June 11, 1999 By detailing the precise molecular pathways of apoptosis, or programmed cell death, scientists at Jefferson Medical College hope to someday develop new drugs against cancer, Alzheimer’s disease and Parkinson’s disease.
In the June 10 issue of the journal Nature, Emad Alnemri, Ph.D., associate professor of microbiology and immunology at Thomas Jefferson University in Philadelphia, in collaboration with Yigong Shi, Ph.D., at Princeton University, describe the workings of an enzyme, caspase-9, that is crucial to understanding apoptosis. In effect, they detail part of the intricate cascade of cellular events leading to activation of this enzyme in apoptosis.
"Biotechnology companies are trying to develop drugs that inhibit caspases to fight neurodegenerative diseases and other diseases in which apoptosis is involved in the pathologic process, and are developing clinical trials," says Dr. Alnemri, who is also deputy director of the Jefferson Center for Apoptosis Research. Understanding the apoptotic pathway and each protein’s role in the cell-to-cell communication process has implications for drug discovery, he says.
Apoptosis is a fundamental biological process that is vital to cell differentiation and normal development. In human embryos, for example, apoptosis creates fingers from mitt-like hands. It occurs during normal aging and sometimes during irreversible cell injury from radiation and other poisons. Scientists believe apoptosis gone awry underlies neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, autoimmune diseases such as lupus, and cancer.
Apoptosis has received a great deal of attention in the popular press in recent years when scientists discovered that part of the reason cancer cells grow with abandon is because they lose the ability to die at a preset time.
Dr. Alnemri explores apoptosis at the molecular level, attempting to understand how and why various molecules affect the process, particularly what triggers it to begin with. The focus of his research is caspases, a family of 14 cysteine proteases, enzymes that degrade critical cellular proteins. Seven of these are known to be involved in apoptosis. Dr. Alnemri and his co-workers discovered many of the caspases themselves.
In the Nature paper, the researchers focused their attentions on better understanding the chemical "recognition complex," or precise binding region, between caspase-9, and Apaf-1 (apoptotic protease activating factor-1), a protein that helps regulate apoptosis. "They bind to each other – we published that previously – but no one knew how. We had never seen the crystal structure of that binding complex," Dr. Alnemri explains. "We wanted to know which amino acids were involved, and the chemical nature of this interaction.
"We overexpressed and crystallized the actual pieces of Apaf-1 and caspase-9 that bind to each other," he explains. The scientists subsequently used x-ray crystallography to analyze the chemical structure of the recognition complex, where the two interact with one another. They showed how mutation of even a single critical amino acid within the recognition complex can affect the binding between the two proteins.
Dr. Alnemri contends that a key to halting the diseases processes involved in many degenerative diseases such as Alzheimer’s may lie in disrupting this attachment. "How do you stop the disease process?," he asks. "If you find a molecule that can disrupt these two proteins from binding, you might have a drug," he says. "A drug that could bind to the surface of the caspase might then block the apoptotic pathway and halt the process from occurring."
The next step is to develop such drugs, he says, which may involve "developing peptides, substances that mimic the chemical ‘recognition sequence’ on the two crystal structures of caspase-9 or Apaf-1 and see if they indeed disrupt apoptosis. No caspase-based drugs currently exist that block apoptosis in this manner."
The research was funded by the National Institute on Aging.
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