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135  structures 3806  species 2  interactions 5341  sequences 27  architectures

Family: Asparaginase (PF00710)

Summary: Asparaginase

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Asparaginase Edit Wikipedia article

Asparaginase
Systematic (IUPAC) name
E. coli L-asparagine amidohydrolase
Clinical data
Trade names Elspar
AHFS/Drugs.com monograph
MedlinePlus a682046
Pregnancy cat. C (US)
Legal status POM (UK)
Routes intramuscular, subcutaneous, or intravenous
Pharmacokinetic data
Half-life 8-30 hrs
Identifiers
CAS number 9015-68-3 YesY
ATC code L01XX02
DrugBank DB00023
UNII G4FQ3CKY5R YesY
KEGG D02997 YesY
Chemical data
Formula C1377H2208N382O442S17 
Mol. mass 31731.9 g/mol
 YesY (what is this?)  (verify)

Asparaginase (EC 3.5.1.1) is an enzyme that catalyzes the hydrolysis of asparagine to aspartic acid. Asparaginases are naturally occurring enzymes expressed and produced by microorganisms.[1]

Colaspase is also known as L-asparaginase (E. coli).[2]

Use[edit]

Different types of asparaginases can be used for different industrial and pharmaceutical purposes.

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.[3]

A different asparaginase is marketed as a drug under the brand name Elspar for the treatment of acute lymphoblastic leukemia (ALL)[4] and is also used in some mast cell tumor protocols.[5] Unlike most of other chemotherapy agents, it can be given as an intramuscular, subcutaneous, or intravenous injection without fear of tissue irritation.

Mechanism of action[edit]

As a food processing aid[edit]

Acrylamide is often formed in starchy foods when they are baked or fried. 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. Unfortunately, suspected carcinogens such as acrylamide and some heterocyclic amines in also formed in Maillard reaction.

By adding asparaginase before baking or frying the food, asparagine is converted into another common amino acid, aspartic acid, and ammonium ions. 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.[3]

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.[6]

As a drug[edit]

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.[7]

Enzyme regulation[edit]

This protein may use the morpheein model of allosteric regulation.[8]

Side effects in drug use[edit]

The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility.[4] 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.[9] Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required.[10]

Other common side effects include pancreatitis.

History[edit]

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.[9] Asparaginase produced by Erwinia chrysanthemi instead is known as crisantaspase (BAN), and is available in the United Kingdom under the trade name Erwinase.[4]

References[edit]

  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. ^ Rossi S, editor, Australian Medicines Handbook 2011, Adelaide: Australian Medicines Handbook Pty Ltd; 2011.
  3. ^ 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.
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ Broome, J. D. (1981). "L-Asparaginase: Discovery and development as a tumor-inhibitory agent". Cancer treatment reports. 65 Suppl 4: 111–114. PMID 7049374.  edit
  8. ^ 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. 
  9. ^ 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.  edit
  10. ^ 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. PMC 1611087. PMID 4604804.  edit
  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. PMC 2136344. PMID 13109110.  edit
  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. PMC 2137570. PMID 14015821.  edit

External links[edit]

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006034

Asparaginase, which 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]. The enzyme is effective in the treatment of human malignant lymphomas, which have a diminished capacity to produce asparagine synthetase: in order to survive, such cells absorb asparagine from blood plasma [PUBMED:2407723, PUBMED:3379033] - if Asn levels have been depleted by injection of asparaginase, the lymphoma cells die. Glutaminase, a similar enzyme, catalyses the deaminination of glutamine to glutamic acid and an ammonium ion [PUBMED:2407723]. Both enzymes are homotetramers [PUBMED:3026924]: two threonine residues in the N-terminal half of the proteins are involved in the catalytic activity.

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Full
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(3548)
Meta
(565)
RP15
(339)
RP35
(683)
RP55
(964)
RP75
(1165)
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Seed source: Pfam-B_652 (release 2.1)
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 157
Number in full: 5341
Average length of the domain: 305.20 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 90.15 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.5 22.5
Trusted cut-off 22.6 22.8
Noise cut-off 22.2 22.4
Model length: 313
Family (HMM) version: 15
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Interactions

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GatB_N Asparaginase

Structures

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 135 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 seqence.

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