“It’s still too early to say whether or not this result will directly suggest a new drug target, but what it does is fill in a blank spot at the heart of the parasite’s metabolic network that’s intimately connected with other drug targets, and so might hopefully let us more intelligently design drugs and drug intervention strategies in the future,” he said.
“Parasites, almost by definition, have a weird metabolism because they try to do as little as possible, and steal everything they can from the host,” he added. “The malaria parasite has a long and complex life cycle, but the actual disease happens when they are growing in the blood stream, burrowing inside your red blood cells and eating them from the inside out before bursting them open to find another red blood cell. In the process they wreak a lot of metabolic havoc, eating up your blood sugar and excreting lactic acid, which acidifies the blood. People have been studying the biology of the parasite for a century or more, and have uncovered a lot of strange aspects of its metabolism, but for about the past 50 years, the parasite TCA cycle has been a black box.”
These parasites do not consume much oxygen, and don’t use respiration to make energy, “and you couldn’t see carbon from the sugar they eat ever enter the cycle,” he said. “However, they do consume a little oxygen, and they seem to have all the genes necessary to run the pathway. People have been scratching their heads for a long time over whether this core pathway existed in the parasite at all, and if so, whether it had been modified.”
Researchers on the Princeton team used new available technology to analyze their samples, including a state-of-the-art mass spectrometer equipped to perform metabolomics, a process that detects the specific chemical fingerprints that cellular processes leave behind. They fed malaria parasites isotope-labeled glucose and amino acids, the most abundant nutrients in human blood, then sent the samples into the instruments to trace how they were broken down.
“Our collaborators in the [Joshua D.] Rabinowitz lab here at Princeton work on ‘metabolomics,’ which is essentially the field of trying to measure all the 500 or so metabolites that cells use to grow, simultaneously, instead of a few at a time, as you have to do in classical biochemistry,” Olszewski said.
“This is a pretty hot field that’s going to revolutionize biomedicine, and it’s been finding its way into all sorts of biomedical and clinical endeavors,” he added. “We realized it would be a great way to try to map out what’s happening in the malaria TCA cycle.”