Asparaginase Escherichia coli
Identification
- Name
- Asparaginase Escherichia coli
- Accession Number
- DB00023 (BTD00011, BIOD00011)
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Other protein based therapies - Description
Asparaginase derived from Escherichia coli (L-asparagine amidohydrolase, EC 3.5.1.1) is an enzyme responsible for the metabolism of L-asparagine, by catalyzing L-asparagine into L-aspartic acid and ammonia. It also facilitates the production of oxaloacetate which is needed for general cellular metabolism. Asparaginase from E. coli has clinically shown to exhibit antitumor actions in models of leukaemias [1, 2]. L-asparaginase of E. coli is marketed under several different trade names, including Elspar, for the treatment of acute lymphoblastic leukemia (ALL) as part of a multi-agent chemotherapeutic regimen. It is available as intramuscular or intravenous injections. Therapeutic L-asparaginase from E. coli works by depleting the levels of non-essential amino acid, asparagine, in lymphoblastic leukemic cells thus promoting apoptotic cell death [3]. For patients who develop hypersensitivity to E. coli-derived formulations of L-asparaginase, the use of PEGylated or non-PEGylated Asparaginase Erwinia chrysanthemi is recommended [3].
- Protein structure
- Protein chemical formula
- C1377H2208N382O442S17
- Protein average weight
- 31731.9 Da
- Sequences
>sp|P00805|ASPG2_ECOLI L-asparaginase 2 OS=Escherichia coli (strain K12) GN=ansB PE=1 SV=2 MEFFKKTALAALVMGFSGAALALPNITILATGGTIAGGGDSATKSNYTVGKVGVENLVNA VPQLKDIANVKGEQVVNIGSQDMNDNVWLTLAKKINTDCDKTDGFVITHGTDTMEETAYF LDLTVKCDKPVVMVGAMRPSTSMSADGPFNLYNAVVTAADKASANRGVLVVMNDTVLDGR DVTKTNTTDVATFKSVNYGPLGYIHNGKIDYQRTPARKHTSDTPFDVSKLNELPKVGIVY NYANASDLPAKALVDAGYDGIVSAGVGNGNLYKSVFDTLATAAKTGTAVVRSSRVPTGAT TQDAEVDDAKYGFVASGTLNPQKARVLLQLALTQTKDPQQIQQIFNQY
Download FASTA Format- Synonyms
- Asparaginase
- Asparaginase (E. coli)
- Colaspase
- Escherichia coli L-asparaginase
- L-asparaginase
- L-asparagine amidohydrolase
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Elspar Injection, powder, lyophilized, for solution 10000 [iU]/1 Intramuscular; Intravenous Lundbeck Inc. 1978-01-10 2013-07-18 US 
Kidrolase Powder, for solution 10000 unit Intramuscular; Intravenous Jazz Pharmaceuticals France Sas 1974-12-31 Not applicable Canada 
Spectrila Injection, powder, for solution 10000 U Intravenous Medac Gesellschaft Fuer Klinische Spezialpraeparate Mb H 2016-01-14 Not applicable EU 
Spectrila Injection, powder, for solution 10000 U Intravenous Medac Gesellschaft Fuer Klinische Spezialpraeparate Mb H 2016-01-14 Not applicable EU - Categories
- UNII
- G4FQ3CKY5R
- CAS number
- 9015-68-3
Pharmacology
- Indication
Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) [Label].
- Associated Conditions
- Pharmacodynamics
In clinical trials of patients with previously untreated, standard-risk ALL, administration of asparaginase resulted in a decrease of plasma asparagine levels from average of 41 μM to less than 3 μM [Label]. The native asparaginase in whom plasma enzyme activity before treatment was greater than 0.1 International Units/mL [Label]. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 μM (pretreatment) to 1.0 μM and 0.3 μM at day 7 and day 28 of induction, respectively [Label]. Native E. coli asparaginase results in asparagine depletion in 14 to 23 days following administration [3].
- Mechanism of action
Asparagine is a non-essential amino acid that maintains DNA, RNA and protein synthesis and promotes cell growth. While healthy and normal cells are capable of obtaining asparagine via dietary intake or synthesizing the asparagine from aspartate via asparagine synthetase activity, lymphoblastic leukemic cells lack the asparagine synthetase enzyme and cannot produce asparagine de novo [3]. Thus, leukemic cells rely on exogenous source of asparagine for protein synthesis and cell survival [3]. L-asparagine from E. coli serves to deplete plasma levels of asparagine in leukemic cells by converting L-asparagine to L-aspartic acid and ammonia [3], leading to reduced reduced DNA, RNA and protein synthesis; inhibition of cell growth; and ultimately the activation of apoptotic cell-death mechanisms [3]. Normal cells, however, are able to synthesize asparagine and thus are affected less by the rapid depletion produced by treatment with the enzyme asparaginase [Label].
Target Actions Organism AL-asparagine other/unknownHumans - Absorption
In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase derived from E. coli resulted in a cumulative increase in plasma levels. Following intramuscular injection in patients with metastatic cancer and leukemia, peak plasma levels of asparaginase was achieved 14 to 24 hours post-dosing [Label].
Peak asparaginase activity of native E. coli asparaginase can be observed in 24 to 48 hours following administration [3].
- Volume of distribution
Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels [3].
- Protein binding
- Not Available
- Metabolism
- Not Available
- Route of elimination
- Not Available
- Half life
Plasma half life of L-asparagine derived from E. coli following intravenous injection was 8-30 hrs [Label]. Plasma half-life was 34 to 49 hours after intramuscular injection [Label]. Half-life (mean ± SD) of native E. coli asparaginase is approximately 1.28 ± 0.35 days [3].
- Clearance
- Not Available
- Toxicity
No studies assessing the mutagenic or carcinogenic potential of E. coli L-asparagine have been conducted. In the Ames assay, no mutagenic effect was demonstrated when tested against Salmonella typhimurium strains [Label]. No studies have been performed on impairment of fertility [Label]. Following a single, intravenous injection of 12,500 to 50,000 International Units L-asparagine/kg in rabbits, edema and necrosis of pancreatic islets were observed. The clinical relevance of this finding is unclear as it does not indicate pancreatitis [Label].
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction Carbamazepine The therapeutic efficacy of Carbamazepine can be increased when used in combination with Asparaginase Escherichia coli. Dantrolene The therapeutic efficacy of Dantrolene can be increased when used in combination with Asparaginase Escherichia coli. Dexamethasone The serum concentration of Dexamethasone can be increased when it is combined with Asparaginase Escherichia coli. Enzalutamide The therapeutic efficacy of Enzalutamide can be increased when used in combination with Asparaginase Escherichia coli. Ethotoin The therapeutic efficacy of Ethotoin can be increased when used in combination with Asparaginase Escherichia coli. Etofenamate The therapeutic efficacy of Etofenamate can be increased when used in combination with Asparaginase Escherichia coli. Fosphenytoin The therapeutic efficacy of Fosphenytoin can be increased when used in combination with Asparaginase Escherichia coli. Furosemide The therapeutic efficacy of Furosemide can be increased when used in combination with Asparaginase Escherichia coli. Heparin The therapeutic efficacy of Heparin can be increased when used in combination with Asparaginase Escherichia coli. Imatinib The risk or severity of liver damage can be increased when Asparaginase Escherichia coli is combined with Imatinib. - Food Interactions
- Not Available
References
- Synthesis Reference
Masao Nambu, "Process for producing immobilized L-asparaginase preparations for the therapy of leukemia." U.S. Patent US4617271, issued January, 1977.
US4617271- General References
- Roberts J, Prager MD, Bachynsky N: The antitumor activity of Escherichia coli L-asparaginase. Cancer Res. 1966 Oct;26(10):2213-7. [PubMed:5331901]
- Boyse EA, Old LJ, Campbell HA, Mashburn LT: Suppression of murine leukemias by L-asparaginase. Incidence of sensitivity among leukemias of various types: comparative inhibitory activities of guinea pig serum L-asparaginase and Escherichia coli L-asparaginase. J Exp Med. 1967 Jan 1;125(1):17-31. [PubMed:5334543]
- Asselin B, Rizzari C: Asparaginase pharmacokinetics and implications of therapeutic drug monitoring. Leuk Lymphoma. 2015;56(8):2273-80. doi: 10.3109/10428194.2014.1003056. Epub 2015 Mar 11. [PubMed:25586605]
- UniProtKB - V6FYV8 (V6FYV8_ECOLX): E. coli L-asparaginase, type II FASTA sequence [Link]
- External Links
- UniProt
- P37595
- Genbank
- U00096
- PubChem Substance
- 46507633
- ChEMBL
- CHEMBL2108989
- PharmGKB
- PA448492
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Asparaginase
- ATC Codes
- L01XX02 — Asparaginase
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- FDA label
- Download (176 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Lundbeck Inc.
- Merck & Co.
- Prescript Pharmaceuticals
- Dosage forms
Form Route Strength Injection, powder, lyophilized, for solution Intramuscular; Intravenous 10000 [iU]/1 Powder, for solution Intramuscular; Intravenous 10000 unit Injection, powder, for solution Intravenous 10000 U - Prices
Unit description Cost Unit Elspar 10000 unit vial 74.6USD vial DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
Property Value Source hydrophobicity 0.059 Not Available isoelectric point 4.67 Not Available
Taxonomy
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
Targets
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
- Wetzler M, Sanford BL, Kurtzberg J, DeOliveira D, Frankel SR, Powell BL, Kolitz JE, Bloomfield CD, Larson RA: Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007 May 15;109(10):4164-7. Epub 2007 Jan 30. [PubMed:17264295]
- Wenner KA, Vieira Pinheiro JP, Escherich G, Wessalowski R, Jorch N, Wolff J, Stehn M, Kohlschutter A, Boos J, Janka-Schaub GE: Asparagine concentration in plasma after 2,500 IU/m(2) PEG-asparaginase i.v. in children with acute lymphoblastic leukemia. Klin Padiatr. 2005 Nov-Dec;217(6):321-6. [PubMed:16307417]
- Appel IM, Pinheiro JP, den Boer ML, Lanvers C, Reniers NC, Boos J, Pieters R: Lack of asparagine depletion in the cerebrospinal fluid after one intravenous dose of PEG-asparaginase: a window study at initial diagnosis of childhood ALL. Leukemia. 2003 Nov;17(11):2254-6. [PubMed:14523472]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Serine-type endopeptidase inhibitor activity
- Specific Function
- Major thyroid hormone transport protein in serum.
- Gene Name
- SERPINA7
- Uniprot ID
- P05543
- Uniprot Name
- Thyroxine-binding globulin
- Molecular Weight
- 46324.12 Da
Drug created on June 13, 2005 07:24 / Updated on April 16, 2019 21:58