How enzymes don’t work

The late, great Linus Pauling, twice Nobel laureate (chemistry and peace) and advocate of mega doses of vitamin C for beating disease and extending life (he died at the ripe old age of 93) was one of the most influential scientists of the 20th century.

He worked out how nature’s catalysts, proteins known as enzymes, speed up biochemical reactions. They bind to the transition states of a substrate molecule and so lower the energy of the highest energy point on a reaction pathway, which means that the reaction can proceed at much greater speed, often millions of times faster than the uncatalyzed reaction in fact.

Chemists have borrowed this in the design of organic catalysts and in making artificial enzymes, for their non-biological reactions. It is not a
complete description of catalytic behavior of enzymes of course, for that you might turn to Nanda and Koder in Nature Chemistry.

However, in a new paper from Simon and Goodman, they reveal a simple system which is common in both enzymic catalysis and organocatalysis, that does not conform to this simple idea of transition state binding. The reaction of carbonyls with a nucleophile to form an oxyanion can be catalyzed by hydrogen bonding, they explain, and there are many examples of this type of process using enzymes and using organocatalysts. The enzymes, however, do not use the arrangement of hydrogen bonds that binds the transition state best.

Instead, the hydrogen bonds are twisted around the carbonyl axis by about ninety degrees. This is less effective for transition state binding, but much less effective for ground state binding. The energy barrier for the reaction is lowered most effectively by arranging the hydrogen bonds to minimize the energy difference between the bound ground state and the bound transition state, and not by maximizing transition state binding.

Enzymes do not bind to transition states; they bind to minimize the energy difference between the ground state and the transition state.

“This has implications for the design of both artificial enzymes and organocatalysts,” says Goodman.

Research Blogging IconSimon, L., & Goodman, J. (2009). Enzyme Catalysis by Hydrogen Bonds: The Balance between Transition State Binding and Substrate Binding in Oxyanion Holes The Journal of Organic Chemistry DOI: 10.1021/jo901503d

This post adapted from materials provided by Dr Goodman. Meanwhile, a quick word about large mens clothes and hairdressing scissors both of which are unrelated to dressing down enzymes or cutting up enzymes.


  1. Christian Ridley

    Umm..Linus Pauling

  2. “This is less effective for transition state binding, but much less effective for ground state binding.”

    With this statement, did you intend to underscore a different but mutually less effective action on either type of binding or did you mean to say, “… much *more* effective for ground state binding.”? If I read the rest correctly, it seems as though you intended to say the latter. If the ground state binding is made more efficient, it would seem the the difference between ground and transition states would be narrower. As I am not a biochemist (or any type of chemist for that matter), I may be treading on ground I have no shoes for, but thought I’d chance the question because I am genuinely curious. :)

  3. @Christian Thanks for spotting the typo, sometimes my fingers work faster than my brain.

    @Lauralee No, the text is correct as it stands. This response from Dr Goodman:

    “This is the counter-intuitive result. Ground state binding is a bad thing, because lowering the energy of the ground state increases the barrier between the (bound) ground state and the transition state. Binding the ground state is like digging a hole in the ground at the take-off for a high-jump. The bar does not get any higher, but the jump gets harder.”

  4. “..they reveal a simple system…that does not conform to this simple idea of transition state binding..”
    So where does that take us in terms of the Secondary School and College Biology? Any re-writing work needed?

  5. I think so, yes.