A dozen or so years ago, I drove my Biochemistry prof to tears with questions – she had 200 people in front of her and she tried hard to make Biochem interesting enough not to get us all bored to tears, and she was pretty good at that, as much as it is possible not to make people bored to tears with Biochem. But my questions exasperated her mainly because she could not answer them, because, as I learned later, the field of biochemistry was not able to answer those questions yet at the time: questions about dynamics – how fast is a reaction, how long it takes for a pathway to go from beginning to end, how many individual molecules are synthesized per unit of time?, etc.
Well, the field is starting to catch up with my questions lately – adding the temporal dimension to the understanding of what is going on inside the cell. In today’s issue of PLoS Biology, there is a new article that is trying to address exactly this concern: Dynamics and Design Principles of a Basic Regulatory Architecture Controlling Metabolic Pathways:
Single-cell organisms must constantly adjust their gene expression programs to survive in a changing environment. Interactions between different molecules form a regulatory network to mediate these changes. While the network connections are often known, figuring out how the network responds dynamically by looking at a static picture of its structure presents a significant challenge. Measuring the response at a finer time scales could reveal the link between the network’s function and its structure. The architecture of the system we studied in this work–the leucine biosynthesis pathway in yeast–is shared by other metabolic pathways: a metabolic intermediate binds to a transcription factor to activate the pathway genes, creating an intricate feedback structure that links metabolism with gene expression. We measured protein abundance at high temporal resolution for genes in this pathway in response to leucine depletion and studied the effects of various genetic perturbations on gene expression dynamics. Our measurements and theoretical modeling show that only the genes immediately downstream from the intermediate are highly regulated by the metabolite, a feature that is essential to fast recovery from leucine depletion. Since the architecture we studied is common, we believe that our work may lead to general principles governing the dynamics of gene expression in other metabolic pathways.
You should also check out the editorial synopsis for the paper, as it places it nicely into the context – exactly the kind of context I was looking for, in vein, back in my Biochem class: The Fourth Dimension of Biochemical Pathways:
Even on a plain wall chart, the intricacies of a cell’s biochemical pathways can boggle the mind. Hundreds of interweaving routes create and consume thousands of intermediate compounds, which are regulated by a dizzying number of enzymes at every step–a drop in nutrient A turns on pathway B to make intermediate C that is converted to regulator D that stimulates gene E that creates enzyme F to divert intermediate G into pathway H to…whew!…make nutrient A. London’s famously complex subway system is a piker compared to even the simplest cell.
But a static map can’t depict the complexity of a subway system in motion, and a wall chart can’t capture the four-dimensional dynamism of a cell in action, because neither one captures the crucial dimension of time. It matters not only where a train is going, but when it will get there, and it matters not only whether a pathway can produce a nutrient, but how quickly it responds when the nutrient is depleted. In a new study, Chen-Shan Chin, Victor Chubukov, Hao Li, and colleagues begin to address this problem by using a novel method to track the time course of a cell’s response to depletion of the amino acid leucine. They show that the time responses of upstream and downstream segments differ dramatically, and they go on to develop a mathematical model that predicts the response of the pathway to experimental perturbations.
This paper is too fresh for the new carnival, but perhaps in 10 years we’ll look at it and say “it’s a classic!”
Update: The grandmaster himself, Larry, answers my questions. I guess that kinetics were outside of the syllabus for a non-majors class and my questions wasted everyone’s time, and I never had to take any other Biochem afterwards.