Research by Israel’s Weizmann Institute wis likely to advance the development of new drugs for Alzheimer’s disease. A study, reported in the January issue of Nature Structural Biology, demonstrates exactly how a substance from a moss used for centuries in Chinese folk medicine blocks a brain enzyme that may be involved in this common type of fatal dementia.
Professor Joel Sussman, Dr. Michael Harel, Israel Silman and graduate student Mia Raves, all of the Rehovot institute, worked in close collaboration with Alan Kozikowsky of Washington’s Georgetown University and Dr. Yuan-Ping Pang of the Mayo Clinic in Jacksonville, Fla.
The team determined the three-dimensional structure of a complex comprising the natural substance Huperzine A (HupA) and the enzyme acetylcholinesterase (AChE). HupA is extracted from the Huperzia serrata moss, used in China in a medicine called qian ceng ta. Solving the puzzle involving the structure revealed a strikingly good fit between HupA and the enzyme and may provide a possible starting point for designing new, improved Alzheimer drugs.
According to one theory, Alzheimer’s patients’ memory loss and other cognitive deficits are due to degeneration of nerve cells, which normally release the neurotransmitter. When there is too little AChE, the shortage is compounded by the action of the AChE, which breaks down the neurotransmitter acetylcholine.
Two drugs approved by the U.S. Food and Drug Administration for Alzheimer’s — tacrine and E2020 — work by inhibiting AChE. HupA also inhibits AChE, but has a different chemical structure and is currently being investigated in China and elsewhere.
That HupA and AChE are so suited means that the Chinese herb could be potent even in small quantities and produce minimal side effects, said Silman, a neurochemist.
The scientists worked with high-quality crystals of AChE derived from the torpedo, a fish that is one of the richest sources of the enzyme. Since there is great similarity in the amino-acid sequence of torpedo and human AChE, it is likely that the torpedo’s 3-dimensional structure is a good model of the human enzyme, he continued.