ATHENS, Ga. -- Biochemists at the University of Georgia have for the first time described the crystal structure of an enzyme crucial to an important class of organic chemicals called aldehydes. The discovery will help researchers understand better how aldehydes are metabolized in both plants and animals.
The research was published today in the British journal Nature Structural Biology and was supported by grants from the National Institutes of Health and the National Institute on Alcohol Abuse and Alcoholism.
"Elimination of aldehydes from living systems is important in maintaining their health," said Dr. B.C. Wang, Georgia Research Alliance Eminent Scholar in Structural Biology and Ramsey professor of biochemistry and molecular biology at UGA. "And the important enzyme aldehyde dehydrogenase is widely distributed in virtually all tissues in plants and animals. Knowing more about it is important."
Aldehydes are a class of highly reactive organic chemical compounds obtained by the oxidation of primary alcohols. They occur in everything from fruits to smoke and can be beneficial to living systems. Retinaldehyde, for example, aids in vision. But far more often, aldehydes can poison cells and even trigger the development of cancers. That's why the elimination of aldehydes is crucial to the health of living cells.
A number of enzymes have evolved to eliminate aldehydes, and one of the most effective is aldehyde dehydrogenase or ALDH. This enzyme oxidizes aldehydes to carboxylic acid. It is found in many places in the human body, including the liver, stomach, kidney, eye and brain. Its exact structure is specific for each location, depending on how the body needs to use it there. Human liver ALDH is one of two key enzymes responsible for alcohol metabolism, for example. Alcohol dehydrogenase converts alcohol to aldehyde, and ALDH converts aldehyde to carboxylic acid, which can then be elminated from the body or used in other metabolic pathways.
A mutation in the human fatty aldehyde dehydrogenase has been linked to a fetal neurological disorder called Sjogren-Larsson syndrome, and a change in ALDH activity has been observed in a number of tumors, including those of the liver, colon and breast. In short, ALDH is a vital enzyme involved with numerous processes of animal and plant health.
Though ALDH was first purified in 1949 and the amino acid sequence determined in 1984, the structure of the compound remained a mystery until it was reported today by the University of Georgia research group headed by Wang, an X-ray crystallographer, in collaboration with scientists at the University of Pittsburgh and the University of South Dakota.
"This is the first look at a member of the ALDH family in atomic detail," said Wang.
X-ray crystallography is a technique of determining a molecule's three-dimensional structure by analyzing the X-ray diffraction pattern of crystals. It is referred to as a "transformed image," because it is not a literal picture of the contents inside a crystal but an interference pattern from which researchers can determine the crystal's contents.
The team found that the active form of the enzyme is a dimer -- a molecule that consists of two similar but not necessarily identical subunits. A molecule of ALDH, however, does have two identical subunits. When Wang's group used X-crystallography techniques to study the molecule, he found something unusual about its structure.
Structure is everything for an enzyme. And how its parts bind together helps determine how it acts and reacts in living cells. The UGA researchers found that the binding domains for ALDH showed something unexpected and entirely new. They discovered that a coenzyme called NAD (nicotinamide adenine dinucleotide) interacted in a highly unusual way with a site called the Rossman fold. This odd interaction was completely different from interactions observed in all other dehydrogenase families with Rossman folds.
Just what this structural anomaly means is unclear.
Wang's group also discovered a funnel-shaped passage in the structure that could be involved in determining how ALDH works. Wang speculates that the funnel's upper part could provide the specific ALDH needed to break down a specific aldehyde.
Structural studies of enzymes using X-ray crystallography have become increasingly important in understanding how the natural world works.