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Many side effects of current FDA-approved L-asparaginases have been related to their secondary L-glutaminase activity. The  Wolinella succinogenes  L-asparaginase ( Wo A) has been reported to be L-glutaminase free, suggesting it would have fewer side effects. Unexpectedly, the  Wo A variant with a proline at position 121 ( Wo A-P 121 ) was found to have L-glutaminase activity in contrast to Uniprot entry P50286 ( Wo A-S 121 ) that has a serine residue at this position. Towards understanding how this residue impacts the L-glutaminase property, kinetic analysis was coupled with crystal structure determination of these  Wo A variants.  Wo A-S 121  was confirmed to have much lower L-glutaminase activity than  Wo A-P 121 , yet both showed comparable L-asparaginase activity. Structures of the  Wo A variants in complex with L-aspartic acid versus L-glutamic acid provide insights into their differential substrate selectivity. Structural analysis suggests a mechanism by which residue 121 impacts the conformation of the conserved tyrosine 27, a component of the catalytically-important flexible N-terminal loop. Surprisingly, we could fully model this loop in either its open or closed conformations, revealing the roles of specific residues of an evolutionary conserved motif among this L-asparaginase family. Together, this work showcases critical residues that influence the ability of the flexible N-terminal loop for adopting its active conformation, thereby effecting substrate specificity.

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The differential ability of asparagine and glutamine in promoting the closed/active enzyme conformation rationalizes the Wolinella succinogenes L-asparaginase substrate specificity