New enzyme theory rewrites catalysis

[phantom power]

06/10/2004 - Scientists have reworked the mechanism of how enzymes work, forcing the pharmaceutical industry to rethink its views on the design of biological catalysts and new drugs.

The discovery may explain why attempts to make artificial enzymes have been disappointing and could provide a stepping stone to the introduction of next generation drugs that take this discovery to produce drugs with improved efficacy.

(edit)

The team, from The University of Leicester, have demonstrated this occurs in enzyme-catalysed reactions, and their studies revealed that carbon-hydrogen bond breakage occurs by the hydrogen passing through, rather than over, the barrier. This is a quantum mechanical effect. The hydrogen passes instantaneously from one side of the barrier to the other. In these tunneling reactions, the rate of reaction depends on both the height and width of the barrier.

(edit)

Sutcliffe said: "In cases where enzymes that break stable bonds are being targeted, it may well no longer be valid to assume that effective inhibitors of these enzymes can be designed solely by considering the binding of a transition state analogue to block the active site."

http://inpharma.com/news/news-NG.asp?n=55200-new-enzyme-theory

[snowFLAKE]

1. NEW?? Really??

I'm too lazy to do a literature search right now - so I can't recite the Entire History of quantum tunneling in enzyme reactions - but I do know that this phenomenon was known to people in the Berkeley Chemistry Department as far back as 1996. And it wasn't even a Closely Guarded secret - Heck, I found out just by passing by and reading posters in The Hallway.

[phantom power]

2. beats me

it sure wouldn't be the first time a researcher claimed something was new, when it wasn't.

It was new to me, but that's not saying much.

[snowFLAKE]

3. The history of enzyme-mediated hydrogen tunneling

The effect has been observed for the O-H bond for 15 years:

Science. 1989 Mar 10;243(4896):1325-30.


Hydrogen tunneling in enzyme reactions.

Cha Y, Murray CJ, Klinman JP.

Department of Chemistry, University of California, Berkeley 94720.

Primary and secondary protium-to-tritium (H/T) and deuterium-to-tritium (D/T) kinetic isotope effects for the catalytic oxidation of benzyl alcohol to benzaldehyde by yeast alcohol dehydrogenase (YADH) at 25 degrees Celsius have been determined. Previous studies showed that this reaction is nearly or fully rate limited by the hydrogen-transfer step. Semiclassical mass considerations that do not include tunneling effects would predict that kH/kT = (kD/kT)3.26, where kH, kD, and kT are the rate constants for the reaction of protium, deuterium, and tritium derivatives, respectively. Significant deviations from this relation have now been observed for both primary and especially secondary effects, such that experimental H/T ratios are much greater than those calculated from the above expression. These deviations also hold in the temperature range from 0 to 40 degrees Celsius. Such deviations were previously predicted to result from a reaction coordinate containing a significant contribution from hydrogen tunneling.

And for the C-H bond (the topic of the current article) for at least 8 years (as described in the following article):

J. Am. Chem. Soc., 118 (42), 10319 -10320, 1996. 10.1021/ja961827p S0002-7863(96)01827-6
Copyright © 1996 American Chemical Society

Experimental Evidence for Extensive Tunneling of Hydrogen in the Lipoxygenase Reaction: Implications for Enzyme Catalysis

[snowFLAKE]

4. Oh boy, do I ever feel foolish now

I've been posting about "tunneling"

But, going directly to the UK researcher's website:

http://www.le.ac.uk/biochem/staff/nss4/nss4.html

I find the new developments are all about "tunnelling"

D'oh, that's no doubt something entirely different. Double D'oh!!

[DrWeird]

5. Yeah, I thought I heard about it years ago too.

at least with the O-H bond.