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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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October 15, 2007

Enzyme Humility

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Posted by Derek

There was a fascinating comment added to the recent discussion here on ammonia synthesis. It was pointed out that the amount of man-made Haber Process available nitrogen is outclassed by the amount fixed biologically. The legumes do their share, but a lot more is handled by free-living single-celled organisms. What's really startling is the estimate for the total amount of nitrogenase enzyme, by weight, that is responsible for the production of at least 100 million metric tons a year of reduced nitrogen: about twelve kilos.

It's important for us, as chemists, to contemplate figures like that lest we forget how unimpressive our own techniques are in comparison. Not all enzymes are that impressive, but many of them are extremely impressive indeed. One of Clarke's laws gets quoted a lot, the one about any sufficiently advanced technology being indistinguishable from magic. But there's no magic involved - these are things that we could do, if we just knew enough about how to do them.

Enzymes use a variety of effects to work these wonders, but a lot of it comes down to holding the reacting species in one place and lining everything up perfectly. It isn't as important to hold on to the starting materials or products, as it is to interact with and stabilize the highest-energy species in the whole process, the fleeting transition state. Various chemical groups can be brought to bear that activate or deactivate specific bonds, and everything works, at its best, with near-perfect timing. If you want molecular level-nanotechnology, this is it, and there's absolutely no reason why it has to be done inside a peptide backbone. If we understood enough, all sorts of other polymers, with all sorts of new functionality built into them, could presumably do things that Nature has never needed to do, under conditions that we could select for.

But we're unfortunately a long way from that. There's still a tremendous amount of argument about how even model enzymes actually work, with some rather exotic mechanisms being proposed. And if we don't understand what's going on, we sure can't design our own imitations. Making enzymes from scratch brings together a whole list of Very Hard Problems, from protein folding to femtosecond reaction dynamics, and making enzymes out of something other than proteins will be even harder. We're going to need to be a lot smarter, as a species, to figure out how to do it.

But learning more about such stuff is one of the things we do best. At least for the last few centuries it has been, and if we keep it up, there seems to reason why we shouldn't be able to figure out this one, too. Then, at long last, human ingenuity will have pulled even with blue-green algae, the fungi that live in rotting logs, and various sorts of pond scum. The little guys have had a big head start, but we're gaining fast.

Comments (8) + TrackBacks (0) | Category: General Scientific News


COMMENTS

1. Anonymous on October 15, 2007 2:29 PM writes...

Want to pick a fight with Mother Nature? Want to compete with billions of years of evolution?

Go ahead. Sometimes, you can win. Most of the times, you will be humiliated.

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2. CMC guy on October 15, 2007 4:47 PM writes...

The desire to (re)construct molecules from nature is what turned me on to doing Org Syn and ultimately pursuit of PhD. That many natural products of interest had useful pharmacological properties lead to aspirations to apply that chemical knowledge to aid sick people. I think you are correct how unimpressive imitators we are and consider are all likely to be apparent hacks if we try to compete with nature in terms of complexity and efficiency (although I do admire groups who undertake such journeys as means to introduce and enable unique chemistries). Whether through classical fermentations, splicing technologies or utilizing enzymes (see Scripps CH Wong, MITs A Klibanov, and many others) there are occasions that do take advantage of these wondrous reagents/systems to manufacture in quantity. The evolution of drug design turned as stereoselective techniques (chemical and biological) allowed single enantiomers beyond direct natural sources to be made and tested.

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3. such.ire on October 15, 2007 5:26 PM writes...

Eric Jacobsen always ends his lecture courses with slides on biological enzymes that do what he's trying to do, but much, much better. One of the things he talks about are the lipoxygenases in leukotriene biosynthesis. The mechanisms there aren't that esoteric (hold the specific substrate double bond next to the active site); it's just that evolution does it so much better.

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4. Monte Davis on October 15, 2007 6:05 PM writes...

When I first learned how much a very little nitrogenase does, I had a brief fantasy about the fortune to be made by someone who'd figure out how to bind a monolayer of it to a membrane and undersell the Haber-Boschmongers.

The fantasy was brief because I then realized that the enzyme action must be exquisitely specific to all kinds of microstructures and concentrations and gradients that the bacteria know how to get just right. As Smil says, if it were simple lots of plants would have come up with it, and soluble N wouldn't be the limiting factor it so often is.

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5. NJBiologist on October 15, 2007 6:56 PM writes...

For those who want to pick a fight with nature yet despair of their chances, it's worth remembering that a turnover number of 2.8 million per second is among nature's best. That's about seven-fold faster than the rate at which bicarbonate goes through carbonic anhydrase, and almost a thousand-fold faster than the rate at which triosephosphate isomerase processes glyceraldehyde-3-phosphate. In other words, your body hasn't evolved anything as fast as nitrogenase for two very important reactions.

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6. Anonymous BMS Researcher on October 15, 2007 8:29 PM writes...


Wow -- what a marvelous way to use one of my favorite poems. Kipling isn't terribly fashionable nowadays (partly because his Imperial worldview wasn't exactly Politically Correct by current standards) but there is considerable wit, power, and wisdom in his works.

He lived briefly in Vermont and built an elegant house there; the summer before last, my wife and I had a wonderful day attending a special musical performance there -- a fundraiser for the Yellow Barn Music School in Putney.

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7. curiousGeorge on October 16, 2007 5:54 PM writes...

There is a significant and growing body of work that seeks to use tuned laser pulses to achieve difficult molecular reactions.

The basic idea is to remove the middleman (the protein). It turns out that optimal control 'landscape' for chemical reactions is not hard to find since there are many equally good solutions (degeneracies). And the quantum yields (ratio of input to output energies) are passable even at this earlier stage in the technology. Still, it will be a while before Nature is put out of business,.

Although there are many now in the field, some of the earliest work began here:

http://www.princeton.edu/~hrabitz/curr-res.html

Permalink to Comment

8. Doc Bushwell on October 24, 2007 3:35 PM writes...

If we understood enough, all sorts of other polymers, with all sorts of new functionality built into them, could presumably do things that Nature has never needed to do, under conditions that we could select for.

Ah, there's the rub. "If we understood enough."

With regard to your third paragraph, keep in mind that conformation change and/or allosteric effectors play major roles in substrate binding, catalysis and product release. Very complex stuff, and rather difficult (at present) to set up effectively in an artificial system.

As a card-carrying mechanistic enzymologist (yes, the card is laminated), I agree with CuriousGeorge that it will be some time before this occurs. I remain in awe of enzyme catalysis.

Hope all's well at...well, you know. Please give my regard to the fellows.

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