Year-end Sale % OFF 
Abstract
l-Asparaginases have remained an intriguing research topic since their discovery ∼120 years ago, especially after their introduction in the 1960s as very efficient antileukemic drugs. In addition to bacterial asparaginases, which are still used to treat childhood leukemia, enzymes of plant and mammalian origin are now also known. They have all been structurally characterized by crystallography, in some cases at outstanding resolution. The structural data have also shed light on the mechanistic details of these deceptively simple enzymes. Yet, despite all this progress, no better therapeutic agents have been found to beat bacterial asparaginases. However, a new option might arise with the discovery of yet another type of asparaginase, those from symbiotic nitrogen-fixing Rhizobia, and with progress in the protein engineering of enzymes with desired properties. This review surveys the field of structural biology of l-asparaginases, focusing on the mechanistic aspects of the well established types and speculating about the potential of the new members of this amazingly diversified family.
Highlights
This review is dedicated to Dr Alexander Wlodawer, who pioneered the field of structural biology of antileukemic L-asparaginases
On the basis of structural and kinetic data, two general catalytic mechanisms have been proposed for Class 1 asparaginases: a single-displacement mechanism was proposed for the mammalian CpAI (Schalk et al, 2016) and a double-displacement mechanism was proposed for bacterial enzymes sensu stricto (Lubkowski & Wlodawer, 2019), which is supposed to proceed via a covalent acyl-enzyme intermediate (Palm et al, 1996)
The same arrangement of hydrogen bonds exists in the free enzyme and in enzyme– product complexes, so the binding of a substrate/product in the active site does not seem to affect the conformation of the catalytic residues. (101)Thr acts as the Ntn-nucleophile, i.e. is the N-terminal residue of subunit ( -strand S1; Fig. 7), (102)Thr is located in -strand S2 and (103)Thr is positioned at -strand S3
Summary
Asparaginases (EC 3.5.1.1) are amidohydrolases that catalyze hydrolysis at the side chain of l-asparagine to release l-aspartate and ammonia. The large-scale use of guinea pig serum in leukemia treatment was not possible, but in 1964 a similar tumor inhibitory effect was reported for Escherichia coli asparaginase (Mashburn & Wriston, 1964) These discoveries opened an era of intensive biochemical and structural studies of l-asparaginases, as l-Asn is vital for the survival of some cancer cells (Luo et al, 2018). L-asparaginases are divided into three structural classes: bacterial-type, plant-type (Michalska et al, 2006) and Rhizobium etli-type (Borek & Jaskolski, 2001) (Fig. 2) This classification, which is based on the sources of the first enzymes that were discovered, may be misleading (see Section 2). A new class of asparaginases was established early on, but its structural confirmation has only just begun to emerge (Loch et al, unpublished work)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
