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Asparaginase (EC 3.5.1.1, USAN) or Colaspase (BAN) is an enzyme that catalyzes the hydrolysis of asparagine to aspartic acid. Asparaginases are enzymes expressed and produced by microorganisms.^[1] These enzymes are on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.^[2]

Uses

Asparaginases can be used for different industrial and pharmaceutical purposes.

Medical

A different asparaginase is marketed as a drug under the brand name Elspar for the treatment of acute lymphoblastic leukemia (ALL)^[3] and is also used in some mast cell tumor protocols.^[4] Unlike most of other chemotherapy agents, it can be given as an intramuscular, subcutaneous, or intravenous injection without fear of tissue irritation.

Manufacturing

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.^[5]

Side effects

The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility.^[3] 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.^[6] Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required.^[7]

Other common side effects include pancreatitis.

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.^[5]

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.^[8]

As a drug

The rationale behind asparaginase is that it takes advantage of the fact that ALL leukemic 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.^[9]

Enzyme regulation

This protein may use the morpheein model of allosteric regulation.^[10]

History

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.^[11] Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase.^[12]

After researches 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.^[6] Asparaginase produced by Erwinia chrysanthemi instead is known as crisantaspase (BAN), and is available in the United Kingdom under the trade name Erwinase.^[3]

References

^ H. Geckil and S. Gencer. (2004). "Production of L-asparaginase in Enterobacter aerogenes expressing Vitreoscilla hemoglobin for efficient oxygen uptake.". Appl. Microbiol. Biotechnol. 63 (6): 691–97. doi:10.1007/s00253-003-1482-5. PMID 14593509.
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ ^a ^b ^c "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): 2377–80. doi:10.1038/sj.leu.2404793. PMID 17554375.
^ ^a ^b Kornbrust, B.A., Stringer, M.A., Lange, N.K. and Hendriksen, H.V. (2010) Asparaginase – 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.
^ ^a ^b Müller, H. (1998). "Use of L-asparaginase in childhood ALL". Critical Reviews in Oncology/Hematology 28 (2): 97–11. doi:10.1016/S1040-8428(98)00015-8.
^ 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): 81–83. 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): 4168–4176. doi:10.1021/jf900174q. PMID 19388639. Retrieved October 8, 2010.
^ Broome, J. D. (1981). "L-Asparaginase: Discovery and development as a tumor-inhibitory agent". Cancer treatment reports. 65 Suppl 4: 111–114. PMID 7049374.
^ T. Selwood and E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function.". Arch. Biochem. Biophys. 519 (2): 131–43. 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): 565–582. 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): 99–120. doi:10.1084/jem.118.1.99. PMC 2137570. PMID 14015821.

External links

Eukaryotic Linear Motif resource motif class CLV_TASPASE1
Asparaginase at the US National Library of Medicine Medical Subject Headings (MeSH)
Crisantaspase information from Macmillan Cancer Support
U.S. NLM, NIH Drug Information Portal - Asparaginase

Molecular and Cellular Biology portal

UpToDate Contents

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1. 成人におけるフィラデルフィア染色体陰性急性リンパ芽球性白血病に対する導入療法 induction therapy for philadelphia chromosome negative acute lymphoblastic leukemia in adults
2. 全身化学療法に対する輸注反応 infusion reactions to systemic chemotherapy
3. 小児および思春期における急性リンパ芽球性白血病の治療の概要 overview of the treatment of acute lymphoblastic leukemia in children and adolescents
4. Venous thrombosis and thromboembolism in infants and children: Risk factors and clinical manifesations

English Journal

Application of repeated aspartate tags to improving extracellular production of Escherichia colil-asparaginase isozyme II.

Kim SK1, Min WK1, Park YC2, Seo JH3.
Enzyme and microbial technology.Enzyme Microb Technol.2015 Nov;79-80:49-54. doi: 10.1016/j.enzmictec.2015.06.017. Epub 2015 Jul 17.
Asparaginase isozyme II from Escherichia coli is a popular enzyme that has been used as a therapeutic agent against acute lymphoblastic leukemia. Here, fusion tag systems consisting of the pelB signal sequence and various lengths of repeated aspartate tags were devised to highly express and to relea
PMID 26320714

The development of thromboembolism may increase the risk of osteonecrosis in children with acute lymphoblastic leukemia.

Badhiwala JH1, Nayiager T2, Athale UH1,2,3.
Pediatric blood & cancer.Pediatr Blood Cancer.2015 Oct;62(10):1851-4. doi: 10.1002/pbc.25553. Epub 2015 Apr 29.
Previous studies indicate pathophysiological and epidemiological parallels between osteonecrosis (ON) and thromboembolism (TE), two common treatment-related morbidities in acute lymphoblastic leukemia (ALL). To elucidate risk factors for ON and explore the relationship between ON and TE, we undertoo
PMID 25931304

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.

Moradi Manesh D1, El-Hoss J1, Evans K1, Richmond J1, Toscan CE1, Bracken LS1, Hedrick A2, Sutton R1, Marshall GM3, Wilson WR4, Kurmasheva RT5, Billups C6, Houghton PJ5, Smith MA7, Carol H1, Lock RB1.
Blood.Blood.2015 Sep 3;126(10):1193-202. doi: 10.1182/blood-2014-12-618900. Epub 2015 Jun 26.
PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 i
PMID 26116659

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★リンクテーブル★

リンク元	「アスパラギナーゼ」

「アスパラギナーゼ」

Asparaginase
Systematic (IUPAC) name
	E. coli L-asparagine amidohydrolase
Clinical data
Trade names	Elspar
AHFS/Drugs.com	monograph
MedlinePlus	a682046
License data	US FDA: Asparaginase;
Pregnancy; category	AU: D; US: C (Risk not ruled out); ;
Routes of; administration	IM or IV
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Biological half-life	39-49 hours (IM), 8-30 hours (IV)
Identifiers
CAS Number	9015-68-3
ATC code	L01XX02 (WHO)
IUPHAR/BPS	7347
DrugBank	DB00023
ChemSpider	none
UNII	G4FQ3CKY5R
KEGG	D02997
Chemical data
Formula	C1377H2208N382O442S17
Molar mass	31731.9 g/mol
(verify)

　　[★]

英: asparaginase
同: L-アスパラギナーゼ L-asparaginase L-ASP
商: ロイナーゼ、Elspar

悪性リンパ腫治療薬

[pmid14593509-1] H. Geckil and S. Gencer. (2004). "Production of L-asparaginase in Enterobacter aerogenes expressing Vitreoscilla hemoglobin for efficient oxygen uptake.". Appl. Microbiol. Biotechnol. 63 (6): 691–97. doi:10.1007/s00253-003-1482-5. PMID 14593509.

[2] "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.

[BNF57-3] "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.

[pmid17554375-4] 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): 2377–80. doi:10.1038/sj.leu.2404793. PMID 17554375.

[kornbrust-5] Kornbrust, B.A., Stringer, M.A., Lange, N.K. and Hendriksen, H.V. (2010) Asparaginase – 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.

[js-6] Müller, H. (1998). "Use of L-asparaginase in childhood ALL". Critical Reviews in Oncology/Hematology 28 (2): 97–11. doi:10.1016/S1040-8428(98)00015-8.

[7] 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): 81–83. doi:10.1136/bmj.3.5923.81. PMC 1611087. PMID 4604804.

[8] 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): 4168–4176. doi:10.1021/jf900174q. PMID 19388639. Retrieved October 8, 2010.

[9] Broome, J. D. (1981). "L-Asparaginase: Discovery and development as a tumor-inhibitory agent". Cancer treatment reports. 65 Suppl 4: 111–114. PMID 7049374.

[pmid22182754-10] T. Selwood and E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function.". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.

[11] 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): 565–582. doi:10.1084/jem.98.6.565. PMC 2136344. PMID 13109110.

[12] 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): 99–120. doi:10.1084/jem.118.1.99. PMC 2137570. PMID 14015821.

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案内

Elspar