Monday, March 02, 2009

Substrate-induced starvation in cells?

I was just reading an article sent to me by my PhD adviser about evolution of metabolic networks.
It is impressive how metabolism is structured in a complex network with apparent redundancies, inefficiencies and bottlenecks.
But this post is about something extremely interesting I read in one of the references: apparently some of these metabolic pathways are "boosted up" by an energy-dependent step. These are called "Turbo-designed pathways" and glycolysis is one of them.
In glycolysis, before glucose catabolism can yield 4 molecules of ATP, first it consumes 2 molecules.
When yeast is grown in culture with high glucose concentration, negative feedback mechanisms prevent the cell from wasting too much energy in accumulating substrates intracellularly and at the cost of a lot of energy. Yeast just uptakes enough glucose, phosphorilates it (2 moles of ATP consumed) and then metabolizes it to get enough energy.
However, when yeast is grown in media with high malate (analogous to glucose) concentration, these cells will deplete all their energy uptaking this substrate and before they are able to make out the ATP surplus, they are already dead.
It is like someone spending all their money in seeds and not saving anything for sowing the crops.

The funny thing is that tumor cells are known for increased glucose metabolism, not only increased glucose consumption but anaerobic glucose metabolism, which is much less efficient. So wouldn't these cells just starve to death? I guess they would, if the increase in the metabolic flux where in the ATP consuming steps, what would lead to accumulation of metabolites and energy deprivation. But if the increase is in the ATP generating steps (after glyceraldehyde-3-phosphate dehydrogenase) then it would yield to energy surplus.

This conclusion is very interesting because it suggests that any increase in expression of glycolytic enzymes pre-GAPD should come only after the ATP-surplus enzymes have already been mutated (or its expression increased) to increase its reactions fluxes.

For references:

The danger of metabolic pathways with turbo design. Teusink et al., 1998
Glycolysis, turbo design and the endocrine pancreatic β cell. Iynedjian, 1998


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