Translating form into function

July 1, 2007

In the last 40 years, scientists have perfected ways to determine the knot-like structure of enzymes, but they’ve been stumped trying to translate the structure into an understanding of function – what the enzyme actually does in the body. This puzzle has hindered drug discovery, since many of the most successful drugs work by blocking enzyme action. Now, in an expedited article in Nature, researchers show that a solution to the puzzle is finally in sight.

A team co-led by UCSF’s Brian Shoichet, Steven Almo of the Albert Einstein College of Medicine, and Frank Raushel of Texas A&M describes the first success “decrypting” an enzyme’s function from its structure. If their new strategy works with other enzymes, it should become a potent tool to determine how key enzymes work in the body. And since enzyme action is crucial to disease, the technique opens an efficient route to drug discovery, Shoichet say.

Schoichet a professor of pharmaceutical chemistry and an investigator in the California Institute for Quantitative Biomedical Research, or QB3, based at UCSF.

The team’s success came by modifying a technique called molecular docking, a computer-aided modeling strategy used to search for potential drugs. Docking works by allowing researchers to first determine the atom-by-atom structure of an enzyme and then screen many thousands of molecules for one that fits into the empty “active site” of the enzyme.

Shoichet calls this a search for the missing piece of a jigsaw puzzle. A molecule that fits the enzyme’s active site will block its activity – just what many promising drugs do.

The strategy works well for one kind of drug discovery -- finding molecules to fit in the active site and physically block enzyme action. But the research team sought to divine from an enzyme’s structure just what natural molecule triggers the enzyme into action -- fitting into the active site and enabling the enzyme to act as a catalyst. This was a search for the so-called substrate for the enzyme, a search that has never succeeded simply from knowing an enzyme’s configuration.

The key to the team’s success was a computational feat: simulating candidate substrates that mimicked unstable “intermediate” molecules – those that exist only briefly as the catalyst turns the substrate into a new molecule.

Because these intermediates are unstable, scientists have until now been unable to test their fit to the enzyme’s active site.

Once the scientists had predicted the substrate, Raushel, a professor of chemistry at Texas A&M University, tested the prediction experimentally. The results confirmed the prediction. Almo, a professor of biochemistry at Albert Einstein College of Medicine, further confirmed the finding by determining the substrate’s atomic level structure through x-ray crystallography.

“To tell the truth, we were very surprised that the docking approach worked to determine the substrate,” says Shoichet. “There’s so many ways that the approach can go wrong. We’re all very gratified.”

For their experiments, the team extracted an enzyme from a bacterium known as Thermotoga maritima, a microbe that normally lives at very high temperatures and pressures near volcanic ocean vents. Its structure was determined as a part of the structural genomics project, a large-scale, worldwide effort to determine the structures of enzymes and receptors.

With the nature of the substrate in hand, the scientists went on to discover that the enzyme works in a previously uncharacterized metabolic pathway in bacteria.

Source: University of California - San Francisco

Explore further: Human lung-on-a-chip technology used to study behavior, drug responses of lung cancer in its natural environment

Related Stories

Human lung-on-a-chip technology used to study behavior, drug responses of lung cancer in its natural environment

October 10, 2017
Cancer researchers have come to understand that generating human tumors in mice by injecting cancer cell lines under the skin does not recapitulate how tumors normally emerge and spread to specific organs in the human body, ...

Epigenetics of addiction: Epigenetic study untangles addiction and relapse in the brain

September 27, 2017
Why do some drug users continue to seek out drugs despite the prospect of losing family, friends, health or livelihood?

A new paradigm for treating transcription factor-driven cancers

September 18, 2017
In the current issue of Proceedings of the National Academy of Sciences, researchers from Nationwide Children's Hospital describe a new paradigm for treating transcription factor-driven cancers. The study focuses on Ewing ...

Engineered therapy for blood clotting disorder shows early promise

September 14, 2017
An investigational treatment that mimics a key clotting enzyme is effective, safe, and may one day eliminate the need for blood products for people with the rare, life-threatening blood disease hereditary thrombotic thrombocytopenic ...

First-ever look at potentially deadly metabolic disorder that strikes infants

August 31, 2017
You may have never heard of congenital disorder of glycosylation, but parents whose children are born with forms of this rare – and underreported – metabolic disorder know all too well the dangers they pose, including ...

Vitamin C may encourage blood cancer stem cells to die

August 17, 2017
Vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone ...

Recommended for you

Engineered protein treatment found to reduce obesity in mice, rats and primates

October 19, 2017
(Medical Xpress)—A team of researchers with pharmaceutical company Amgen Inc. report that an engineered version of a protein naturally found in the body caused test mice, rats and cynomolgus monkeys to lose weight. In their ...

Cancer drug found to offer promising results in treating sepsis in test mice

October 19, 2017
(Medical Xpress)—A combined team of researchers from China and the U.S. has found that a drug commonly used to treat lung cancer in humans offers a degree of protection against sepsis in test mice. In their paper published ...

New procedure enables cultivation of human brain sections in the petri dish

October 19, 2017
Researchers at the University of Tübingen have become the first to keep human brain tissue alive outside the body for several weeks. The researchers, headed by Dr. Niklas Schwarz, Dr. Henner Koch and Dr. Thomas Wuttke at ...

Study reveals key molecular link in major cell growth pathway

October 19, 2017
A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth. Their work, which ...

Tracing cell death pathway points to drug targets for brain damage, kidney injury, asthma

October 19, 2017
University of Pittsburgh scientists are unlocking the complexities of a recently discovered cell death process that plays a key role in health and disease, and new findings link their discovery to asthma, kidney injury and ...

Inflammation trains the skin to heal faster

October 18, 2017
Scars may fade, but the skin remembers. New research from The Rockefeller University reveals that wounds or other harmful, inflammation-provoking experiences impart long-lasting memories to stem cells residing in the skin, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.