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122  structures 1712  species 1  interaction 3745  sequences 60  architectures

Family: Asparaginase_2 (PF01112)

Summary: Asparaginase

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Asparaginase Edit Wikipedia article

Asparaginase
3eca.jpg
Clinical data
Trade names Elspar, others
AHFS/Drugs.com Monograph
MedlinePlus a682046
License data
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
Routes of
administration
IM or IV
ATC code
Legal status
Legal status
Pharmacokinetic data
Biological half-life 39-49 hours (IM), 8-30 hours (IV)
Identifiers
Synonyms crisantaspase, colaspase
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C1377H2208N382O442S17
Molar mass 31731.9 g/mol
 NYesY (what is this?)  (verify)

Asparaginase is an enzyme that is used as a medication and in food manufacturing.[1][2] As a medication it is used to treat acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and non-Hodgkin's lymphoma.[1] It is given by injection into a vein, muscle, or under the skin.[1] A pegylated version is also available.[3] In food manufacturing it is used to decrease the acrylamide.[2]

Common side effects when used by injection include allergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction.[1] Use in pregnancy may harm the baby.[4] As a food it is generally recognized as safe.[2] Asparaginase works by breaking down the amino acid known as asparagine without which the cancer cells cannot make DNA.[1]

Asparaginase was approved for medical use in the United States in 1978.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] The wholesale cost in the developing world is about 42.00 USD for per 10,000 IU vial.[6] This amount in the United Kingdom costs the NHS 613.00 pounds.[7] It is often made from Escherichia coli or Erwinia chrysanthemi.[3][8]

Uses

Asparaginases can be used for different industrial and pharmaceutical purposes.

Medical

E. coli strains are the main source of medical asparaginase.[9] Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar.[9]:5 (Crasnitin has been discontinued.) Spectrila is a new recombinant E. coli asparaginase.[10]

Asparaginase produced by Erwinia chrysanthemi instead is known as crisantaspase (BAN), and is available in the United Kingdom under the trade name Erwinase.[11]

One of the E. coli asparaginases marketed under the brand name Elspar for the treatment of acute lymphoblastic leukemia (ALL)[11] is also used in some mast cell tumor protocols.[12]

Unlike most of other chemotherapy agents, asparaginase can be given as an intramuscular, subcutaneous, or intravenous injection without fear of tissue irritation.

Food 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.[13]

Side effects

The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility.[11] 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.[14]

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.[13]

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.[15]

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.[16] 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.[17]

Enzyme regulation

This protein may use the morpheein model of allosteric regulation.[18]

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.[19] Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase.[20]

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.[9]

Names

Crisantaspase is British Approved Name (BAN) for asparaginase obtained from Erwinia chrysanthemi. Colaspase is the BAN of asparaginase obtained from Escherichia coli.[21][9][11] The United States Adopted Name of crisantaspase is asparaginase Erwinia chrysanthemi.[21] Elspar, Kidrolase, Leunase and Spectrila are brand names for colaspase, while Erwinase and Erwinaze are brand names for crisantaspase.[21] The pegylated version of colaspase is called pegaspargase. Oncaspar is the brand name of pegaspargase.[21]

References

  1. ^ a b c d e "Asparaginase". The American Society of Health-System Pharmacists. Retrieved 8 December 2016. 
  2. ^ a b c Gökmen, Vural (2015). Acrylamide in Food: Analysis, Content and Potential Health Effects. Academic Press. p. 415. ISBN 9780128028759. 
  3. ^ a b c Kim, Kyu-Won; Roh, Jae Kyung; Wee, Hee-Jun; Kim, Chan (2016). Cancer Drug Discovery: Science and History. Springer. p. 147. ISBN 9789402408447. 
  4. ^ "Asparaginase escherichia coli (Elspar) Use During Pregnancy". www.drugs.com. Retrieved 20 December 2016. 
  5. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016. 
  6. ^ "Asparaginase". International Drug Price Indicator Guide. Retrieved 8 December 2016. 
  7. ^ British National Formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 600. ISBN 9780857111562. 
  8. ^ Farmer, Peter B.; Walker, John M. (2012). The Molecular Basis of Cancer. Springer Science & Business Media. p. 279. ISBN 9781468473131. 
  9. ^ a b c d e Müller, H. (1998). "Use of L-asparaginase in childhood ALL". Critical Reviews in Oncology/Hematology. 28 (2): 97–113. doi:10.1016/S1040-8428(98)00015-8. 
  10. ^ https://www.medicines.org.uk/emc/medicine/32147
  11. ^ a b c d "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. 
  12. ^ 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. PMID 17554375. doi:10.1038/sj.leu.2404793. 
  13. ^ 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.
  14. ^ 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 1611087Freely accessible. PMID 4604804. doi:10.1136/bmj.3.5923.81. 
  15. ^ 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. PMID 19388639. doi:10.1021/jf900174q. Retrieved October 8, 2010. 
  16. ^ 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): null. ISSN 1354-3776. PMID 27813440. doi:10.1080/13543776.2017.1254194. 
  17. ^ Broome, J. D. (1981). "L-Asparaginase: Discovery and development as a tumor-inhibitory agent". Cancer treatment reports. 65 Suppl 4: 111–114. PMID 7049374. 
  18. ^ T. Selwood; E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function.". Arch. Biochem. Biophys. 519 (2): 131–43. PMC 3298769Freely accessible. PMID 22182754. doi:10.1016/j.abb.2011.11.020. 
  19. ^ 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 2136344Freely accessible. PMID 13109110. doi:10.1084/jem.98.6.565. 
  20. ^ 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 2137570Freely accessible. PMID 14015821. doi:10.1084/jem.118.1.99. 
  21. ^ a b c d Brayfield, A, ed. (June 2017). "Asparaginase: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 9 August 2017. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000246

Threonine peptidases are characterised by a threonine nucleophile at the N terminus of the mature enzyme. The threonine peptidases belong to clan PB or are unassigned, clan T-. The type example for this clan is the archaean proteasome beta component of Thermoplasma acidophilum.

This group of sequences have a signature that places them in MEROPS peptidase family T2 (clan PB(T)). The glycosylasparaginases (EC) are threonine peptidases. Also in this family is L-asparaginase (EC), which catalyses the following reaction: L-asparagine + H2O = L-aspartate + NH3

Glycosylasparaginase catalyses: N4-(beta-N-acetyl-D-glucosaminyl)-L-asparagine + H(2)O = N-acetyl-beta-glucosaminylamine + L-aspartate cleaving the GlcNAc-Asn bond that links oligosaccharides to asparagine in N-linked glycoproteins. The enzyme is composed of two non-identical alpha/beta subunits joined by strong non-covalent forces and has one glycosylation site located in the alpha subunit [PUBMED:8877373] and plays a major role in the degradation of glycoproteins.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan NTN (CL0052), which has the following description:

In the N-terminal nucleophile aminohydrolases (Ntn hydrolases) the N-terminal residue provides two catalytic groups, nucleophile and proton donor. These enzymes use the side chain of the amino-terminal residue, incorporated in a beta-sheet, as the nucleophile in the catalytic attack at the carbonyl carbon. The nucleophile is cysteine in GAT, serine in penicillin acylase, and threonine in the proteasome. All the enzymes share an unusual fold in which the nucleophile and other catalytic groups occupy equivalent sites. This fold provides both the capacity for nucleophilic attack and the possibility of autocatalytic processing [1].

The clan contains the following 16 members:

AAT Asparaginase_2 CBAH DUF1933 DUF3700 G_glu_transpept GATase_2 GATase_4 GATase_6 GATase_7 IMP_cyclohyd Penicil_amidase Peptidase_C69 Phospholip_B Proteasome Proteasome_A_N

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(55)
Full
(3745)
Representative proteomes UniProt
(7957)
NCBI
(12582)
Meta
(836)
RP15
(781)
RP35
(1988)
RP55
(3318)
RP75
(4716)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

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  Seed
(55)
Full
(3745)
Representative proteomes UniProt
(7957)
NCBI
(12582)
Meta
(836)
RP15
(781)
RP35
(1988)
RP55
(3318)
RP75
(4716)
Alignment:
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Sequence:
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  Seed
(55)
Full
(3745)
Representative proteomes UniProt
(7957)
NCBI
(12582)
Meta
(836)
RP15
(781)
RP35
(1988)
RP55
(3318)
RP75
(4716)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Sarah Teichmann
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 55
Number in full: 3745
Average length of the domain: 249.60 aa
Average identity of full alignment: 26 %
Average coverage of the sequence by the domain: 79.05 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 19.4 19.4
Trusted cut-off 19.5 19.4
Noise cut-off 19.3 19.3
Model length: 306
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

Asparaginase_2

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_2 domain has been found. There are 122 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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