Better Biochemistry: Good Enough Enzymes

Some enzymes catalyze reactions at extremely fast rates that are only limited by the rate of diffusion of substrate molecules into the active site of the enzyme (diffusion-controlled rate). Some of these enzymes are covered in all the standard biochemistry textbooks; examples are canbonic anhydrase (CAN), triose phosphate ismerase (TIM), and superoxide dismutase (SOD). Superoxide dismutase (right) actually catalyzes reactions at a rate that's faster than the diffusion-controlled limit [Superoxide Dismutase Is a Really Fast Enzyme].

These enzymes are often referred to as "perfect" enzymes but that's a very misleading term because it implies that all other enzyme are less than perfect.

Most enzyme don't need to act any faster than they do. They are quite happy catalyzing reactions at rates that are far below their theoretical optimum [Better Biochemistry: The Perfect Enzyme]. As long as it's good enough there's no selective pressure to get better.

The other day, while browsing one of the latest issue of Science, I came across a paper on plant metabolism that had an interesting figure. The authors looked at nearly 2000 different enzymes and plotted the relative frequencies of their rate constants (k_cat/K_M) and of their turnover numbers (number of reactions they catalyze per second) (Milo and Last, 2012).

Here are the data.

The positions of the really fast enzymes (CAN, TIM, SOD) are shown way out on the right-hand tail of the distribution. The vast majority of enzymes are much slower and their rates tend to form a typical Gaussian distribution with a median turnover number of about 14 reactions per second. (The fast enzymes catalyze reactions at rates of 10,000 to 100,000 reactions per second.)

There are several ways to interpret this data. Adaptationists prefer explanations based on optimality and the balance of competing selective pressures. They think that positive selection has led to the evolution of a reasonably fast rate but negative selection (constraint) has kept the rate below a certain optimal value. According to the adaptationists, there may be some negative effects if the rate is too fast.

The non-adaptationists (I am one) look at the data differently. We tend to view cell metabolism as a workable set of reactions that are good enough for survival. There's lots of sloppiness and lots of mistakes but the bottom line is that the cell gets the job done. Enzymes and metabolic pathways are not optimal or perfect—they are just "good enough."

Typical enzymes are under selective pressure to evolve mechanisms that catalyze rates much faster than the spontaneous chemical reactions but once the rates reach a certain speed there is no more selective pressure to improve them. There will be random neutral mutations that improve the rate and sometimes these will become fixed by drift but these "improvements" can also be lost without negative consequences. Thus, the typical rate of an enzyme reaction is likely to fluctuate around the rate that's good enough. That's not the same as the "optimal" rate because there's nothing that prevents the enzyme from evolving a faster rate by accident.

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Image Credit: Moran, L.A., Horton, H.R., Scrimgeour, K.G., and Perry, M.D. (2012) Principles of Biochemistry 5th ed., Pearson Education Inc. page 175 [Pearson: Principles of Biochemistry 5/E]

Milo, R. and Last, R.L. (2012) Achieving diversity in the face of constraints: lessons from metabolism. Science 336:1663-1667. [PubMed] [DOI: 10.1126/science.1217665 ]