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Geometric considerations support the double-displacement catalytic mechanism of l-asparaginase.

Lubkowski J, Wlodawer A
Protein Sci 28 1850-1864 (2019)
Related entries: 6pa2, 6pa3, 6pa4, 6pa5, 6pa6, 6pa8, 6pa9, 6paa, 6pab, 6pae

Cited: 11 times
EuropePMC logo PMID: 31423681

Abstract

Twenty crystal structures of the complexes of l-asparaginase with l-Asn, l-Asp, and succinic acid that are currently available in the Protein Data Bank, as well as 11 additional structures determined in the course of this project, were analyzed in order to establish the level of conservation of the geometric parameters describing interactions between the substrates and the active site of the enzymes. We found that such stereochemical relationships are highly conserved, regardless of the organism from which the enzyme was isolated, specific crystallization conditions, or the nature of the ligands. Analysis of the geometry of the interactions, including Bürgi-Dunitz and Flippin-Lodge angles, indicated that Thr12 (Escherichia coli asparaginase II numbering) is optimally placed to be the primary nucleophile in the most likely scenario utilizing a double-displacement mechanism, whereas catalysis through a single-displacement mechanism appears to be the least likely.

Articles - 6pac mentioned but not cited (3)

  1. Geometric considerations support the double-displacement catalytic mechanism of l-asparaginase. Lubkowski J, Wlodawer A. Protein Sci 28 1850-1864 (2019)
  2. Generalized enzymatic mechanism of catalysis by tetrameric L-asparaginases from mesophilic bacteria. Strzelczyk P, Zhang D, Dyba M, Wlodawer A, Lubkowski J. Sci Rep 10 17516 (2020)
  3. The E. coli L-asparaginase V27T mutant: structural and functional characterization and comparison with theoretical predictions. Strzelczyk P, Zhang D, Wlodawer A, Lubkowski J. FEBS Lett 596 3060-3068 (2022)


Reviews citing this publication (2)

  1. Structural and biophysical aspects of l-asparaginases: a growing family with amazing diversity. Loch JI, Jaskolski M. IUCrJ 8 514-531 (2021)
  2. Engineering and Expression Strategies for Optimization of L-Asparaginase Development and Production. Shishparenok AN, Gladilina YA, Zhdanov DD. Int J Mol Sci 24 15220 (2023)

Articles citing this publication (6)

  1. Improving the Treatment of Acute Lymphoblastic Leukemia. Radadiya A, Zhu W, Coricello A, Alcaro S, Richards NGJ. Biochemistry 59 3193-3200 (2020)
  2. Selection of the Optimal L-asparaginase II Against Acute Lymphoblastic Leukemia: An In Silico Approach. Baral A, Gorkhali R, Basnet A, Koirala S, Bhattarai HK. JMIRx Med 2 e29844 (2021)
  3. Identification and characterization of the key enzyme in the biosynthesis of the neurotoxin β-ODAP in grass pea. Goldsmith M, Barad S, Knafo M, Savidor A, Ben-Dor S, Brandis A, Mehlman T, Peleg Y, Albeck S, Dym O, Ben-Zeev E, Barbole RS, Aharoni A, Reich Z. J Biol Chem 298 101806 (2022)
  4. Insights into the Distribution and Functional Properties of l-Asparaginase in the Archaeal Domain and Characterization of Picrophilus torridus Asparaginase Belonging to the Novel Family Asp2like1. Sharma A, Kaushik V, Goel M. ACS Omega 7 40750-40765 (2022)
  5. Revealing Escherichia coli type II L-asparaginase active site flexible loop in its open, ligand-free conformation. Maggi M, Meli M, Colombo G, Scotti C. Sci Rep 11 18885 (2021)
  6. Structural Aspects of E. coli Type II Asparaginase in Complex with Its Secondary Product L-Glutamate. Maggi M, Scotti C. Int J Mol Sci 23 5942 (2022)


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