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A Review on L-Asparaginase
Published in Se-Kwon Kim, Marine Biochemistry, 2023
Worldwide treatment of ALL currently involves the asparaginase produced from E. chrysanthemi. The United Nations has approved Erwinia for the treatment of leukemia. When compared to bacterial L-asparaginase, Erwinia L-asparaginase has a decreased half-life; hence, the drug must be given in greater doses and more often so as to remove asparagine completely (Asselin et al.,1999). According to Boos et al. (1996), the patients receiving Erwinia recover their asparagine level more quickly. Allergic reactions caused by the long-term use of bacterial L-asparaginase can be effectively overcome by the L-asparaginae from Erwinia, which makes it a prominent drug (Panosyan et al., 2004).
Chemical Structure of Lipid A: Recent Advances in Structural Analysis of Biologically Active Molecules
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Ulrich Zähringer, Buko Lindner, Ernst T. Rietschel
FAB-MS has also been applied to lipid A of the S. enterica sv. Minnesota Re mutant, strain R595 (65), Erwinia carotovora (66), Chlamydia trachomatis (26), and Pseudomonas aeruginosa (67), the latter study using FAB-MS and NMR confirming results previously obtained in our laboratory (68). LSI-MS of heterogeneous lipid A samples followed by collision-induced decomposition (CID) experiments performed on selected molecular ions have been performed by Kaltashov et al. (69) to confirm the presence of two iso-forms in dimethyl-diphosphoryl lipid A isolated from R. sphaeroides (69). Recently, MS/MS analyses were also performed with a pentaacyl monophosphoryl lipid A of E. carotovora in the positive and negative ion mode, giving evidence that different fatty acids are cleaved in the two modes (70).
Biocatalytic Nanoreactors for Medical Purposes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Oscar González-Davis, Chauhan Kanchan, Rafael Vazquez-Duhalt
Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia, is a type of blood and bone marrow cancer and is the most common type of cancer in children. This disease progresses rapidly and creates immature blood cells that are auxotrophic for asparagine. Thus, l-asparaginase is an essential therapeutic enzyme widely used for the treatment of this specific cancer (Galluzzi et al., 2013; Ghoshoon et al., 2015). The treatment goal is to reduce the concentration of asparagine in blood by the transformation of this amino acid to aspartic acid and therefore induce selective growth inhibition of sensitive tumor cells. The FDA first approved an enzymatic preparation of asparaginase from Escherichia coli in 1978, and 15 years later PEGylated asparaginase was approved to avoid undesirable immune responses. The main problem with asparaginase from E. coli is that it exhibits a high glutaminase activity, which could render the treatment toxic. Site-directed mutagenesis has been performed in order to reduce the glutaminase activity while maintaining high asparaginase activity (Ramya et al., 2011). Also, in several cases, asparaginase from E. coli has had a reduced lifetime due to inactivation. Thus, immunologically distinct asparaginase from Erwinia chrysanthemi is being tested (Pieters et al., 2011).
Therapeutic drug monitoring: applying the ‘Goldilocks Principle’ to clinical pharmacology
Published in Expert Review of Clinical Pharmacology, 2023
Peter E Penson, Alice P McCloskey
In severe disease states, the pharmacokinetics of drugs is often altered, and TDM has a role to play in optimizing therapy. In this issue, Li et al. establish machine-learning models to individualize therapy with busulfan (an alkylating agent) in patients undergoing hematopoietic stem cell transplantation. The authors describe how such models may be used in the future to inform decision-support systems to allow prescribers to choose the most appropriate dose regimen considering the individual characteristics of their patient [6]. TDM may also have a role in ensuring the most rational use of drugs in short supply. Vagrecha et al. describe how TDM can be used to reduce the use of Erwinia asparaginase (during a worldwide shortage) in pediatric patients with acute lymphoblastic leukemia, by restricting its use to a very small subset of patients [7].
In silico analysis revealing CsrA roles in motility-sessility switching and tuning VBNC cells in Vibrio parahaemolyticus
Published in Biofouling, 2021
Dan Wang, Steve H. Flint, Dragana Gagic, Jon S. Palmer, Graham C. Fletcher, Stephen L. W. On
Other studies provide evidence of a switching role from motility to sessility for CsrA. A csrA mutant produced non-motile phenotypes in Erwinia amylovora (Ancona et al. 2016). In Escherichia coli, CsrA has been reported to be critical to activate the expression of the master flagellum operon flhDC and the steady‐state level of flhDC was 3-4 fold greater in the wild‐type strain compared with in a csrA mutant (Wei et al. 2001). The csrA can stabilize expression of the master flagella regulator FlhDC and repress biofilm formation. In E. coli, poly-β-1,6-N-acetyl-D-glucosamine (PGA) overexpression can promote cell attachment, cell to cell adherence and biofilm structure stability, CsrA can repress pga gene expression and PGA translation by binding to the transcript of the pgaA gene (Wang et al. 2004). CsrA can also repress biofilm formation by down-regulating or binding GGDEF/EAL proteins which induce contributions to c-di-GMP dependent biofilm formation (Jonas et al. 2010). CsrA was reported to activate biofilm dispersal, resulting in sessile bacteria returning to a planktonic state (Jackson et al. 2002).
Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity
Published in Pediatric Hematology and Oncology, 2018
Chintan Vyas, Sandeep Jain, Gauri Kapoor, Anurag Mehta, Parul Takkar Chugh
L-asparaginase is an essential element of childhood acute lymphoblastic leukemia (ALL) therapy and its prolonged and intensive use has been associated with better outcome.1–6 The mechanism of action is based on the systemic depletion of asparagine, a non-essential amino acid. Leukemic cells, being more reliant on exogenous asparagine for survival than normal host cells, are selectively affected by the drug.7 L-asparaginase is available for clinical use in several formulations with different pharmacokinetic profiles.3,8 The two preparations commonly used in the therapy of childhood ALL include native (N-Asp) and pegylated (P-Asp) Escherichia coli asparaginase. Erwinia chrysanthemi asparaginase (Erwinase) is generally reserved as a second line option for patients hypersensitive to either of the E coli preparations. The N-Asp is highly immunogenic and hypersensitivity may be observed in up to 30% of patients.9 This may lead to discontinuation of its use which has been reported to be associated with poorer survival. P-Asp is less immunogenic and has a longer half-life. From the point of view of a clinician, this amounts to achieving adequate and sustained asparaginase levels during the scheduled phases of therapy. This dual advantage is better accomplished by the pegylated formulation as compared to the native one and is, therefore, used as frontline agent in contemporary ALL protocols in developed countries.