Asparaginase

Asparaginase is an enzyme capable of catalysing the hydrolysis of l-asparagine, yielding aspartic acid and ammonia (Figure 12.14). In the late 1970s, researchers illustrated that serum transferred from healthy guinea pigs into mice suffering from leukaemia contained some agent capable of inhibiting the proliferation of the leukaemic cells. A search revealed the agent to be asparaginase.

Table 12.8 Enzymes used therapeutically

Enzyme

Application

Tissue plasminogen activator

Thrombolytic agent

Urokinase

Thrombolytic agent

Ancrod

Anticoagulant

Factor IXa

Haemophilia B

Asparaginase

Anti-cancer agent

Nuclease (DNase)

Cystic fibrosis

Glucocerebrosidase

Gaucher's disease

a-Galactosidase

Fabry disease

Urate oxidase

Hyperuricaemia

Laronidase

Mucopolysaccharidosis

Superoxide dismutase (SOD)

Oxygen toxicity

Acid a-glucosidase

Pompe disease

a-l-Iduronidase

Mucopolysaccharidosis I (MPS I)

N-Acetylgalactosamine-4-sulfactase

Mucopolysaccharidosis IV

Trypsin/papain/collagenase

Debriding/anti-inflammatory agents

Lactase/pepsin/papain/pancrelipase

Digestive aids

Most healthy (untransformed) mammalian cells are capable of directly synthesizing asparagine from glutamine (Figure 12.14). Hence, asparagine is generally classified as a non-essential amino acid (i.e. we do not require it as an essential component of our diet). However, many transformed cells lose the ability to synthesize asparagine themselves. For these, asparagine becomes an essential amino acid. In the case of the leukaemic mice, the guinea pigs' asparaginase deprived the transformed cells of this amino acid by hydrolysing plasma asparagine. This approach has been successfully applied to treating some forms of human leukaemia. For example, the PEG-l-asparaginase previously mentioned was approved for the treatment of refractory childhood acute lymphoblastic leukaemia.

Generally, the plasma concentration of asparagine is quite low (~40 ^mol l_1). Therefore, therapeutically useful asparaginases must display a high substrate affinity (i.e. low Km values). Asparaginase from E. coli and Erwinia, as well as from Pseudomonas and Acinetobacter, has been studied in greatest detail. It has proven effective in inhibiting growth of various leukaemias and other transformed cell lines. PEG-coupled enzymes are often preferred, as they display an extended plasma half-life.

Although asparaginase therapy has proven effective, a number of side effects have been associated with initiation of therapy. These have included severe nausea, vomiting and diarrhoea, as well as compromised liver and kidney function. Side effects are probably due to a transient asparaginase deficiency in various tissues. Under normal circumstances, dietary-derived plasma asparag-ine levels are sufficient to meet normal tissue demands, and the cellular asparagine biosynthetic pathway remains repressed. Reduced plasma asparagine levels result in the induction of cellular asparagine synthesis. High-dose asparaginase administration will immediately reduce plasma as-paragine levels. However, the ensuing initiation of cellular asparagine synthesis may not occur for several hours. Thus, a more suitable therapeutic regimen may entail initial low-dose asparaginase administration, followed by stepwise increasing dosage levels.

COO-

COO I

Asparaginase

nh4+

Asparagine

Aspartic acid

COO I

COO I

Glutamine amidotransferase

COO I

COO I

COO-

Aspartic acid Glutamine Asparagine Glutamic acid

Figure 12.14 (a) Hydrolytic reaction catalysed by l-asparaginase. (b) Reaction by which asparagine is synthesized in most mammalian cells

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