Asparaginase Escherichia coli

Identification

Name

Asparaginase Escherichia coli

Accession Number

DB00023

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.

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Other protein based therapies

Protein Structure

Protein Chemical Formula

C₁₃₇₇H₂₂₀₈N₃₈₂O₄₄₂S₁₇

Protein Average Weight

Not Available

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

Pharmacology

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Indication

Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) ^Label.

Associated Conditions

• Acute Lymphoblastic Leukaemias (ALL)

Contraindications & Blackbox Warnings

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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/unknown	Humans

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

Adverse Effects

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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

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Allantoin	The therapeutic efficacy of Allantoin can be increased when used in combination with Asparaginase Escherichia coli.
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.
Darbepoetin alfa	The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined 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.
Erythropoietin	The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Asparaginase Escherichia coli.
Ethotoin	The therapeutic efficacy of Ethotoin 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.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Elspar	Injection, powder, lyophilized, for solution	10000 [iU]/1	Intramuscular; Intravenous	Lundbeck Inc.	1978-01-10	2013-07-18
Kidrolase	Powder, for solution		Intramuscular; Intravenous	Jazz Pharmaceuticals France Sas	1974-12-31	Not applicable
Spectrila	Injection, powder, for solution		Intravenous	Medac Gesellschaft Fuer Klinische Spezialpraeparate Mb H	2016-09-08	Not applicable
Spectrila	Injection, powder, for solution		Intravenous	Medac Gesellschaft Fuer Klinische Spezialpraeparate Mb H	2016-09-08	Not applicable

Categories

ATC Codes

L01XX02 — Asparaginase

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amidohydrolases
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Asparaginase
• Asparagine-specific Enzyme
• Enzymes
• Enzymes and Coenzymes
• Hydrolases
• Narrow Therapeutic Index Drugs
• Thyroxine-binding globulin inhibitors

Chemical TaxonomyProvided by Classyfire

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

Chemical Identifiers

UNII

G4FQ3CKY5R

CAS number

9015-68-3

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

1. Roberts J, Prager MD, Bachynsky N: The antitumor activity of Escherichia coli L-asparaginase. Cancer Res. 1966 Oct;26(10):2213-7. [PubMed:5331901]
2. 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]
3. 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]
4. UniProtKB - V6FYV8 (V6FYV8_ECOLX): E. coli L-asparaginase, type II FASTA sequence [Link]

External Links

UniProt

P37595

Genbank

U00096

PubChem Substance

46507633

RxNav

1156

ChEMBL

CHEMBL2108989

PharmGKB

PA448492

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Asparaginase

AHFS Codes

• 10:00.00 — Antineoplastic Agents

FDA label

Download (176 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Acute Lymphobkastic Leukemia	1
4	Completed	Treatment	Acute Lymphoblastic Leukaemias (ALL)	5
4	Completed	Treatment	Adult Acute Lymphocytic Leukemia	3
4	Completed	Treatment	Lymphoma, Lymphoblastic	1
4	Recruiting	Treatment	Peripheral T Cell Lymphoma (PTCL) / Peripheral T-Cell Lymphoma (PTCL)	1
4	Unknown Status	Treatment	Acute Lymphoblastic Leukaemias (ALL)	1
4	Unknown Status	Treatment	Adult Acute Lymphocytic Leukemia	2
3	Active Not Recruiting	Treatment	Acute Lymphoblastic Leukaemias (ALL) / Acute Undifferentiated Leukemia (AUL) / Childhood T Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia	1
3	Active Not Recruiting	Treatment	Acute Lymphoblastic Leukaemias (ALL) / Adult B Lymphoblastic Lymphoma / Ann Arbor Stage I B Lymphoblastic Lymphoma / Ann Arbor Stage II B Lymphoblastic Lymphoma / Childhood B Acute Lymphoblastic Leukemia / Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 / Childhood B Lymphoblastic Lymphoma / Down Syndrome (DS) / Hypodiploid B Acute Lymphoblastic Leukemia / Philadelphia Chromosome Positive	1
3	Active Not Recruiting	Treatment	Acute Lymphoblastic Leukaemias (ALL) / B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative	1

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
Injection, powder, for solution	Parenteral
Powder, for solution	Intramuscular; Intravenous
Injection, powder, lyophilized, for solution	Intramuscular; Intrathecal; Intravenous
Injection, powder, for solution
Injection, powder, lyophilized, for solution	Intravenous
Powder
Injection, powder, for solution	Intravenous

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

Targets

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Details1. L-asparagine

Kind

Small molecule

Organism

Humans

Pharmacological action

Yes

Actions

Other/unknown

References

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]

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Drug created on June 13, 2005 13:24 / Updated on April 23, 2021 04:04