The "Judas Enzyme" exposed

An enzyme in the body can sometimes "change personality" and cause diseases such as psoriasis. Berit Johansen and her colleagues have discovered a substance which seems to block this "Judas enzyme". The result might be a new kind of drug to treats the disease. Photo: Rune Petter Ness

A new generation of psoriasis medication may come into being thanks to painstaking research into molecular biology.

By Nina E. Tveter

What happens when we develop psoriasis? Molecular biologists at NTNU have come much closer to finding an answer to this question. They have revealed what happens to one particular enzyme when healthy tissue falls ill, and they have developed a substance which seems to have the ability to block - or at least to delay - the progression of the disease. The substance is at present in the process of being patented.

The "Judas enzyme"
Until recently researchers did not know anything about the important function of the enzyme phospholipase A2 in epidermal cells. Under certain circumstances the enzyme contributes to an alteration of the cell function by activating new genes in the cell nucleus. In such cases the enzyme changes its role from being of benefit to body and cells, to one of causing illness. When other genes take command in the cells, they may divide at a more rapid pace. We can see this happening in psoriasis patients, whose skin thickens and starts to peel.
The enzyme phospholipase A2 is found inside our cells, and its task is to transmit "messages" from the cell surface to the nucleus. When molecular biologists discovered that this "Judas enzyme" was capable of deprogramming cells, they started to wonder whether it might be possible to trick the enzyme. In the laboratories, some researchers were cultivating cell cultures which resembled the skin of psoriasis patients. These cells were subjected to different chemical compounds, which researchers had reason to believe were able to block the negative behaviour of the enzyme.
Then one day the researchers found the key to the lock, so to speak: a type of modified fatty acid which easily binds with the enzyme. When the enzyme is bound to the modified fatty acid, it is unable to "transmit messages" to those nasty genes in the cell nucleus which cause the increase in cell division and the inflammation in the cells.

Patented drug
The researchers have recently developed a synthetic variety of this chemical compound that is based on fatty marine acids, and they have applied for patents on this "blocker", and the knowledge of how the problematic enzyme works and the effect it has on skin cells. But before the molecular biologists can be granted patent protection for its use, they have to be able to prove in vivo - on living organisms - that the blocker works.
This can be done by transplanting psoriasis-infected human skin onto mice. Some mice are treated with the blocker, while others are not. This method will confirm whether or not the blocker is effective in the treatment of psoriasis. The tests are to be carried out in collaboration with a university hospital in Germany.
"If the blockers are patented, rights in them can either be sold to a pharmaceutical company able to develop a drug, or a spin-off firm from the research environment may develop the concept further," says Professor Berit Johansen.
She explains that knowledge about the enzyme phospholipase A2 and the method of blocking unwanted activity in the cells most probably can be applied to the treatment of other diseases.
"This new knowledge is of more general interest, not least in relation to chronic diseases such as allergies, asthma, rheumatism, chronic enteric diseases, and cardiovascular diseases. A symptom common to all these diseases is a physical inflammatory reaction."

Methods for developing future medicinal drugs
"Earlier methods for developing a medicinal drug have often been a bit like breaking a butterfly on a wheel: you have to try out a vast number of different drugs in order to end up with one that works. So far, psoriasis has been treated with cortisone drugs, among others. But even if these products are quite efficient, long-term usage may cause unfortunate side effects. It is only recently that research has been able to unveil how such drugs work. Understanding disease at a molecular level - that is, understanding what is actually going on in cells when we become ill, and then develop drugs for treatment or total cure - this is the future for medicinal drugs," says Johansen.
This approach, which is called mechanism-based drug development, was begun at the Unigen Centre at NTNU. After Unigen was closed down, the research continued at the Faculty of Chemistry and Biology at NTNU, the present Faculty of Natural Sciences and Technology. The Research Council of Norway supports the research financially.

Contact: Berit Johansen
Department of Biology, NTNU
Tel: +47 73 59 86 91
Email: Berit.Johansen@bio.ntnu.no