Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
After an Anopheles mosquito bites a hole in its victim's skin, it injects a deadly malarial parasite, Plasmodium falciparum, into the wound. There that sinister bug heads for its human target's bloodstream, and gorges on the hemoglobin in its red blood cells.
But the well-fed P. falciparum is not home free. The hemoglobin it ingested is itself toxic to the parasite. The way the bug prevents itself from being killed by the degradation of its own metabolism is by inducing the poison to crystallize into hematin - an end-product of hemoglobin metabolism. So the parasite digests hemoglobin - its main food source - in its meal of blood cells, and precipitates the crystals of hematin.
Those micron-size crystals hide away in P. falciparum's food vacuoles. There they're hunted down and rooted out by powerful antimalarial drugs such as chloroquine and quinoline. These inhibit the crystals from growing, so they hang loose and kill the bugs.
But chloroquine and its antimalarial ilk aren't out of the woods, either. A potent derivative of quinine, the original therapeutic against malaria, chloroquine for half a century ruled the roost of antimalarial compounds. Then the plasmodial parasites caught up with this panacea and generated drug resistance against it. This takes the form of blocking the drug from holing up in the bug's food vacuole. Now parasitologists and drug developers around the world are intently seeking successor drugs to the fast-fading chloroquine.
Among them are scientists at the Weizmann Institute of Science in Rehovot, Israel, and TransForm Pharmaceuticals Inc., of Lexington, Mass. They are co-authors of a paper in the November/December 2002 issue of the journal Crystal Growth & Design. Its title: "Quinoline binding site on malaria pigment crystal: A rational pathway for antimalaria drug design."
Their data showed that drugs like chloroquine slow the growth of hematin crystals. This brake allows heme to accumulate to toxic levels, and ultimately kill the parasite. TransForm utilized the recently reported crystal structure of synthetic beta-hematin, enhanced with computational technologies, to test the novel binding site for the quinoline drugs.
"This discovery," TransForm's chief scientific officer, Colin Gardner, told BioWorld Today, "illustrates the value of understanding physical chemistry and crystalline surface structure to explain the mechanism of a drug's action. It demonstrates the importance of examining biophysical crystals as drug targets."
Hypertoxic Polychlorinated Biphenyls, Outlawed In U.S. Since 1976, Still Await Bacterial Remediation
Because of their extreme toxicity, persistent pollution and ecological damage, the U.S. withdrew the manufacture of polychlorinated biphenyls (PCBs) in 1976. Ever since then, PCBs have festered underground as hazardous wastes too expensive to neutralize. Of late, strategies for removing PCBs from environmental deposits are turning to microorganisms that can convert these liquid time bombs into smaller, less harmful molecules. Such bioremedial microbes possess special enzymes that catalyze the breakdown of PCBs.
A paper in the December issue of Nature Structural Biology investigates the catalytic activity and structure of a key bacterial enzyme in the breakdown pathway, and identifies how certain PCBs can inhibit this enzyme. The paper, released online Nov. 5, 2002, bears the title: "Identification and analysis of a bottleneck in PCB biodegradation." Its lead co-authors are at the University of British Columbia and Purdue University in Lafayette, Ind.
"Ortho-chlorinated PCB congeners [close taxonomic cousins] elicit a wide range of toxic responses and are among the most recalcitrant to chemical and biological remediation," the paper pointed out. It continued: "The ortho-substituted congeners are neurotoxic and tumor-promoting, and elicit endocrine changes. They are poorly destroyed by various chemical and biological treatments.
"The range of PCBs transformed by the pathway," the paper notes, " is highly dependent upon the bacterial strain. Some strains do not transform PCBs that contain more than three chlorines, whereas other strains, such as Burkholderia species LB400, transform up to hexachlorinated biphenyls. This variation," the authors point out, "has been studied extensively in terms of biphenyl dioxygenase, the first bacterial pathway enzyme, with the ultimate goal of improving the biodegradations of PCBs. (See also BioWorld Today, Nov. 1, 2002, p. 1.)