COLLEGE STATION – Like an aspirin speeds through the body to inhibit fever, research is finding how other compounds might treat neurological disorders such as PKU in infants and Parkinson's disease in adults, a scientist at Texas A&M University says.
"The modern approach is to determine the structure of proteins so you can see what will inhibit them, then determine the chemical reaction that allows to you design inhibitors," said Dr. Paul Fitzpatrick, Texas Agricultural Experiment Station biochemist.
Aspirin, originally derived from willow bark, is known to have been used in the fifth century by Hippocrates to ease aches and pains. But for centuries, even after becoming commercially successful in the 20th century, the fact that aspirin works by inhibiting enzymes was not known, according to the U.S. Food and Drug Administration.
Just as aspirin's mechanism of action finally became understood, Fitzpatrick explained, researchers now are trying to more fully understand a host of enzymes responsible for certain disorders. But rather than try willow bark powder, so to speak, in an attempt to find cures, scientists are exploring enzymes at their molecular level and then looking for chemicals that will inhibit the undesired traits.
For Fitzpatrick, research centers around three enzymes that are closely related by evolution: phenylalanine hydroxylase, which is in the liver and linked to Phenylketonuria, or PKU, a disease that causes a form of mental retardation if not detected early in newborns; tyrosine hydroxylase, which is in the adrenal gland and makes adrenaline; and, tryptopham hydroxylase, which is in the liver and makes serotonin which is involved with moods.
Since liver and adrenal gland tissues are not easy to come by, Fitzpatrick said, his lab engineered bacteria to express each of them.
"All multicellular organisms have these three enzymes. We are born with them. So we are looking at them in detail – from the fruit fly to humans to bacteria – to understand the molecular basis for the differences," Fitzpatrick said. "Once we can see what inhibits them, we can determine the chemical reaction that will allow pharmaceutical companies to design drugs for that condition."
In the case of PKU, infants and children who have this inherited condition must limit all protein foods such as meat, eggs, fish, milk and cheese and to a lesser extent cereals, vegetables and fruits that contain the amino acid phenylalanine, according to a March of Dimes Public Health Education information sheet.
Fitzpatrick suggested that if a drug could be developed to stabilize the enzyme thus reversing the effect, those with this condition would be able to eat anything without fear of massive, irreversible mental retardation occurring. Other drugs possibily will be developed, Fitzpatrick said, to regulate the enzyme that pertains to Parkinson's disease and perhaps the enzyme associated with hormone imbalance that is suspected in schizophrenia.
"There is not much known about the hydroxylases, and this is not a crowded field of research," Fitzpatrick said. "But it's physiologically important and could make a big difference for people with these disorders."