Lopes André Moreni, Oliveira-Nascimento Laura de, Ribeiro Artur, Tairum Carlos Abrunhosa, Breyer Carlos Alexandre, Oliveira Marcos Antonio de, Monteiro Gisele, Souza-Motta Cristina Maria de, Magalhães Pérola de Oliveira, Avendaño Jorge Gonzalo Farías, Cavaco-Paulo Artur Manuel, Mazzola Priscila Gava, Rangel-Yagui Carlota de Oliveira, Sette Lara Durães, Converti Attilio, Pessoa Adalberto
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.
Crit Rev Biotechnol. 2017 Feb;37(1):82-99. doi: 10.3109/07388551.2015.1120705. Epub 2015 Dec 23.
l-asparaginase (l-asparagine amino hydrolase, E.C.3.5.1.1) 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.
L-天冬酰胺酶（L-天冬酰胺氨基水解酶，E.C.3.5.1.1）是一种临床上被认可的用于治疗急性淋巴细胞白血病和淋巴肉瘤的抗肿瘤药物。它催化L-天冬酰胺（Asn）水解为L-天冬氨酸和氨，Asn的有效消耗会导致对白血病细胞的细胞毒性。微生物L-天冬酰胺酶（ASNase）的生产因其成本效益和生态友好性而备受关注。本综述的重点是对微生物ASNase的生产进行全面综述，特别强调微生物生产者、酶生产条件、蛋白质工程、下游工艺、生化特性、酶稳定性、生物利用度、毒性和过敏潜力。还强调了一些在癌症治疗中为实现更好的治疗效果和减少ASNase使用的副作用而必须解决的问题：（a）寻找该酶的新来源以增加其作为药物的可获得性；（b）生产具有改善的药效学、药代动力学和毒理学特征的新型ASNase；以及（c）通过重组微生物提高ASNase的产量。在这方面，合理的蛋白质工程、定向诱变、代谢通量分析和纯化方案的优化有望在不久的将来发挥至关重要的作用。
