Asparaginase
| Asparaginase ( Homo sapiens ) | ||
|---|---|---|
| Properties of human protein | ||
| Mass / length primary structure | 309 amino acids | |
| Isoforms | 2 | |
| Identifier | ||
| Gene name | ASRGL1 | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 3.5.1.1 , hydrolase | |
| Response type | hydrolysis | |
| Substrate | L -asparagine + H 2 O | |
| Products | L -aspartate + NH 3 | |
| Occurrence | ||
| Homology family | Asparaginase | |
| Parent taxon | Creature | |
| Asparaginase 2 ( Escherichia coli K12 ) | ||
|---|---|---|
|
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| Surface model of the tetramer, with asparagine as a cap, according to PDB 3ECA | ||
| Mass / length primary structure | 326 amino acids | |
| Secondary to quaternary structure | Homotetramer | |
| Identifier | ||
| Gene name (s) | ansB (EcoGene) | |
| External IDs |
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| Drug information | ||
| ATC code | L01 XX02 | |
| DrugBank | BTD00011 | |
| Drug class | Cytostatics | |
| Enzyme classification | ||
| EC, category | 3.5.1.1 , hydrolase | |
| Response type | hydrolysis | |
| Substrate | L -asparagine + H 2 O | |
| Products | L -aspartate + NH 3 | |
Asparaginases (L-asparagine amidohydrolases) are generally enzymes that catalyze the hydrolysis of asparagine to aspartic acid. This reaction is one way of breaking down asparagine. Asparaginases occur in all living things; they were found in large quantities in the serum of guinea pigs and agoutis , as well as in the liver of several vertebrate species, as well as in fungi and several bacterial strains. In humans, it is expressed in the brain, kidneys, testes and intestines.
Aspergillus asparaginase is used to reduce acrylamide levels in foods , e.g. B. baked goods used.
Asparaginase in the narrower sense is a drug from the group of cytostatics used to treat acute lymphocytic leukemia (ALL) and subtypes of non-Hodgkin's lymphoma . It is obtained from various bacteria, especially Escherichia coli .
Clinical information
Application areas (indications)
As a cytostatic , asparaginase is used to treat acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma . It can be used both as monotherapy and as part of a polytherapy and has been used for induction and consolidation treatment of malignant lymphatic diseases since the 1960s.
Dosis, kind and Time of the Use
Asparaginase is dissolved in water as a powder and given intramuscularly or intravenously .
With asparaginase, it is particularly important to have good control of serum asparaginase. Improvement in disease-free and overall survival only occurs with the correct dosage. If the dosage is too low, asparaginase can even have negative effects on both. Frequent blood draws cannot be avoided for this “drug monitoring”, which can cause difficulties especially in young patients (ALL is very common in children of four years of age and also occurs at an age of less than one year).
Contraindications (contraindications)
Asparaginase should not be given to patients with pancreatitis . As a result, cases of acute hemorrhagic pancreatitis resulting in death have become known throughout history.
Asparaginase should also be avoided in patients who have already shown anaphylactic reactions .
Drug interactions
Studies have shown that asparaginase, or the low level of asparagine in the blood, reduces the effects of methotrexate on malignant cells. So these should not be given in combination.
Use during pregnancy and breastfeeding
There are no studies in pregnant women, but studies in mice and rats have shown that asparaginase could adversely affect the child's growth and weight gain. It also seems to increase the risk of miscarriage or deformity. Malformations have been observed in rabbits.
It is not known whether and how asparaginase gets into breast milk.
Pregnancy and breastfeeding is generally not recommended during treatment with asparaginase.
Special patient groups (diabetics, kidney patients)
Asparaginase therapy can lead to increased blood sugar levels.
Adverse effects (side effects)
The most common side effects are loss of appetite, nausea, and vomiting. These are mostly easy to treat today. Asparaginase also has a negative effect on the immune system, which can lead to infections.
Because asparaginase is a foreign protein, it has a high immunogenicity, which ensures immunological reactions . These can be clinical reactions up to anaphylactic shock , but also reactions that do not manifest themselves clinically but that influence the activity of asparaginase.
Cases of pancreatitis and liver dysfunction as well as coagulopathy are also known . Since asparaginase affects protein synthesis, it also affects the synthesis of clotting factors . This can cause bleeding or thrombosis.
Pharmacological properties
Mechanism of action (pharmacodynamics)
Healthy cells can make their own asparagine. Leukemic cells (lymphoblasts) in ALL cannot. They are therefore dependent on circulating asparagine. This is used in the treatment with asparaginase. Asparaginase catalyzes the breakdown of asparagine into aspartic acid and ammonium and thus ensures a low concentration of asparagine in the blood . The leukemic cells no longer get enough asparagine to survive.
Other Information
It was accepted into everyday therapy in the 1960s.
Studies
- Sallan et al. (Significant improvement in disease-free survival)
- EORTC (comparison of L-asparaginase obtained from E. coli and Erwinia Chrysanthemi)
- Desai et al. (Study on Disease-Free Survival in Children with Acute Leukemia and Non-Hodgkin Lymphoma)
Web links
- Entry for asparaginase in the University of Alberta's DrugBank .
- Drugs.com: Asparaginase Injection consumer information
- Data sheet Asparaginase from Escherichia coli from Sigma-Aldrich , accessed on June 16, 2011 ( PDF ).
Individual evidence
- ↑ John C. Wriston, Jr .: L-Asparaginase. In: Paul D. Boyer, Edwin G. Krebs, David S. Sigman (Eds.): The Enzymes. Edition: 3, Academic Press, 1971. ISBN 0-12-122704-9 , pp. 101ff.
- ↑ UniProt Q7L266
- ↑ Zofia Olempska-Beer: asparaginase from Aspergillus Niger overexpressed in A. Niger. (PDF; 98 kB) Chemical and Technical Assessment. In: fao.org. Food and Agriculture Organization of the United Nations, accessed February 24, 2016 .
- ↑ RH Adamson, S Fabro: Antitumor activity and other biologic properties of L-asparaginase (NSC-109229) -a review . In: Cancer Chemother Rep . 52, No. 6, October 1968, pp. 617-626. PMID 4895425 .
- ↑ RL Capizzi, JR Bertino, RE Handschumacher: L-asparaginase . In: Annu. Rev. Med. . 21, 1970, pp. 433-44. doi : 10.1146 / annurev.me.21.020170.002245 . PMID 4913953 .
- ↑ SE Sallan, BM Cammita, JR Cassady, DG Nathan, E Free: Intermittent combination chemotherapy with adriamycin for acute lymphoblastic leukemia childhood: clinical results . In: Blood . 51, No. 3, March 1978, pp. 425-33. PMID 272207 .
- ↑ MD Amylon, J Shuster, J Pullen et al .: Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study . In: Leukemia . 13, No. 3, March 1999, pp. 335-42. PMID 10086723 .
