Copyright 2001, The American Chemical Society

Terpene isonitriles bind heme

The antimalarial activity of the compound shown, isolated from a marine sponge, stems from its ability to coordinate with pure heme, a recent study shows [J. Med. Chem., 44, 873 (2001)]. Pure heme is formed when the malaria parasite feeds on hemoglobin. The product is toxic to the parasite, which disposes of it in various ways. The well-known quinoline antimalarials prevent these detoxification processes. Now, researcher Anthony D. Wright and others at the University of Bonn, in Germany; La Trobe University in Bundoora, Australia; and Heinrich-Heine University in Dusseldorf, Germany, have found that compounds of the type shown--terpene isonitriles--achieve the same effect to different degrees by forming a complex with pure heme. The complex prevents destruction of pure heme, allowing it to build up and damage proteins and lipids in the parasite. Through modeling studies and structure-activity analysis of a series of terpene isonitriles, the researchers establish that, in this compound class, a lipophilic core comprising at least a tricyclic frame and carrying an axial isonitrile group at C-7 is associated with the ability to bind pure heme.
 
 

Top

Even ordinary proteins can change shape

Under the right conditions of temperature, salt concentration, and pH, even a globular protein like myoglobin will lose its structure and convert to threadlike fibrils "that closely resemble the amyloid and prion aggregates seen in pathological conditions such as Alzheimer's and Creutzfeldt-Jakob disease," according to Oxford University chemists Marcus Fändrich, Matthew A. Fletcher, and Christopher M. Dobson [Nature, 410, 165 (2001)]. Their experiments with the protein portion of myoglobin (without its heme group) suggest that any polypeptide is susceptible to radical rearrangement under the right conditions. Thus the amino acid sequences of the polypeptides associated with amyloid or prion diseases may not be particularly important. They propose that native proteins have protective mechanisms, such as cooperativity in folding and molecular chaperones, that ordinarily suppress amyloid formation. Conditions that compromise these protective measures--including aging, mutations, and, in the case of prion diseases, ingestion of infectious material--could cause proteins to convert to a fibrillar conformation.