Faster by Design, Part 1 of 2
Scientists Create Enzyme from Scratch
I have three teenage daughters who frustrate me to no end at times. I’m the type of person that likes to get where I’m going a few minutes early. And they never seem to be able to leave the house on time. Waiting for them to put on their make-up, fix their hair, choose the right outfit, etc. (who knows what else they do to get ready) seems to take an eternity. If only I could come up with a way to speed up the process. (I’ve discovered that standing at the bottom of the stairs yelling, “We are never going to get there if you don’t hurry up!” doesn’t work all that well.)
Not only am I an impatient parent, I’m also an impatient chemist. In fact, most chemists are in hurry. As part of their research efforts, these scientists often look for ways to speed up chemical reactions. Fortunately chemists have discovered a way to hustle things along. The rate of many chemical reactions can be accelerated by using compounds called catalysts.
The use of catalysts is not confined to the chemistry laboratory. They feature prominently in living systems as well. Most chemical reactions necessary for life are accelerated by special types of biological catalysts called enzymes. These biomolecules are proteins specifically structured to catalyze biochemical activities and operations. In some cases, enzymes can increase the rate of biochemical reactions by over a billion fold! If not for enzymes, life would be impossible because, without some assistance, most chemical transformations needed to sustain life proceed at too slow a pace under physiological conditions.
Whenever possible, chemists and chemical engineers take advantage of the special properties of enzymes for industrial, commercial, food, and agricultural applications. Scientists and technologists find enzymes useful because of their ability to accelerate chemical reactions with a high degree of chemical specificity. But there are also numerous problems with using enzymes for most large-scale applications. These biomolecules are not stable in organic solvents, or at high temperatures. Enzymes also have limited catalytic range, since not all types of chemical reactions are used by living systems.
In response to these deficiencies, biochemical engineers strive to redesign enzymes found in nature. They look to stabilize them under harsh conditions and extend their utility. (This endeavor is referred to as protein engineering.) Researchers also look to produce enzymes from scratch that will catalyze novel, nonbiological reactions.
Recently, a large team of collaborators published two papers in Science and Nature reporting on two enzymes, created from scratch and capable of catalyzing non-biological chemical transformations (the retro-aldol and the Kemp Elimination reaction, respectively).
Their work has several important implications. It paves the way for biochemists to develop a better understanding of the relationship between enzyme structure and function. It establishes an approach to generate novel enzymes with a wide array of practical applications. It also affects attempts by life scientists to create artificial life in the lab, and consequently, impacts the creation/intelligent design/evolution controversy. Before I discuss their work and its implications (next week), some background information will help.
Enzymes are proteins. Proteins are chain-like molecules that fold into precise three-dimensional structures. The protein’s three-dimensional architecture determines its function.
Proteins form when the cellular machinery links together, in a head-to-tail fashion, smaller subunit molecules called amino acids. Cells employ twenty different amino acids to make proteins (to a first approximation). In principle, the twenty amino acids can link up in any possible amino acid combinations to form a protein chain.
The amino acids that make up the cell’s protein chains possess a variety of chemical and physical properties. Each amino acid sequence imparts the protein with a unique chemical and physical profile along its chain. This profile determines how the protein folds, and therefore, how it interacts with other protein chains to form a functional protein. The amino acid sequence of a protein ultimately determines its function, since the amino acid sequence determines the protein’s structure, and structure dictates function.
Even though enzymes are large molecules, only a small portion of their structure plays an immediate role in catalysis. The business portion of an enzyme is called the active site. Enzymes bind the chemical compounds destined to react with each other in the active site. Biochemists refer to these compounds as substrates. Once the chemical reaction is completed, the resulting products are released from the active site and more substrate molecules bind to the active site. This allows the enzyme to catalyze round after round of chemical reactions.
Enzyme active sites can only bind select molecules. In this way, enzymes have a high chemical specificity. This selectivity stems from the ability of the enzyme’s active site to precisely match the geometry of the substrate molecules and from the exacting molecular interactions that take place between the chemical groups found in the active site and the substrates.
The active site is typically a pocket or crevice located on the three-dimensional surface of the folded protein chain. The active site surface consists of a variety of chemical groups precisely positioned in space. These chemical groups come from amino acids that form the protein chain. Amino acids contributing to the active site may be located in completely different regions of the protein chain. They are brought into the appropriate juxtaposition when the protein chain folds into a three dimensional shape. (Go here for a close up of a typical enzyme active site.)
The spatial orientation of these chemical groups plays a critical role in the enzyme’s ability to speed up chemical reactions. These chemical groups stabilize the transition state of the enzyme substrates when they react and they shield the reactants from unwanted side reactions. Let me explain.
When molecules react, chemical bonds are broken and formed. Atoms within the molecule become redistributed. Chemical groups within and among the molecules temporarily associate and dissociate. These atomic-scale events proceed sequentially along what chemists call the reaction coordinate. At specific points along the reaction coordinate temporary molecular entities exist called transition states. Theses molecular configurations are unstable and are more energetic than either the original reactants or the final products. The less stable the transition state (or the higher the energy), the slower the reaction proceeds.
Chemical groups located within an enzyme’s active site are oriented in space in such a way that they interact with the reactants as they advance along the reaction coordinate. These interactions stabilize the transition states, lowering their energy. This allows the reactions to proceed at a more rapid rate.
Fine-Tuning of Enzyme Structure
Enzyme active sites are exquisitely fine-tuned molecular systems. Sometimes slight repositioning of active site chemical groups in space readily compromises the functional efficiency of enzyme-mediated catalysis.
As I point out in my new book The Cell’s Design over the last half-century, biochemists have discovered time and time again that molecular precision and fine-tuning define biochemical systems. Enzyme active sites are but one example. But the biochemical fine-tuning and exactness far exceed the best efforts of engineers.
Precision and fine-tuning are hallmark characteristics of intelligent design. These features dominate the best human designs and are often synonymous with exceptional quality. The fine-tuning and precision of enzyme active sites and other biochemical systems points to the work of a Divine Designer.
Next week I will describe what it takes to design an enzyme and its active site from scratch.
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