Journal:Acta Cryst D:S2059798324005461

Toward a dependable data set of structures for L-asparaginase

Alexander Wlodawer, Zbigniew Dauter, Jacek Lubkowski, Joanna I. Loch, Dariusz Brzezinski, Miroslaw Gilski, Mariusz Jaskolski ^[1]

Molecular Tour

L-Asparaginase (ASNase) catalyzes the hydrolysis of L-Asn to L-Asp, according to the reaction: ASNase + L-Asn + H2O → ASNase + L-Asp + NH3

Most ASNases have at least residual glutaminolytic activity, which in some cases exceeds the asparaginolytic activity and is often associated with the name glutaminase-asparaginase. Whereas first identified in a mammalian source, these enzymes were also found in bacteria, archaea, and eukarya. Members of the ASNase family primarily catalyze the hydrolysis of unmodified L-Asn. There are several groups of ASNases, defined by such factors as the source organism, amino acid sequence, 3D structure, substrate-specificity, biophysical properties, etc. So far, three completely different structural Classes of ASNases have been identified, originally named according to the source organism of their isolation, namely Class 1 (bacterial-type), Class 2 (plant-type), and Class 3 (Rhizobium etli-type). This new 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, there are two types 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).

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). Since the late 1970s, Class 1 type II L-asparaginases of bacterial origin have been used in the clinical treatment of ALL, and there are recent reports that ASNases could be effective against solid tumors as well. However, in view of the frequent severe side effects accompanying current administration protocols, it is not surprising that significant research effort has been directed into engineering the other types of ASNases into useful drugs. Thus, careful analysis of all known structures of ASNases, with the view of indicating enzymes with potential for becoming novel therapeutics, is still very important.

Dependable Structures

References

1. ↑ Wlodawer A, Dauter Z, Lubkowski J, Loch JI, Brzezinski D, Gilski M, Jaskolski M. Towards a dependable data set of structures for L-asparaginase research. Acta Crystallogr D Struct Biol. 2024 Jul 1;80(Pt 7):506-527. PMID:38935343 doi:10.1107/S2059798324005461