Tuesday 30 August 2011

How'd he DO that? Real Chemical Magicians


Enzymes 101: Peaking into the black box



            The term “enzyme” has a pretty specific meaning to people who define themselves by such terms as “enzymologists” (go figure). To most people, however, it’s a less well-understood term. For many of the folks I know, the term “enzyme” can be virtually interchangeable with “protein,” or perhaps only recognized in the context of specific and dubious dietary supplements. For the purposes of this and further discussions, I’d like to talk about enzymes as proteins or nucleic acid that act as a catalyst to speed along chemical reactions. That’s what enzymes are and what they do, but how on earth do they do it? In this post we’ll use broad strokes to discuss some of the general strategies enzymes use to put eons of biochemical evolution to work.

            It can be a bit hard to really appreciate, and I mean fully appreciate, what enzymes do for us, and how difficult this task is chemically. When I think of the power of enzyme chemistry it always brings me back to early organic chemistry classes. As a bright-eyed, eager young undergrad I dutifully learned the rules of traditional organic chemistry: what bonds can be broken by what chemicals under what impossibly harsh boiling acidic conditions. We learned that by the natural laws of energy, matter, and all that is chemically holy there are just certain reactions that wouldn’t happen at room temperature during the length of an average PhD. How then, I would ask, could these types of reactions be magically popping up in textbooks looking perfectly and innocently plausible? The professor’s answer? Enzymes.

            Upon receiving such a disyllabic and seemingly self-evident answer I’m sure that I nodded my head knowingly, pretending that I fully understood how the biochemical black box could perform chemical black magic. Since then I’ve made a few strides toward actually understanding the mechanisms behind these baffling enzymatic chemoacrobatics, and continue to be amazed by the underlying simplicity and elegance in complicated enzyme systems. As an introduction to the broad concepts of enzyme mechanisms I’ll talk about the very basic catalytic strategies they use, and leave more detailed mechanisms for a later date. So let’s talk about shape, strain, orientation sequestration, and transformation. Lets talk about enzymes.

            One of the ways that enzymes are able to shift chemical reaction rates into high gear is simply by bringing the necessary components, or substrates, together. Understandably, this seems trivial on the surface but practically it is both very important and very effective. Being macromolecules (proteins or nucleic acid), enzymes have lots of different chemical groups: hydroxyl groups, aromatic groups, amine groups, etc. These have been positioned during evolution of specific enzymes to be in just the right places to interact very specifically with their substrate molecules. The “lock and key” analogy is used a lot in explaining these interactions, and is as apt an analogy as any. Basically the enzyme is able to bind very specific compounds, while completely ignoring others. By doing this for more than one substrate, they are able to bring two or more reacting molecules into very close proximity and hold them there, allowing them to interact much more efficiently. Additionally, enzymes don’t bind their substrates in just any old way, but in a precise orientation, effectively lining up slot A with tab B. This very simple enzyme function is kind of like a good match maker, taking the chance out of two compatible things coming together and setting the mood just right for the chemistry to happen.

            Another power that enzymes have is a consequence of their size; enzymes are huge compared to the small molecules involved in many of the reactions they catalyze. This means that they can completely surround these small molecules, and in so doing can control the immediate environment in which the reaction is taking place. Practically this can mean separating the substrates from interfering water molecules or creating pockets of positive or negative charge in specific places. This gives the substrate molecule(s) a custom-built productivity space where all of the elements are designed to help the chemistry along and exclude interfering substances.

            The general mechanisms we’ve talked about so far involve concepts that I like to think of in terms of “tweaking the chemical circumstances,” but enzymes can play a much more “active” role in chemical reactions as well. One way that enzymes can shove a reaction in the right direction is an offshoot of the “lock and key” tight interaction concept mentioned above. Some enzymes bind their substrates in such a way that they actually bend, twist, or otherwise strain their shape. This changes the energy state of the molecule and helps to push the chemical reaction to its conclusion. Alternatively, the enzymes themselves can actually react chemically with their substrates, forming a covalent bond between enzyme and substrate. This bond is broken by the end of the reaction cycle to release the product and regenerate the enzyme. This latter mechanism is often referred to as providing an alternate path for the chemical reaction to go through, effectively using the substrate-enzyme reaction as a handy detour to avoid more difficult chemistry.

            The concepts of catalytic mechanism explored above are incredibly general, and the specifics that happen in each individual system can be complex enough to fill the contents of a research career (or several). With all of the complicated and truly challenging chemistry that’s going on in our bodies every day, however, I think it’s inspiring that such simple and intuitive concepts are at the root of such complex mechanisms. It’s amazing what we can understand about our own chemistry if we choose to start looking inside the black box.

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