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Crit Rev Biotechnol. 2017 Feb;37(1):82-99. Epub 2015 Dec 23.

Therapeutic l-asparaginase: upstream, downstream and beyond.

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a Department of Biochemical and Pharmaceutical Technology , School of Pharmaceutical Sciences, University of São Paulo , São Paulo , Brazil.
b Department of Biochemistry and Tissue Biology , Institute of Biology, State University of Campinas - UNICAMP , Campinas , Brazil.
c Centre of Biological Engineering (CEB), School of Engineering, University of Minho , Braga , Portugal.
d Biosciences Institute, Coastal Campus, São Paulo State University - UNESP , São Vicente , Brazil.
e Department of Mycology , Federal University of Pernambuco , Recife , Brazil.
f Department of Pharmacy , School of Health Sciences, University of Brasilia - UnB , Brasilia , Brazil.
g Department of Chemical Engineering , Faculty of Engineering and Science, University of La Frontera , Temuco , Chile.
h Faculty of Pharmaceutical Sciences , University of Campinas - UNICAMP , Campinas , Brazil.
i Department of Biochemistry and Microbiology , Institute of Biosciences, São Paulo State University - UNESP , Rio Claro , Brazil , and.
j Department of Civil , Chemical and Environmental Engineering, University of Genoa , Genoa , Italy.


l-asparaginase (l-asparagine amino hydrolase, E.C. is an enzyme clinically accepted as an antitumor agent to treat acute lymphoblastic leukemia and lymphosarcoma. It catalyzes l-asparagine (Asn) hydrolysis to l-aspartate and ammonia, and Asn effective depletion results in cytotoxicity to leukemic cells. Microbial l-asparaginase (ASNase) production has attracted considerable attention owing to its cost effectiveness and eco-friendliness. The focus of this review is to provide a thorough review on microbial ASNase production, with special emphasis to microbial producers, conditions of enzyme production, protein engineering, downstream processes, biochemical characteristics, enzyme stability, bioavailability, toxicity and allergy potential. Some issues are also highlighted that will have to be addressed to achieve better therapeutic results and less side effects of ASNase use in cancer treatment: (a) search for new sources of this enzyme to increase its availability as a drug; (b) production of new ASNases with improved pharmacodynamics, pharmacokinetics and toxicological profiles, and (c) improvement of ASNase production by recombinant microorganisms. In this regard, rational protein engineering, directed mutagenesis, metabolic flux analysis and optimization of purification protocols are expected to play a paramount role in the near future.


Acute lymphoblastic leukemia; antineoplastic activity; biopharmaceutical; l-asparaginase; microbial l-asparaginase production

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