Ther 20:1597–1606CrossRefPubMedGoogle Scholar
  151. Yang J, Gan Z, Lou Z, Tao N, Mi Q, Liang L, Sun Y, Guo Y, Huang X, Zou C, Rao Z, Meng Z, Zhang K-Q (2010) Crystal structure and mutagenesis analysis of chitinase CrChi1 from the nematophagous fungus Clonostachys rosea in complex with the inhibitor caffeine. Microbiology 156:3566–3574CrossRefPubMedGoogle Scholar
  152. Zhang H, Ng KP, Therriault J, Kang MS, Pascoal TA, Rosa-Neto P, Gauthier S, Initiative TaSDN, Aging NIO, Imaging NIOB, Bioengineering, Abbvie ASA, Foundation ASDD, Biotech A, Bioclinica I, Biogen Company B-MS, Cerespir I, Inc., CE Elan Pharmaceuticals, I Lilly, E, Company, Euroimmun, Hoffmann-La, F., Ltd., R., Its Affiliated Company Genentech, I., Fujirebio, Healthcare G, Ltd., I, Research, JaI Development, L, Johnson, Research JP, Llc., D, Lumosity Lundbeck Merck Co., I, Meso Scale Diagnostics L, Research N, Technologies N, Corporation, NP, Inc. P, Imaging P, Servier, Company TP, Therapeutics T, Research, CIOH, Health, FFTNIO (2018) Cerebrospinal fluid phosphorylated tau, visinin-like protein-1, and chitinase-3-like protein 1 in mild cognitive impairment and Alzheimer’s disease. Transl Neurodegenerat 7, 23Google Scholar
  153. Zhao J, Zhu H, Wong CH, Leung KY, Wong WSF (2005) Increased lungkine and chitinase levels in allergic airway inflammation: a proteomics approach. Proteomics 5:2799–2807CrossRefPubMedPubMedCentralGoogle Scholar
  154. Zheng T, Rabach M, Chen NY, Rabach L, Hu X, Elias JA, Zhu Z (2005) Molecular cloning and functional characterization of mouse chitotriosidase. Gene 357:37–46CrossRefPubMedGoogle Scholar
  155. Zhou Y, Peng H, Sun H, Peng X, Tang C, Gan Y, Chen X, Mathur A, Hu B, Slade MD, Montgomery RR, Shaw AC, Homer RJ, White ES, Lee C-M, Moore MW, Gulati M, Geun Lee C, Elias JA, Herzog EL (2014) Chitinase 3–Like 1 suppresses injury and promotes fibroproliferative responses in mammalian lung fibrosis. Sci Transl Med 6:240ra276-240ra276CrossRefGoogle Scholar
  156. Zhu Z, Zheng T, Homer RJ, Kim Y-K, Chen NY, Cohn L, Hamid Q, Elias JA (2004) Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304:1678–1682Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Laboratory for Structural BioinformaticsCenter for Biosystems Dynamics Research, RIKENTsurumi, YokohamaJapan

Personalised recommendations