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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Most healthy (untransformed) mammalian cells are capable of directly synthesizing asparagine from glutamine (Figure 9.22). Hence, asparagine is generally classified as a nonessential amino acid (i.e. we do not require it as an essential component of our diet). However,
Figure 9.22. (a) Hydrolytic reaction catalysed by L-asparaginase. (b) Reaction by which asparagine is
synthesized in most mammalian cells
many transformed cells lose the ability to synthesize asparagine themselves. For these, asparagine becomes an essential amino acid. In the case of leukaemic mice, guinea-pig asparaginase deprived the transformed cells of this amino acid by hydrolysing plasma asparaginase. This approach has been successfully applied to treating some forms of human leukaemia, e.g. 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 mM). Therefore, therapeutically useful asparaginases must display a high substrate affinity (i.e. low Km values). Asparaginase from E. coli and Erwinia, as well as Pseudomonas and Acinetobacter have been studied in greatest detail. All have proved 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 proved 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 asparagine 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 asparagine 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.
Recombinant DNase preparations have been used in the treatment of cystic fibrosis (CF) since the end of 1993. This genetic disorder is common, particularly in ethnic groups of northern European extraction, where the frequency of occurrence can be as high as 1 in 2500 live births. A higher than average incidence has also been recorded in southern Europe, as well as in some Jewish populations and American blacks.
A number of clinical symptoms characterize cystic fibrosis. Predominant among these is the presence of excess sodium chloride in CF patients’ sweat. Indeed, measurement of chloride levels in sweat remains the major diagnostic indicator of this disease. Another characteristic is the production of an extremely viscous, custard-like mucus in various body glands/organs, which severely compromise their function. Particularly affected are:
• the lungs, in which mucus compromises respiratory function;
• the pancreas, in which the mucus blocks its ducts in 85% of CF patients, causing pancreatic insufficiency; this is chiefly characterized by secretion of greatly reduced levels of digestive enzymes into the small intestine;
• the reproductive tract, in which changes can render males, in particular, sub-fertile or infertile;
• the liver, in which bile ducts can become clogged;
• the small intestine, which can become obstructed by mucus mixed with digesta.
These clinical features are dominated by those associated with the respiratory tract. The physiological changes induced in the lung of cystic fibrosis sufferers renders this tissue susceptible to frequent and recurrent microbial infection, particularly by Pseudomonas species. The presence of microorganisms in the lung attracts immune elements, particularly phagocytic neutrophils. These begin to ingest the microorganisms and large quantities of DNA are released from damaged microbes and neutrophils at the site of infection. High molecular mass DNA is itself extremely viscous and substantially increases the viscosity of the respiratory mucus.
The genetic basis of this disease was underlined by the finding of a putative CF gene in 1989. Specific mutations in this gene, which resides on human chromosome 7, were linked to the development of cystic fibrosis, and the gene is expressed largely by cells present in sweat glands, the lung, pancreas, intestine and reproductive tract.
70% of all CF patients exhibit a specific three-base pair deletion in the gene, which results in the loss of a single amino acid (phenylalanine 508) from its final polypeptide product. Other CF patients display various other mutations in the same gene.
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