Biomedical Engineering Reference
In-Depth Information
from cultures of the fungus Aspergillus fl avus has been used to treat this condition for a number of
years. More recently, a recombinant form of the fungal enzyme (tradename Fasturtec) has gained
regulatory approval in the EU. Produced in an engineered strain of S. cerevisiae , the enzyme is a
tetramer composed of four identical polypeptide subunits. Each subunit contains 301 amino acids,
displays a molecular mass of 34 kDa and is N-terminal acetylated.
Laronidase is yet an additional recombinant enzyme now approved for general medical use. The
product, used to treat mucopolysaccharidosis, is overviewed in Box 12.2.
12.5.5 Superoxide dismutase
Under normal circumstances in aerobic metabolism, oxygen is reduced by four electrons, forming
H 2 O. Although this usually occurs uneventfully, incomplete reduction will result in the generation
of oxygen radicals and other reactive species. These are: the superoxide radical O 2 , hydrogen
peroxide (H 2 O 2 ) and the hydroxyl radical (OH ). The superoxide and hydroxyl radicals are partic-
ularly reactive and can attack membrane components, nucleic acids and other cellular macromol-
ecules, leading to their destruction/modifi cation. O 2 and OH radicals, for example, are believed
to be amongst the most mutagenic substances generated by ionizing radiation.
Oxygen-utilizing organisms have generally evolved specifi c enzyme-mediated systems that
serve to protect the cell from such reactive species. These enzymes include SOD and catalase or
glutathione peroxidase (GSH-px), which catalyse the following reactions:
OO H
2
⎯→
SOD
⎯⎯
HOO
2
2
22
2
HO
HO
catalase or GSH-px
⎯⎯⎯⎯⎯
2HO
O
22
22
2
2
In general, all aerobic organisms harbour these oxygen-defence systems. At least three types of
SOD have been identifi ed: a cytosolic eukaryotic dismutase, generally a 31 kDa dimer, containing
both copper and zinc; a 75 kDa mithocondrial form and a 40 kDa bacterial form, each of which
contains two manganese atoms. There is also an iron-containing form found in some bacteria,
blue-green algae and many plants. The metal ions play a direct role in the catalytic conversion,
serving as transient acceptors/donors of electrons.
In humans, increased generation of O 2 and/or reduced SOD levels have been implicated in a
wide range of pathological conditions, including ageing, asthma, accelerated tumour growth, neu-
rodegenerative diseases and infl ammatory tissue necrosis. Furthermore, administration of SOD
has been found to reduce tissue damage due to irradiation, or to other conditions that generate O 2 .
Increased SOD production in Drosophila melanogaster leads to increased oxygen tolerance and,
interestingly, increased life span.
SOD isolated from bovine liver or erythrocytes has been used medically as an anti-infl amma-
tory agent. Human SOD has also been expressed in several recombinant systems, and is currently
being evaluated to assess its ability to prevent tissue damage induced by exposure to excessively
oxygen-rich blood.
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