Scientists Find Atomic Structure Of Chinese Herb, Chang Shan

Scripps Research Institute scientists have determined a molecular structure that helps explain how the Chinese herbal medicine Chang Shan works.

AsianScientist (Dec. 31, 2012) – Scientists have figured out the mysterious inner workings of Chang Shan, a Chinese herbal medicine used to treat malarial fever for thousands of years.

The study, published in the journal Nature this week, shows in atomic detail how a two-headed compound derived from the active ingredient in Chang Shan works.

Scientists have known that this compound, called halofuginone (a derivative of the febrifugine), can suppress parts of the immune system, but the exact mechanism for action was not known.

Thanks to a high-resolution structure solved at The Scripps Research Institute (TSRI), we now know that halofuginone acts like a wrench by jamming the gears of a molecular machine that carries out aminoacylation, a crucial biological process that allows organisms to synthesize the proteins they need to live.

Chang Shan, also known as Dichroa febrifuga Lour, is believed to help with malarial fevers because traces of a halofuginone-like chemical in the herb interfere with protein synthesis in malaria parasites, killing them in an infected person’s bloodstream.

“Our new results solved a mystery that has puzzled people about the mechanism of action of a medicine that has been used to treat fever from a malaria infection going back probably 2,000 years or more,” said Prof. Paul Schimmel, who led the research.

Halofuginone has been in clinical trials for cancer, but the high-resolution picture of the molecule suggests it has a modularity that would make it useful as a template to create new drugs for numerous other diseases.

The new work shows that halofuginone gets its potency by interfering with an enzyme called tRNA synthetase that is important during protein synthesis.

Interestingly, said Schimmel, the ATP substrate is also needed for the halofuginone to bind – a mechanism that has never been observed in biochemistry before.

“This is a remarkable example where a substrate of an enzyme (ATP) captures an inhibitor of the same enzyme, so that you have an enzyme-substrate-inhibitor complex,” said Schimmel.

The article can be found at: ATP-Directed Capture of Bioactive Herbal-Based Medicine on Human tRNA Synthetase.


Source: Scripps Research Institute; Photo: Schimmel Lab.
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