23.02.1 Proteins that Function through Enzymatic or Regulatory Activity.

It is apparent that many pathophysiological states occur when a component, usually a protein or a metabolite occurring from the action of that protein, of a normal biological process is compromised in some way. Disease may occur when one of these proteins is defective or present in abnormally high or low concentrations. Thus supplementation with firstly proteins purified from animal sources and, now, with recombinant human protein homologues allows for new therapeutic targets in the treatment of these diseases.

Treatment of type I diabetes mellitus with exogenous insulin is perhaps the best and most illustrative example of how a protein has come to be used therapeutically. Diabetes mellitus results from an inability to sequester glucose from the blood. Diabetes mellitus occurs when circulating insulin levels decline or when the target cells become resistant to the hormone. As well as carbohydrates, insulin has a profound effect on the metabolism and utilisation of lipids and fats. Insulin was first isolated from porcine and bovine pancreas in 1922 and was used therapeutically almost immediately as a lifesaving daily injection. However two problems associated with their use became quickly apparent; firstly an immune reaction to the animal proteins and secondly, purifying it from animal sources is expensive and time consuming. For example, in 1923, Harold Ward Dudley published a purification scheme where he was able to purify 74g of insulin from 104kg of pancreas tissue using a procedure that took about 3 days.

Once the human gene for insulin was isolated, it became a prime target for recombinant DNA technology. This has resulted in the production of large amounts of human insulin that is inexpensive, of low immunogenicity and free from other animal pancreatic substances. Indeed recombinant human insulin was approved in the United States in 1982 and was the first commercially available recombinant protein drug. More recently, “genetic tinkering” has allowed the production of new insulin types with altered properties such as quicker onset and longer duration of action. The use of recombinant insulin in the treatment of type I diabetes is discussed in Chapter 15.

However, great success has also been achieved using purified protein preparations from animal and microbial sources. For example in cystic fibrosis, defects in the chloride channel can result in abnormally thick secretions that can block pancreatic enzymes from travelling down the pancreatic duct to the duodenum preventing food being properly digested resulting in patient malnutrition. Patients can be treated with a combination of porcine pancreatic enzymes (Pancrease) purified from pigs to aid digestion.

Similarly, lactose intolerance is the condition in which lactase, an enzyme needed for proper metabolism of lactose (a constituent of milk and other dairy products), is not produced in adulthood. The management of lactose intolerance includes preparing foods (Digestelact) in which the lactose content is decreased by treating with lactase from the food yeast Saccharomyces Sp.