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72  structures 1641  species 1  interaction 2653  sequences 21  architectures

Family: Asparaginase_2 (PF01112)

Summary: Asparaginase

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Asparaginase Edit Wikipedia article

Asparaginase
L-Asparaginase.png
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

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

As a food processing aid

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

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

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

Side effects in drug use

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

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

  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

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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

In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:

  • Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
  • Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.

In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

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

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

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 14 members:

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

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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(7)
Full
(2653)
Representative proteomes NCBI
(2127)
Meta
(867)
RP15
(291)
RP35
(539)
RP55
(822)
RP75
(1019)
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Format an alignment

  Seed
(7)
Full
(2653)
Representative proteomes NCBI
(2127)
Meta
(867)
RP15
(291)
RP35
(539)
RP55
(822)
RP75
(1019)
Alignment:
Format:
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Sequence:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(7)
Full
(2653)
Representative proteomes NCBI
(2127)
Meta
(867)
RP15
(291)
RP35
(539)
RP55
(822)
RP75
(1019)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped 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.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Sarah Teichmann
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 7
Number in full: 2653
Average length of the domain: 259.80 aa
Average identity of full alignment: 32 %
Average coverage of the sequence by the domain: 88.17 %

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 19.4 19.4
Trusted cut-off 19.9 19.5
Noise cut-off 19.1 19.2
Model length: 319
Family (HMM) version: 13
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 72 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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