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What Are Proteases?

For more information on proteases see the Australian Protease Network ARC Report
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.

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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