Enzyme Kinetics Can Be Fun!

I want to talk today about a topic in science that can really help with the way we view nutrition day to day. This concept is taken from chemistry and is useful to describe the way that systems behave when exposed to varying concentrations of a substance. To make this topic make sense I need to explain a couple of important aspects on the topic.

 1.) Affinity: This term describes the level of attraction of one molecule to another molecule.
 Example: Hemoglobin has affinity for several substrates including oxygen. The affinity for oxygen is not as high as the affinity for carbon monoxide making carbon monoxide a toxic substance since oxygen cannot bind to hemoglobin when it is present resulting in suffocation.

 2.) Disassociation Constant (Kd): In scientific terms the affinity of a substance is measured by describing the concentration at which half of all the available substance is bound to a partner in solution. This is called the Kd, or the disassociation constant described in units of molarity or moles/liter denoted with a capital M. The Kd can vary depending on the pairs of molecules being described. This is important for things like neurotransmitters that have multiple binding partners but may prefer particular receptors over others.
 Example: A molecule that has high affinity will have a low Kd value since few molecules are needed to have half of them bind to its substrate.

 3.) Enzyme kinetics: This is a term that is used to describe how enzymes behave when they are exposed to a substrate. Enzymes are catalysts for reactions and their behavior is dictated by their intrinsic properties. When they are in solution with their substrate under the proper conditions they will exhibit a reaction that is related to their affinity for their substrate. Due to the constraints of their physical properties enzymes are limited at how fast they can react with their substrate to create a product (substrate+enzyme-> enzyme/substrate ->product+enzyme). This means that an enzyme has a maximum potential for the rate at which it can catalyze a reaction with the fastest enzymes limited only by diffusion (~10-9/Msec) with the rest falling below this limit. Each step of the process is subject to regulation making this process a lot more complicated.

 A long time ago in the beginning of biochemistry, scientists studied the rates and reactions of enzymes and discovered many properties of enzyme kinetics. There are many and may be too confusing to describe in detail here but there is an important lesson in all of this. Concentration matters!
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 Enzymes regulate vast and seemingly complicated processes by having different rates at which they catalyze reactions. These reactions are regulated not only by the enzymes themselves but by the reactants they use. This is how our body regulates everything inside the cell. If levels of a particular substrate rise too high then it can inhibit the enzyme that is upstream creating the substrate. Nucelotide synthesis is regulated in this way. DNA is comprised of four nucleotides, adenine, cytosine, thymine and guanine. Each is necessary in equal proportions to create DNA. When the enzyme the levels of one nucleotide rises it inhibits the enzymes that catalyze the reactions to create the other nucleotides resulting in a balance of available nucleotides in the cell.   
 These examples are useful because they can give us an idea about how the cell works autonomously. The cell's intelligence is based on the ability to react to changes in its environment. The way it does this is by creating a balancing act from the interplay between substrates, enzymes, cofactors and all of the other environmental stimuli it encounters. This interplay comes together at the level of the organism to provide us with robust responses to our environment. Here is a great example that relates to nutrition and everyday life.
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Credit: Human Metabolism Michael Palmer, MD, Department of Chemistry University of Waterloo Ontario Canada
(4.4-6 mM is average blood glucose of the blood)

This graph illustrates an important concept that actually can come in handy when thinking about carbohydrate metabolism. What is shown is three different versions of a molecule called the glucose transporter (GLUT). This protein comes in a variety of flavors and is denoted with a different number after GLUT. Each of the members of this family can transport glucose and some can transfer other sugars as well. What is shown on this graph is that there is difference in the rate at which these transporters will move glucose out of the bloodstream and into the cell. The brain is a glucose hungry organ and so its transporters have a high affinity for glucose to keep up with demands. The liver on the other hand only needs to soak up excess glucose that is circulating around in the bloodstream. The GLUT4 transporter lies in the middle of the two and is important since it is only called into action after high energetic demand created from keeping muscles under tension (i.e. weightlifting). This effort activates glycolytic pathways in muscle tissue quickly depleting the muscles stores of glycogen. Each transporter exists to serve a function of the body in order to preserve homeostasis.

"Sure, all this sounds good and dandy but how does this help me?"
 Great question! This topic is important because it relates directly back to health and nutrition. Our brains are like the glucose sponge of the body, it soaks up glucose all the time and its GLUT3 is quick to reach its maximum efficiency at relatively low concentrations. On the graph the GLUT3 line starts to max out at what is considered the "normal" blood glucose level. This makes sense because we want our brains to have all the energy it needs all the time. If we had to eat to get to optimal glucose levels for the brain then we may not survive all that long. Notice that as blood glucose levels rise the brain GLUT3 doesn't get any faster at transporting glucose from the bloodstream. This is an important fact and is analogous to a car in first gear. The GLUT3 protein trades its maximum velocity for a quick start. This means that once glucose levels go too high GLUT3 cant bring down blood glucose levels on its own at any significant rate. Excess glucose is toxic to cells beginning around 11mM and thus other systems are needed to keep blood sugar in an appropriate range.

 The bottom line of the graph depicts the liver transporter GLUT2. It is interesting to note because it is important for how fat deposition occurs. When blood sugar levels rise past the range at which they can be handled by the tissue GLUTs then insulin is released to help transport glucose into tissues. In addition to insulin the GLUT2 protein works to bring blood glucose levels down. GLUT2 is a slow transporter that gains velocity as concentration increases. The GLUT2 transporter is also found on the pancreatic islet cells that release insulin. It is the transport of glucose into these cells that causes them to release insulin in response to increased levels of glucose.

 Example: Say you were to consume a food item that was comprised mostly of simple sugars. Once digested, the quick release of sugars into the bloodstream will begin to overwhelm the mechanisms in place to keep blood sugar in its normal range. The rise in blood sugar causes the release of insulin along with the GLUT2 transporter in the liver soaking up blood glucose to turn into glycogen. Once glycogen levels are maximal then the excess transported glucose is turned into fatty acids.

 This is how the majority of weight gain occurs. When blood glucose levels rise the glucose needs to go somewhere and usually that somewhere doesn't help get my pants on. Adipose tissue is extremely sensitive to insulin and when there is excess glucose not only is glucose being turned into fat by the liver but it is also being stored in fat cells. This glucose storage needs water to occur which is where the bloating feeling and look of excess carbohydrates come from. Its about a 4:1 ratio of water to glucose storage that occurs in cells and is the first weight to be lost when adopting a lower carbohydrate eating regime.
 I want to end this discussion with a little bit of useful information.
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 Fact: Exercise can help us lose weight and control blood sugar levels.

 This may not be new or groundbreaking but it may make a lot more sense after all this information. Lets refer to the graph one more time and look at the GLUT4 line. This line shows that as blood glucose levels rise the GLUT4 transporter begins to pick up steam before the liver gets dibs on that blood glucose. This means that if timed properly we can eat carbohydrates and get them to the tissues that need them the most, our muscles. The GLUT4 transporter is tricky though, it only comes to the surface of cells in response to strenuous exercise. I repeat, STRENUOUS exercise. This doesn't mean running, walking, yoga or any other light to moderate exercise. While those activities will cause GLUT4 translocation it wont be to the levels the warrant massive carbohydrate repletion. Its translocation, or movement to the exterior of the muscle cell depends on the kind of exercise being done. Time under load is an important factor to consider when consuming carbohydrates for the intent to replete muscle glycogen. Choosing starchy carbohydrates allows the sugars to digest slowly whereas simple sugars will raise the blood glucose too high, too quickly to be useful for shuttling glucose exclusively into the muscle tissue since the liver will compete with the other transporters for glucose. Keeping glucose levels at the moderate range will allow more glucose to make it into the muscle cells over being deposited as fat. Gaining an understanding on how glucose is metabolized in our bodies can give us better insight into food choices and nutrient timing to achieve maximum results.  

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