Glutaminase-Asparaginase (Pseudomonas 7A)

Function

L-asparaginase is an enzyme that converts L-asparagine into asparctic acid and ammonia. In adition this enzyme have a side activity analogous to previous one, which is the catalysis of D-glutamine into glutamate and ammonia.

Disease

Lymphoblastic Acute Leukemia, is a blood cancer that affects mainly childs (2-5 age); consists of non-controled proliferation of lymphocytic lineages since lymphoblasts to younges lymphocitic cells.

Relevance

Cancer cells are unable to perform synthesis of L-asparagine due to the lack of Asparagine Synthetase enzyme, which means that all source of L-asparagine is exogenous, unlike normal cells that can synthesize their own L-asparagine. When bacterial L-asparaginase is injected into the bloodstream, circulating L-asparagine is depleted, so cancer cells become unable to perform protein synthesis, that leads affected cells to apoptosis without harm to normal cells.

Structural highlights

Pseudomonas 7A Glutaminase-Asparaginase (PGA) consists of a tetrameric structure. Each is identical and possesses 337 residues. In the amminoterminal portion of each monomer, is able to identify and , unlike the carboxyl-terminal domain which have and , you can also note that 5 beta-strands of the sheet are parallel and 4 are parallel. The PGA structure exhibit 4 active sites, they can be found in the intersection of monomers between the first and the third parallel beta sheets and loops from the carboxyl-terminal of the adjacent subunit, being the the loop from carboxyl terminal and really important on catalysis due to their high flexibility; the main residues of this loop are Thr20, tyr34 and gly40. In adition to flexible loop, there's a rigid group that takes part on catalysis and is represented by residues , which Thr100 plays as nucleophile, Lys173 is a base that enhance the nucleophilicity of Thr and Asp101 could stabilize the protonation state of Lys. The flexible loop of active site plays a dual role, in the open conformation is responsible for substrate recognition, and in closed conformation is responsible for the proper spatial orientation of substrate in order to catalytic triad act the proper way.