Summary: Asparaginase, N-terminal
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Asparaginase Edit Wikipedia article
|Trade names||Elspar, others|
|Other names||crisantaspase, colaspase|
|IM or IV|
|Elimination half-life||39-49 hours (IM), 8-30 hours (IV)|
|Chemical and physical data|
|Molar mass||31731.9 g/mol gÂ·molâˆ’1|
|(what is this?)|
Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and non-Hodgkin's lymphoma. It is given by injection into a vein, muscle, or under the skin. A pegylated version is also available. In food manufacturing it is used to decrease acrylamide.
Common side effects when used by injection include allergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction. Use in pregnancy may harm the baby. As a food it is generally recognized as safe. Asparaginase works by breaking down the amino acid known as asparagine without which the cancer cells cannot make protein.
Asparaginase was approved for medical use in the United States in 1978. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about US$42.00 per 10,000 IU vial. This amount in the United Kingdom costs the NHS 613.00 pounds. It is often made from Escherichia coli or Erwinia chrysanthemi.
Asparaginases can be used for different industrial and pharmaceutical purposes.
E. coli strains are the main source of medical asparaginase. Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar.:5 (Crasnitin has been discontinued.) Spectrila is a new recombinant E. coli asparaginase.
Unlike most of other chemotherapy agents, asparaginase can be given as an intramuscular, subcutaneous, or intravenous injection without fear of tissue irritation.
The most common use of asparaginases is as a processing aid in the manufacture of food. Marketed under the brand names Acrylaway and PreventASe, asparaginases are used as a food processing aid to reduce the formation of acrylamide, a suspected carcinogen, in starchy food products such as snacks and biscuits.
The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility. Additionally, it can also be associated with a coagulopathy as it decreases protein synthesis, including synthesis of coagulation factors (e.g. progressive isolated decrease of fibrinogen) and anticoagulant factor (generally antithrombin III; sometimes protein C & S as well), leading to bleeding or thrombotic events such as stroke. Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required.
Other common side effects include pancreatitis. These side effects mainly attributes to the dual activity of L.Asparaginase as it can also hydrolysis L.Glutamine to Glutamic acid and ammonia
Mechanism of action
As a food processing aid
Acrylamide is often formed in the cooking of starchy foods. During heating the amino acid asparagine, naturally present in starchy foods, undergoes a process called the Maillard reaction, which is responsible for giving baked or fried foods their brown color, crust, and toasted flavor. Suspected carcinogens such as acrylamide and some heterocyclic amines are also generated in the Maillard reaction. By adding asparaginase before baking or frying the food, asparagine is converted into another common amino acid, aspartic acid, and ammonium. As a result, asparagine cannot take part in the Maillard reaction, and therefore the formation of acrylamide is significantly reduced. Complete acrylamide removal is probably not possible due to other, minor asparagine-independent formation pathways.
As a food processing aid, asparaginases can effectively reduce the level of acrylamide up to 90% in a range of starchy foods without changing the taste and appearance of the end product.
As a drug
The rationale behind asparaginase is that it takes advantage of the fact that acute lymphoblastic leukemia cells and some other suspected tumor cells are unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death.
The discovery and development of asparaginase as an anti-cancer drug began in 1953, when scientists first observed that lymphomas in rat and mice regressed after treatment with guinea pig serum. Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase.
After researchers comparing different kinds of asparaginases, the one derived from Escherichia coli and Erwinia chrysanthemi turned out to have the best anti-cancer ability. E. coli has thereby become the main source of asparaginase due to the factor that it is also easy to produce in large amount.
Crisantaspase is British Approved Name (BAN) for asparaginase obtained from Erwinia chrysanthemi. Colaspase is the BAN of asparaginase obtained from Escherichia coli. The United States Adopted Name of crisantaspase is asparaginase Erwinia chrysanthemi. Elspar, Kidrolase, Leunase and Spectrila are brand names for colaspase, while Erwinase and Erwinaze are brand names for crisantaspase. The pegylated version of colaspase is called pegaspargase. Oncaspar is the brand name of pegaspargase.
- "Asparaginase". The American Society of Health-System Pharmacists. Archived from the original on 27 March 2017. Retrieved 8 December 2016.
- GÃ¶kmen, Vural (2015). Acrylamide in Food: Analysis, Content and Potential Health Effects. Academic Press. p. 415. ISBN 9780128028759. Archived from the original on 2016-12-21.
- Kim, Kyu-Won; Roh, Jae Kyung; Wee, Hee-Jun; Kim, Chan (2016). Cancer Drug Discovery: Science and History. Springer. p. 147. ISBN 9789402408447. Archived from the original on 2016-12-21.
- "Asparaginase escherichia coli (Elspar) Use During Pregnancy". www.drugs.com. Archived from the original on 27 March 2017. Retrieved 20 December 2016.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- "Asparaginase". International Drug Price Indicator Guide. Archived from the original on 27 March 2017. Retrieved 8 December 2016.
- British National Formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 600. ISBN 9780857111562.
- Farmer, Peter B.; Walker, John M. (2012). The Molecular Basis of Cancer. Springer Science & Business Media. p. 279. ISBN 9781468473131. Archived from the original on 2016-12-21.
- MÃ¼ller, H. (1998). "Use of L-asparaginase in childhood ALL". Critical Reviews in Oncology/Hematology. 28 (2): 97â€“113. doi:10.1016/S1040-8428(98)00015-8.
- "Spectrila 10,000 U powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)". Archived from the original on 2016-11-09. Retrieved 2016-11-08.
- "8.1.5: Other antineoplastic drugs". British National Formulary (BNF 57). United Kingdom: BMJ Group and RPS Publishing. March 2009. p. 476. ISBN 978-0-85369-845-6.
- Appel IM, van Kessel-Bakvis C, Stigter R, Pieters R (2007). "Influence of two different regimens of concomitant treatment with asparaginase and dexamethason] on hemostasis in childhood acute lymphoblastic leukemia". Leukemia. 21 (11): 2377â€“80. doi:10.1038/sj.leu.2404793. PMID 17554375.
- Kornbrust, B.A., Stringer, M.A., Lange, N.K. and Hendriksen, H.V. (2010) Asparaginase â€“ an enzyme for acrylamide reduction in food products. In: Enzymes in Food Technology, 2nd Edition. (eds Robert J. Whitehurst and Maarten Van Oort). Wiley-Blackwell, UK, pp. 59-87.
- Johnston, P. G.; Hardisty, R. M.; Kay, H. E.; Smith, P. G. (1974). "Myelosuppressive effect of colaspase (L-asparaginase) in initial treatment of acute lymphoblastic leukaemia". British Medical Journal. 3 (5923): 81â€“83. doi:10.1136/bmj.3.5923.81. PMC 1611087. PMID 4604804.
- Hendriksen, H.V.; Kornbrust, B.A.; Oestergaard, P.R.; Stringer, M.A. (April 23, 2009). "Evaluating the Potential for Enzymatic Acrylamide Mitigation in a Range of Food Products Using an Asparaginase from Aspergillus oryzae". Journal of Agricultural and Food Chemistry. 57 (10): 4168â€“4176. doi:10.1021/jf900174q. PMID 19388639.
- Fernandes, H. S.; Teixeira, C. S. Silva; Fernandes, P. A.; Ramos, M. J.; Cerqueira, N. M. F. S. A. (4 November 2016). "Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections". Expert Opinion on Therapeutic Patents. 0 (ja): 283â€“297. doi:10.1080/13543776.2017.1254194. ISSN 1354-3776. PMID 27813440.
- Broome, J. D. (1981). "L-Asparaginase: Discovery and development as a tumor-inhibitory agent". Cancer Treatment Reports. 65 Suppl 4: 111â€“114. PMID 7049374.
- T. Selwood; E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131â€“43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.
- Kidd, J. G. (1953). "Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. I. Course of transplanted cancers of various kinds in mice and rats given guinea pig serum, horse serum, or rabbit serum". The Journal of Experimental Medicine. 98 (6): 565â€“582. doi:10.1084/jem.98.6.565. PMC 2136344. PMID 13109110.
- Broome, J. D. (1963). "Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. I. Properties of the L-asparaginase of guinea pig serum in relation to those of the antilymphoma substance". The Journal of Experimental Medicine. 118 (1): 99â€“120. doi:10.1084/jem.118.1.99. PMC 2137570. PMID 14015821.
- Brayfield, A, ed. (June 2017). "Asparaginase: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 9 August 2017.
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Asparaginase, N-terminal Provide feedback
This is the N-terminal domain of this enzyme.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR027474
This entry represents the N-terminal domain of the L-asparaginase. Each monomer of L-asparaginase is arranged into two easily identifiable domains, the larger N-terminal domain and the smaller C-terminal domain, connected by a linker consisting of approximately 20 residues [ PUBMED:12499544 ]. The N-terminal domain covers two conserved threonine residues, which have been shown to play a catalytic role [ PUBMED:1906013 , PUBMED:8348975 ]. One of them is located in the N-terminal extremity while the second one is located at the end of the first third of the sequence.
Asparaginase is found in various plant, animal and bacterial cells, catalyses the deamination of asparagine to yield aspartic acid and an ammonium ion, resulting in a depletion of free circulatory asparagine in plasma [ PUBMED:3026924 ]. Glutaminase, a similar enzyme, catalyses the deaminination of glutamine to glutamic acid and an ammonium ion [ PUBMED:2407723 ]. Both asparaginase and glutaminase contain the domain represented in this entry.
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|Seed source:||Pfam-B_652 (release 2.1)|
|Number in seed:||104|
|Number in full:||8107|
|Average length of the domain:||190.70 aa|
|Average identity of full alignment:||29 %|
|Average coverage of the sequence by the domain:||51.13 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||22|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Asparaginase domain has been found. There are 389 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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