Detailed mechanism of catalysis by tetrameric L-glutaminase-asparaginase from Pseudomonas 7A (PGA)

Presented During:

07/31/2022: 5:30 PM - 7:30 PM
Portland Marriott Downtown Waterfront  

Conference:

2022: 72nd ACA Annual Meeting

Session Type:

Poster 

Presenting Author :

Pawel Strzelczyk  
Center for Structural Biology, Center for Cancer Research, National Cancer Institute

Additional Author(s):

Di Zhang  
Center for Structural Biology, Center for Cancer Research, National Cancer Institute
Marzena Dyba  
Center for Structural Biology, Center for Cancer Research, National Cancer Institute
Alexander Wlodawer  
Center for Structural Biology, Center for Cancer Research, National Cancer Institute
Jacek Lubkowski  
Center for Structural Biology, Center for Cancer Research, National Cancer Institute

Abstract Body:

L-asparaginases (EC 3.5.1.1) are widely distributed enzymes among both bacterial and eukaryotic organisms. For over 40 years, L-asparaginases have played a critical role in the treatment of juvenile leukemias and lymphomas. Their primary biochemical function is to catalyze the hydrolysis of L-Asn to L-Asp. Most L-asparaginases also catalyze the hydrolysis of L-Gln to L-Glu, and those that exhibit glutaminase activity that is comparable or higher than asparaginase activity are often referred to as glutaminases-asparaginases. Based on extensive structural and functional studies of L-glutaminase-asparaginase from Pseudomonas 7A (PGA), we were able to show unequivocally that the reaction catalyzed by this enzyme proceeds through formation of a covalent intermediate and utilizes a common ping-pong catalytic mechanism consisting of two subsequent nucleophilic substitutions, as previously observed for EcAII. Additionally, by confirming that the same mechanism applies to L-Asn and L-Gln, we postulate that it is common for all these structurally related enzymes. Detailed structural studies of PGA and its complexes with substrates should create a foundation for rational development of L-asparaginases with modulated relative activities vs. L-Asn or L-Gln, which may be beneficial toward the development of improved anti-leukemia therapeutics.

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