What Are Proteases?
Proteases, proteinases, or peptidases are enzymes that are essential for all life.
They are biology's version of Swiss army knives,
cutting long sequences of amino acids (called peptides) into fragments
that fold into proteins. Amino acids are common building blocks for all
life. Organisms (including humans and other mammals) extract them from
their environment (diet) or synthesize them, and link them together to
form biological polymers (called polypeptides), and then control their
size and shape through a variety of mechanisms to form folded globular
shapes, known as proteins. Proteases are essential for the synthesis of
all proteins, controlling protein composition, size, shape, turnover
and ultimate destruction. Their actions are exquisitely selective, each
protease being responsible for splitting very specific sequences of
amino acids under a preferred set of environmental conditions. They are
numerous. There are over 500 human proteases, accounting for 2% of human genes (DNA
sequences that code for amino acids), and similar numbers of proteases
occur in every plant, insect, marine organism and in all infectious
organisms that cause disease.
Why Are Proteases Important?
Proteases play pivotal regulatory roles in conception, birth,
digestion, growth, maturation, ageing, and death of all organisms.
Proteases regulate most physiological processes by controlling the
activation, synthesis and turnover of proteins. Proteases are also
essential in viruses, bacteria and parasites for their replication and
the spread of infectious diseases, in all insects, organisms and
animals for effective transmission of disease, and in human and animal
hosts for the mediation and sustenance of diseases.
In medicine, proteases represent important potential targets for medical intervention because of their important regulatory roles
in life. It is now known that single amino acid mutations in over 50
human proteases result in hereditary/genetic diseases, a few of which
are
Also, other genetic or environmental conditions can result in an over-
or under- abundance of a particular crucial protease or abnormal levels
of natural inhibitors/activators of proteases, leading to abnormal
physiology and disease.
Blockbuster drugs have been developed to block (inhibit) viral
proteases required for replication of HIV and are currently the most
effective treatments for HIV/ AIDS; others block a human protease
(thrombin) involved in blood clotting and are among the most effective
treatments for stroke and coronary infarction,; and others blocking
another human protease (ACE) that raises blood pressure are among the
best treatments for high blood pressure or hypertension. Other protease
inhibitors are being developed to treat parasitic, fungal, and viral
infections; inflammatory, immunological, and respiratory conditions;
cardiovascular and neurodegenerative disorders including Alzheimer's
disease, and cancers. Human proteases have also been identified as
important prognostic indicators of diseases, such as kallikreins (e.g.
prostate specific antigen) which are promising diagnostics for prostate
cancer. A number of other proteases are experimental vaccines currently
in development to fight infectious diseases.
In our environment, proteases are key regulators of the life of insects
and other agricultural pests, key regulators of growth and health of
farm animals, and principal regulators of plants and marine food
sources. Research into these relatively under-studied proteases has the
potential to contribute spectacularly to our economy by improving plant
and animal health through enhanced growth and treatment/prevention of
parasite infections, crop protection through new herbicides and
pesticides, and increased or faster production of food resources.
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Some
human proteases (kallikreins, metalloproteases, cathepsins) have been
identified as important prognostic indicators of diseases. For example,
prostate specific antigen is a protease used in the diagnosis of
prostate cancer. A number of other proteases are experimental vaccines
in current development to fight infectious diseases caused by parasite
and viral infections. For example experimental vaccination programmes
are either in progress or on the horizon in less developed countries
for widespread diseases like malaria, schistosomiasis, and Dengue
fever. Proteases associated with toxins such as Clostridium tetani
(tetanus toxin) and Bacillus anthracis (anthrax toxin) are also being
investigated as possible vaccines.
References
Puente, X. S.; Sanchez, L. M.; Overall, C. M.; Lopez-Otin, C., Human
and mouse proteases: a comparative genomic approach. Nat Rev Genet
2003, 4, (7), 544-58.
Seife, C., Blunting nature's Swiss army knife, Science, 277, 1602-3.
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