Understanding the Malaria-Causing Parasite

[Guest guest]

Just

thought this was interesting bc I had never really pondered malaria before...rose

http://www.usnews.com/science/articles/2010/08/06/understanding-the-malaria-causing-parasite.html?PageNr=1

By

Cimons, National Science Foundation

In

the early part of the 20th century, German-born biochemist Hans Krebs figured

out one of the most universal ways living things use nutrients in order to

produce energy, grow and reproduce. His discovery of the cycle, which was named

for him, led to a Nobel Prize in 1953.

The

Krebs cycle, also known as the tricarboxylic acid (TCA) cycle, is a process

where dietary sugars in the presence of oxygen burn off carbon, which is

released as carbon dioxide. This process—respiration—makes much of

the energy that drives metabolism. Scientists have found some version of the

Krebs cycle in almost all living things, from animals and plants to yeast and

bacteria.

Recently,

however, researchers have discovered at least one exception: the parasite that

causes malaria. Unlike almost every other organism yet studied, the breakdown

of sugar by the malaria parasite is completely disconnected from the TCA

cycle—it is instead fed by the amino acids glutamine and

glutamate—and, in fact, is not even a cycle at all.

“The

parasite has basically take the standard textbook circular cycle and broken it

in half, running one half in the normal direction and the other

backwards,” said Kellen Olszewski, a graduate student on the laboratory

team of Llinas at Princeton University. “This turns the textbook

model on its head.”

The

research, published recently in the journal Nature, was funded by the National

Science Foundation with several grants, including an estimated $2.3 million

from the American Recovery and Reinvestment Act of 2009.

Malaria

is a major global public health problem--one of the top ten killers in the

world, according to the World Health Organization (WHO). It exacts the heaviest

toll of disease and death among the poorest nations in the world, particularly

in children and pregnant women.

WHO

estimates between 300 to 500 million cases occur annually, with between 1.5 to

2.7 million deaths, 90 percent of them in tropical Sahara. Outside Africa,

approximately two-thirds of the remaining cases occur in Brazil, India and Sri

Lanka, although the disease exists in about 100 countries, according to WHO.

Malaria

is caused by Apicomplexan parasites of the genus Plasmodium, with four species

that affect humans. Transmission occurs through the female Anopheles mosquito.

Llinas’ lab studies the deadliest form of the parasite, Plasmodium

falciparum.

Thus

far, “a rewiring of the TCA cycle as significant as this one hasn’t

been observed in any other parasite,” said Olszewski, lead author of the

paper. “However, a few parasites, like Cryptosporidium, have lost the

pathway entirely during their evolution. There are quite a few parasites

related to the Plasmodium malaria parasites, but we doubt that any of them have

evolved a pathway similar to this one.”

A

clearer understanding of how the parasite functions ultimately could present

possible new drug targets. “We’re investigating that avenue, but

it’s too early to say anything definitive,” Olszewski said.

“At best, it clarifies our understanding of how a lot of other pathways

that are drug targets work, since they are connected to TCA metabolism.

“Why

did the parasite change such a fundamental pathway in such a weird way?”

he added. “We think it goes back again to the fact that it’s a

parasite. Most free-living organisms have to worry about starving, or about

their environment changing suddenly on them, and the normal TCA cycle is a very

versatile hub that lets creatures eat a wide variety of nutrients and generate

energy in a very efficient way. The parasite, however, is floating around in

your bloodstream with a pretty stable environment and a constant supply of

glucose and glutamine. If these ever run out, the host and everything inside it

is dead or soon will be, so it doesn’t need to worry about finding

another food source and can burn sugar for energy in a much less efficient

way—fermentation—and still be fine.”

Instead,

this new branched pathway seems to serve at least two other purposes, he said.

One arm produces a molecule the parasites need to make heme, a substance that

allows the parasite to make a protein necessary to transport electrons, and the

other produces acetyl-CoA, which is used to regulate protein function, and

possibly gene expression.

“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 [ 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.”