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The Digestive System / How the Liver Works
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An adequate level of dietary protein is an essential for good health. Protein molecules are composed of a family of twenty different smaller molecules. These are known collectively as "amino acids" since each contains both an acid group (COOH) and an amino group (NH3). While the twenty amino acids share this common structure, they differ from one another in that each has a different "side chain." The side chain gives each amino acid a different molecular shape.
There are thousands of different kinds of protein molecules, each composed a a linked chain of amino acids arranged in a particular unique sequence. The particular sequence of differently shaped amino acids drives the folding of the chain in a highly specific manner. The unique folding pattern, determined by the unique sequence of amino acids, produces a protein molecule with a unique shape, and as a consequence a unique surface. Proteins have the ability to form the structural elements of cells by a kind of "self assembly" process in which particular proteins "recognize" one another, and because of their unique surfaces, come together to form more complex structures.
In a similar way, the particular specialized surfaces of proteins can recognize small molecules and bring them together in a way that makes possible chemical reaction between these molecules. Such proteins carry the name "enzyme" and serve as very effective catalysts, making it possible for chemical reactions to occur at high rates at physiological temperatures (98.6 degrees F in humans.) In the absence of catalysis by a particular enzyme, a most reactions would occur only very slowly, or not at all. In addition, the protein surface provides a powerful kind of "guidance" to a particular reaction since it recognizes only two particular molecules, holds the molecules near one another in a highly specific way, and thus promotes only a single chemical reaction.
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Electron micrograph of a human liver cell. Protein compounds are used to form distinctive receptor sites on the surface of the cell membrane. |
You can see that protein molecules play critical roles in the cell. As enzymes and catalysts, they provide the molecular surfaces that determine the particular reactions that can occur within the cell, and thus regulate the overall set of reactions that make up cellular metabolism. As structural components they provide the molecular scaffolding for the cell and assist in arranging and ordering the spatial relationships between the different enzymes.
Living cells have a constant and very active "maintenance and housekeeping" program where they are constantly synthesizing new protein molecules and degrading old ones. This process has two functions. First, it assures that cellular protein is in good repair as damaged and defective protein molecules are somehow (mechanisms are unknown) selectively identified and degraded. Second, the overall metabolism of the cell needs to be constantly adjusted and "tuned" as the body adjusts to changing levels of fuels and nutrients (fed and fasting states), levels of activity, time of day, etc.
There is a large amount of protein turnover. In a human, approximately one pound of protein is degraded and resynthesized each day. Most of the amino acid liberated by protein degradation is used again in the resynthesis of new protein. But about 10% of the total amino acid is lost as it is converted to other important molecules involved in nervous system function, pigments, various hormones, and a variety of other essential activities. Amino acids are also used as fuel and, when present in excess in the diet, can be converted to fat for storage of excess calories.
Because of the universal importance of protein molecules to living cells, both plant and animal tissues can provide dietary protein. During digestion, the long chains of amino acids that make up complex protein molecules are disassembled to produce the twenty different single amino acids. These are taken up by cells in our digestive system, mostly in small intestine, and released to the blood where they are transported to all of the cells of the body.
Amino acids from the diet are used in three ways. They are uniquely used in the synthesis of new protein and in the fed state cells are actively synthesizing the structural and enzymatic proteins required for healthy functioning. As described in the section "DNA, RNA, Protein, and the Code of Life" the synthesis of these proteins is closely regulated by the expression of particular genes. And, of course, it is this selective regulation that determines which proteins are to be synthesized, and in a more global sense, the characteristics, abilities, and activities of each individual cell.
When present in excess, amino acids are also used as fuel. The twenty different carbon skeletons of the twenty different amino acids are each metabolized through a more or less unique series of reactions. Said differently, the degradation of each amino acid occurs by means of a specific pathway. However, the end products of these pathways are the same as various intermediates in the breakdown of glucose. Thus, overall, amino acid degradation results in the production of acetyl-CoA or its precursors and several of the organic acids involved the the TCA cycle (tricarboxylic acid cycle) discussed above. This means that, like carbohydrate, the carbon atoms that make up the amino acids can be converted to CO2 with the production of energy need to support the life of the cell and the organism.
Excess amino acids can also be converted to fat. Again the picture is similar to that for carbohydrate in that carbon structures derived from the amino acids can be converted to Citrate (a TCA cycle component.) Recall that citrate is the required first intermediate in the synthesis of fat. Since liver is the major site of fat synthesis, excess amino acids are taken up by the liver, converted to fat, packaged into transport structures (VLDL) and stored as fat in adipose tissue.
We have seen that carbohydrate and fat can be stored by cells, and by the organism, for use at a later time. Glycogen represents the storage form for carbohydrate and is present in many types of cells, particularly in the liver. Triglyceride represents the storage form for fatty acids synthesized in the liver and stored in adipose (fat) tissue.
There is no storage form for amino acids. They are either converted into protein or they are converted into other compounds. As a consequence, during the fasting state the body begins to break down protein to obtain the amino acids that to support the synthesis of new protein molecules needed for maintenance or to change metabolic activities.
Each individual kind of protein molecule, each particular type of enzyme for example, appears to have a particular rate of turnover. Some proteins are degraded rapidly, such that half of the total amount of the enzyme in a single cell is broken down every 15 minutes or so. Others are degraded more slowly, where the time it takes to degrade half is perhaps an hour, a few hours, or in some instances, several days or weeks.
In addition to their essential role in supporting the synthesis of needed proteins, during the fasting state the amino acids liberated by protein breakdown also assist in energy production. This occurs both at the level of the individual cell in which protein degradation occurs and in whole body metabolism.
Earlier we discussed the importance of sugars, particularly glucose, as a source of TCA cycle intermediates and the essential role of the TCA cycle in the production of energy. Recall that oxaloacetate (OAA) is a critical intermediate in the TCA cycle and that the first step in the cycle involves the combination of OAA and acetyl-CoA to form citrate.
During breakdown of amino acids, the carbon skeleton of many of the amino acids is converted to one on the intermediates of the TCA cycle. Because of its cyclic character, once these intermediates enter the TCA cycle they are easily converted to OAA. The production of OAA from amino acids means that the cell no longer needs to use as much glucose to maintain adequate levels of OAA in the TCA cycle. This, in turn, means that blood glucose is used more sparingly.
In the fasting state, a significant portion of the amino acid produced by the breakdown of protein in peripheral tissues, such as muscle, is released to the blood. Because of its very rich blood supply, the liver has excellent access to these circulating amino acids.
These free amino acids are used for two major purposes. The first, just as in peripheral tissue, is for the support of the synthesis of proteins needed by the liver to maintain its own structures and processes. The second is the synthesis of additional glucose for use by other tissues. As discussed earlier (gluconeogenesis - see above), this is a process that is unique to liver. The importance of glucose synthesis is easy to appreciate in the light of the critical role that glucose in supporting the production of energy from other fuels, particularly fat.
Glucose can be synthesized from several key intermediates in metabolism. One of these is from one of the components of the TCA cycle, malate. Just as for OAA, all of the TCA cycle intermediates can be converted to malate. Since the carbon skeletons of many of the amino acids are converted into TCA cycle intermediates, they also serve as starting material for the synthesis of glucose.
With that in mind, it is easy to see that amino acid released from peripheral tissues can be converted to glucose in the liver. (Amino acids are released, taken up by the liver, converted into TCA cycle intermediates that are converted to malate, with malate then being used for the synthesis of glucose.) As we have seen, this newly synthesized glucose can be released to the blood for use by the central nervous system and by other tissues.
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