Asparaginase

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Contents

Function

L-Asparaginases are enzymes that hydrolyze the amide group of the amino acid L-asparagine (L-Asn) to L-aspartate, with the simultaneous release of ammonia. They are often referred to as ASNase and assigned the EC number 3.5.1.1; if significant glutaminase co-activity (hydrolysis of the similar amino acid L-glutamine) is also present, the EC number is 3.5.1.38. Some ASNases that belong to other classes (see below) are assigned EC 3.4.19.5.

  • Glycosylasparaginase hydrolyzes the bond between asparagine and the sugar moiety in N-linked glycoproteins[1].
  • Isoaspartyl peptidase/L-asparaginase enables aparaginase and beta-aspartyl-peptidase activity. Invovved in asparagine catabolic process via L-Asp [2].

Relevance

Beyond pure academic curiosity, ASNases are also studied because of their potential application as first-line drugs for the treatment of acute lymphoblastic leukemia (ALL) [1-4][3][4][5][6]. By clearing L-asparagine from circulation, they starve the L-Asn-dependent malignant cells to death, while sparing the L-Asn-independent healthy cells. The first L-asparaginase introduced for clinical treatment of ALL was Elspar (EcAII from E. coli), followed by Erwinase (ErA from E. chrysanthemi). ASNases are also used in food industry to prevent the formation of acrylamide from L-Asn in fried starch foods[7][8].

Division of ASNases into three classes

So far, three completely different structural classes of ASNases have been identified[9], originally named according to the source organism of their isolation[10], namely Class 1 (bacterial-type), Class 2 (plant-type), and Class 3 (Rhizobium etli-type). This newer classification is intersected with an older convention, which divided the known enzymes with L-asparaginase activity into five types, since in both, Class 1 and Class 3, two types are distinguished according to their compartmentalization and expression profile. The prototypes of types I and II (in Class 1), and III (in Class 2), are the E. coli enzymes EcAI (cytosolic), EcAII (periplasmic), and EcAIII (also cytosolic), respectively. The prototypes of types IV and V (Class 3) are the R. etli enzymes ReAIV (constitutive) and ReAV (inducible).

Structural studies

The first L-asparaginase structure was published and deposited in the PDB in 1993 for the EcAII enzyme [11] and may serve as an example of a Class 1 type II enzyme EcAII. Structure of Class 1 type I enzymes is exemplified by EcAI[12], whereas Class 2 type III enzymes may be represented by EcAIII[13][14]. Class 2 L-asparaginases belong to the family of Ntn-hydrolases, which are expressed as inactive precursors that must undergo autoproteolytic cleavage into α and β subunits to achieve maturation[15]. While the existence of an alien type of ASNase in the symbiotic nitrogen-fixing bacterium Rhizobium etli had been recognized long ago[16], the structure of the iducible and thermolabile prototype Class 3 ReAV was solved and deposited in the PDB only recently[17], followed by structures of the constitutive and thermostable isoform ReAIV[18]. More than 200 structures of ASNases have been deposited in the Protein Data Bank (PDB) by April 2024[19][20].

Evaluation of the ASNase structures in the PDB

Evaluation of 189 structures of ASNases that were present in the PDB as of November 2023 was described in Wlodawer et al. (2024)[20]. Most structures did not raise any significant concerns. However, 30 models had various kinds of stereochemical problems and/or doubtful agreement with the experimental electron density maps. Consequently, they were re-refined in order to remove the shortcomings. The revised models (listed here) may be downloaded from this site in both the legacy PDB and mmCIF formats.


3D structures of asparaginase

Asparaginase 3D structures


First Asparaginase structure (Class_II - [3eca]) dimer, 3eca

Drag the structure with the mouse to rotate

References

  1. ↑ Park H, Vettese-Dadey M, Aronson NN Jr. Glycosylation and phosphorylation of lysosomal glycosylasparaginase. Arch Biochem Biophys. 1996 Apr 1;328(1):73-7. PMID:8638940 doi:10.1006/abbi.1996.0144
  2. ↑ Prahl A, Pazgier M, Hejazi M, Lockau W, Lubkowski J. Structure of the isoaspartyl peptidase with L-asparaginase activity from Escherichia coli. Acta Crystallogr D Biol Crystallogr. 2004 Jun;60(Pt 6):1173-6. Epub 2004, May 21. PMID:15159592 doi:10.1107/S0907444904003403
  3. ↑ Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016 Apr-Jun;7(2):62-71. PMID:27440950 doi:10.4103/0976-500X.184769
  4. ↑ Beckett A, Gervais D. What makes a good new therapeutic L-asparaginase? World J Microbiol Biotechnol. 2019 Sep 24;35(10):152. PMID:31552479 doi:10.1007/s11274-019-2731-9
  5. ↑ Ghasemian A, Al-Marzoqi AH, Al-Abodi HR, Alghanimi YK, Kadhum SA, Shokouhi Mostafavi SK, Fattahi A. Bacterial l-asparaginases for cancer therapy: Current knowledge and future perspectives. J Cell Physiol. 2019 Nov;234(11):19271-19279. PMID:30993718 doi:10.1002/jcp.28563
  6. ↑ Chan WK, Horvath TD, Tan L, Link T, Harutyunyan KG, Pontikos MA, Anishkin A, Du D, Martin LA, Yin E, Rempe SB, Sukharev S, Konopleva M, Weinstein JN, Lorenzi PL. Glutaminase Activity of L-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia. Mol Cancer Ther. 2019 Sep;18(9):1587-1592. PMID:31209181 doi:10.1158/1535-7163.MCT-18-1329
  7. ↑ Hendriksen HV, Kornbrust BA, Østergaard PR, Stringer MA. Evaluating the potential for enzymatic acrylamide mitigation in a range of food products using an asparaginase from Aspergillus oryzae. J Agric Food Chem. 2009 May 27;57(10):4168-76. PMID:19388639 doi:10.1021/jf900174q
  8. ↑ Chand S, Mahajan RV, Prasad JP, Sahoo DK, Mihooliya KN, Dhar MS, Sharma G. A comprehensive review on microbial l-asparaginase: Bioprocessing, characterization, and industrial applications. Biotechnol Appl Biochem. 2020 Jul;67(4):619-647. PMID:31954377 doi:10.1002/bab.1888
  9. ↑ Loch JI, Jaskolski M. Structural and biophysical aspects of l-asparaginases: a growing family with amazing diversity. IUCrJ. 2021 Jun 30;8(Pt 4):514-531. PMID:34258001 doi:10.1107/S2052252521006011
  10. ↑ Michalska K, Jaskolski M. Structural aspects of L-asparaginases, their friends and relations. Acta Biochim Pol. 2006;53(4):627-40. Epub 2006 Dec 1 PMID:17143335
  11. ↑ Swain AL, Jaskolski M, Housset D, Rao JK, Wlodawer A. Crystal structure of Escherichia coli L-asparaginase, an enzyme used in cancer therapy. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1474-8. PMID:8434007
  12. ↑ Yun MK, Nourse A, White SW, Rock CO, Heath RJ. Crystal structure and allosteric regulation of the cytoplasmic Escherichia coli L-asparaginase I. J Mol Biol. 2007 Jun 8;369(3):794-811. Epub 2007 Mar 30. PMID:17451745 doi:http://dx.doi.org/10.1016/j.jmb.2007.03.061
  13. ↑ Prahl A, Pazgier M, Hejazi M, Lockau W, Lubkowski J. Structure of the isoaspartyl peptidase with L-asparaginase activity from Escherichia coli. Acta Crystallogr D Biol Crystallogr. 2004 Jun;60(Pt 6):1173-6. Epub 2004, May 21. PMID:15159592 doi:10.1107/S0907444904003403
  14. ↑ Michalska K, Hernandez-Santoyo A, Jaskolski M. The mechanism of autocatalytic activation of plant-type L-asparaginases. J Biol Chem. 2008 May 9;283(19):13388-97. Epub 2008 Mar 10. PMID:18334484 doi:10.1074/jbc.M800746200
  15. ↑ Linhorst A, Lübke T. The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives. Cells. 2022 May 10;11(10):1592. PMID:35626629 doi:10.3390/cells11101592
  16. ↑ Borek D, Jaskólski M. Sequence analysis of enzymes with asparaginase activity. Acta Biochim Pol. 2001;48(4):893-902 PMID:11996000
  17. ↑ Loch JI, Imiolczyk B, Sliwiak J, Wantuch A, Bejger M, Gilski M, Jaskolski M. Crystal structures of the elusive Rhizobium etli L-asparaginase reveal a peculiar active site. Nat Commun. 2021 Nov 18;12(1):6717. doi: 10.1038/s41467-021-27105-x. PMID:34795296 doi:http://dx.doi.org/10.1038/s41467-021-27105-x
  18. ↑ Loch JI, Worsztynowicz P, Sliwiak J, Grzechowiak M, Imiolczyk B, Pokrywka K, Chwastyk M, Gilski M, Jaskolski M. Rhizobium etli has two L-asparaginases with low sequence identity but similar structure and catalytic center. Acta Crystallogr D Struct Biol. 2023 Aug 1;79(Pt 8):775-791. PMID:37494066 doi:10.1107/S2059798323005648
  19. ↑ Lubkowski J, Wlodawer A. Structural and biochemical properties of L-asparaginase. FEBS J. 2021 Jul;288(14):4183-4209. PMID:34060231 doi:10.1111/febs.16042
  20. ↑ 20.0 20.1 Wlodawer, A., Dauter, Z., Lubkowski, J., Loch, J.I., Brzezinski, D., Gilski, M., Jaskolski, M. (2024) Toward a dependable dataset of structures for L-asparaginase research(submitted).

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