Week # 13: Lipid Metabolism and Protein Metabolism
Lectures - 35, 36, 37
Concepts:
Uses of Lipids in the Body
Fatty Acid Sprial
Ketone Bodies
Fatty Acid Synthesis
Protein Metabolism - Transamination, Oxidative Deamination
Urea Cycle
Synthesis of Amino Acids
Ques. 1. List the functions of lipids in the body.
Ques. 2. List the order in which the energy reserves of the body are depleted.
Include protein, fat, glucose, and glycogen.
Ques. 3:. What are the two possible metabolic fates for glycerol.
Ques. 4. Complete the following reactions which are part of the fatty acid spiral. Use the general name of each reaction to write out the specific structures involved. Start with CH3 (CH2) 10COOH and follow the example in the text.
a. Oxidative deydrogenation using FAD.
b. Hydration
c. Oxidative deydrogenation using NAD+.
d. Hydrolysis or cleavage of acetyl CoA.
Ques. 5. Which is the final product of the fatty acid spiral? ______
How many of the these are made for CH3(CH2) 10COOH? ______
How many turns of the fatty acid spiral are required? ______
Ques. 6: Use the diagram above to answer the following questions:
a. Name the reactions: 1 =2 =3 = 4 =
b. Write the structure in the boxes above for: Rx 2 =
Rx 3 =
Ques. 7. Calculate the total ATP produced from the fatty acid spiral of CH3(CH2) 14COOH. Show your work.
Ques. 8. Calculate the total ATP produced from the complete metabolism of CH3(CH2)14COOH using both the fatty acid spiral and on into the citric acid cycle. Show your work.
Ques. 9. Calculate the total ATP produced from the fatty acid spiral of CH3(CH2) 10COOH. Show your work.
Ques. 10. Calculate the total ATP produced from the complete metabolism of CH3(CH2)10COOH using both the fatty acid spiral and on into the citric acid cycle. Show your work.
Ques. 11. Explain how the lipogenesis spiral differs from fatty acid oxidation
spiral? Just give general information. How are they similar?
Ques. 12. List the major steps in the conversion of a lipid into CO2 and water.
Ques. 13. List the major steps in the conversion of a carbohydrate into a lipid.
Ques. 14. List four or five uses for acetyl CoA.
Ques. 15. Describe how the condition of ketosis develops.
Ques. 16. List the names of three ketone bodies. Which one is not really a ketone?
Info in Lipids, Diabetes in Virtual Chembook for the rest of the questions.
Ques. 17. Define hyperglycemia and hypoglycemia. What is the relation to insulin
Ques. 18. Using the urine tests for glucose and ketones, how could you distinguish between diabetes insipidus, renal diabetes, and diabetes mellitus?
Ques. 19. What is meant by the renal threshold?
Ques. 20. Explain the metabolic disorders associated with diabetes mellitus. Include the following terms: glucosuria, ketosis, acidosis, hyperglycemia, hypoinsulinism, polyuria, and acetonuria.
Ques. 21. How is the glucose tolerance test used to identify diabetes mellitus and distinguish it from renal diabetes?
Glucose Tolerance Test: In order to measure the metabolic response of a patient to glucose, the glucose tolerance test was devised. The test consists of giving 100 g of glucose in place of breakfast and then testing the concentrations of glucose in the blood and urine at specific timed intervals. This test establishes when the blood glucose reaches its highest concentration, when glucosuria occurs, and how rapidly the blood glucose concentration returns to normal.
In normal persons, the venous blood sugar value usually does not exceed 200 mg/100 ml blood and returns below 120 mg in two hours. In diabetes mellitus, the glucose level peaks above 200 mg and does not return below 120 mg after two hours. In renal diabetes, the blood glucose curve is normal. Glucose tolerance curves may produce different results at different times on the same person.
Protein Metabolism:
Transamination
Transamination as the name implies, refers to the transfer of an amine group from one molecule to another. This reaction is catalyzed by a family of enzymes called transaminases. Actually, the transamination reaction results in the exxhange of an amine group on one acid with a ketone group on another acid. It is analogous to a double replacement reaction.
The general reaction is:
Amino acid + ketoacid new ketoacid + new amino acid
The most usual and major keto acid involved with transamination reactions is -ketoglutaric acid, an intermediate in the citric acid cycle. A specific example is the transamination of alanine - below.
Ques. 22: Transamination:
b. What are the common names of products formed?
Ques. 23: Finish the transamination with aspartic acid.
Other Transamination Reactions:
Aspartic acid can be converted into oxaloacetic acid, another intermediate of the citric acid cycle. Other amino acids such as glutamine, histidine, arginine, and proline are first converted into glutamic acid.
Glutamine and asparagine are converted into glutamic acid and aspartic acid by a simple hydrolysis of the amide group.
All of the amino acids can be converted through a variety of reactions and transamination into a keto acid which is a part of or feeds into the citric acid cycle. The interrelationships of amino acids with the citric acid cycle are illustrated in the graphic on the left.
Ques. 24a: List the amino acids that can be converted into glucose.
b: List the amino acids that can be converted into lipids.
Synthesis of New Amino Acids
In addition to the catabolic function of transamination reactions, these reactions can also be used to synthesize amino acids needed or not present in the diet. An amino acid may be synthesized if there is an available "root" ketoacid with a synthetic connection to the final amino acid. Since an appropriate "root" ketoacid does not exist for eight amino acids, (lys, leu, ile, met, thr, try, val, phe), they are essential and must be included in the diet because they cannot be synthesized.
Glutamic acid usually serves as the source of the amine group in the transamination synthesis of new amino acids. The reverse of the reactions mentioned earlier are the most obvious methods for producing the amino acids alanine and aspartic acid
Ques. 25: Write the transamination reaction for the synthesis of the following new amino acids.
Oxidative Deamination Reaction
Deamination is also an oxidative reaction that occurs under aerobic conditions in all tissues but especially the liver. During oxidative deamination, an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia and the amine functional group is replaced by the ketone group. The ammonia eventually goes into the urea cycle.
Oxidative deamination occurs primarily on glutamic acid because glutamic acid was the end product of many transamination reactions.
Ques. 26: Oxidative Deamination:
Central Role for Glutamic Acid:
Apparently most amino acids may be deaminated but this is a significant reaction only for glutamic acid. If this is true, then how are the other amino acids deaminated? The answer is that a combination of transamination and deamination of glutamic acid occurs which is a recycling type of reaction for glutamic acid. The original amino acid loses its amine group in the process. The general reaction sequence is shown on the left.
Urea Cycle
Urea is the major end product of nitrogen metabolism in humans and mammals. Ammonia, the product of oxidative deamination reactions, is toxic in even small amounts and must be removed from the body. The urea cycle or the ornithine cycle describes the conversion reactions of ammonia into urea. Since these reactions occur in the liver, the urea is then transported to the kidneys where it is excreted. The overall urea formation reaction is: (Memorize it)
The step wise process of the urea cycle is summarized in the graphic below. One amine group comes from oxidative deamination of glutamic acid while the other amine group comes from aspartic acid. Aspartic acid is regenerated from fumaric acid produced by the urea cycle. The fumaric acid first undergoes reactions through a portion of the citric acid cycle to produce oxaloacetic acid which is then changed by transamination into aspartic acid.
Urea is routinely measured in the blood as: Blood Urea Nitrogen (BUN). BUN levels may be elevated (a condition called uremia) in both acute and chronic renal (kidney) failure. Various diseases damage the kidney and cause faulty urine formation and excretion. Congestive heart failure leads to a low blood pressure and consequent reduced filtration rates through the kidneys, therefore, BUN may be elevated. Urinary tract obstructions can also lead to an increased BUN. In severe cases, hemodialysis is used to remove the soluble urea and other waste products from the blood. Waste products diffuse through the dialyzing membrane because their concentration is lower in the dialyzing solution. Ions, such as Na+ and Cl- which are to remain in the blood, are maintained at the same concentration in the dialyzing solution - no net diffusion occurs.
As stated previously, high ammonia levels are toxic to humans. A complete block of any step in the urea cycle is fatal since there is no known alternative pathway for the synthesis of urea. Inherited disorders from defective enzymes may cause a partial block in some of the reactions and results in hyperammonemia which can lead to mental retardation. Extensive ammonia accumulation leads to extensive liver damage and death. Liver cirrhosis caused by alcoholism creates an interference in the enzymes which produce carbamyl phosphate in the first step on the cycle.
Hemoglobin Catabolism and Bilirubin
The catabolism of hemoglobin is outlined in the graphic on the left. Red blood cells are continuously undergoing a hemolysis (breaking apart) process. The average life-time of a red blood cell is 120 days. As the red blood cells disintegrate, the hemoglobin is degraded or broken into globin, the protein part, iron (conserved for latter use), and heme. The heme initially breaks apart into biliverdin, a green pigment which is rapidly reduced to bilirubin, an orange-yellow pigment (see middle graphic). These processes all occur in the reticuloendothelial cells of the liver, spleen, and bone marrow. The bilirubin is then transported to the liver where it reacts with a solubilizing sugar called glucuronic acid. This more soluble form of bilirubin (conjugated) (see bottom graphic) is excreted into the bile.
The bile goes through the gall bladder into the intestines where the bilirubin is changed into a variety of pigments. The most important ones are stercobilinogen, which is excreted in the feces, and urobilinogen, which is reabsorbed back into the blood. The blood transports the urobilinogen back to the liver where it is either re-excreted into the bile or into the blood for transport to the kidneys. Urobilinogen is finally excreted as a normal component of the urine.
Types of Jaundice:
Various conditions of jaundice result from the accumulation of bilirubin in the blood. A jaundice condition is characterized by yellow colored skin due to the presence of bilirubin.
Hemolytic Jaundice:
Excessive hemolysis or breakdown of red blood cells causes the formation of higher than normal amounts of bilirubin. Bilirubin made in the liver goes into bile and then into the gall bladder and into the intestines where most is excreted. The liver works normally, but could eventually be damaged from overwork. Usually the liver can handle the excess and the bilirubin is excreted via intestines and does not usually spill over into the kidneys. Urobilinogen levels are likely to be elevated in the blood and urine.
Hepatic Jaundice:
Hepatic jaundice is caused by damage or disease in the liver. Heme enters the liver but it does not take out as much bilirubin as is normal. Bilirubin builds up in the blood and spills over into the kidneys which filter it out into the urine. The amount of urobilinogen in the urine will be either normal or low if not enough bilirubin is being removed by the liver into bile and the intestines.
Biliary Obstruction:
If bilirubin cannot reach the intestinal area because of a blockage in the bile duct, than bilirubin builds up in the blood because it cannot get out of the liver. Bilirubin is then removed by the kidneys into the urine. Little if any, urobilinogen will be found in the urine since little or no bilirubin is reaching the intestines.
Ques. 27: Lab tests on urine may be made for both bilirubin and urobilinogen. Complete the types of results expected for the various jaundice conditions. Answer with positive, negative, lower, higher, etc.
LAB TEST
NormalBiliary ObstructionHepaticDiseaseHemolytic Disease
Bilirubin: neg.
Urobilinogen: pos.
Review Metabolism
By this time in your study you should have a pretty good knowledge of the individual metabolic relationships in carbohydrates, lipids, and protein. Hopefully, you have also begun to see that there are numerous interconnecting points between all three types of metabolism. This should be particularly evident in the considerations of diabetes, the amino acid transaminations, and the urea cycle.
As a further exercise in summarizing the metabolic interrelationships, you may be asked to do "road map" problems for pieces of the overall metabolism sequences.
A "road map" problem is merely the diagramming of a particular metabolic pathway. The pathways described should be at least as detailed as that shown on the graphic on the left. In all cases, the starting point is the ingestion of the particular food listed.
Ques. 28: You should be able to diagram road maps for:
a) carbohydrate to CO2 and H2O
b) carbohydrate to lipid
c) protein to lipid
d) protein to CO2, H2O, urea
e) protein to glucose or glycogen
f) carbohydrate to glycogen
g) lipid to CO2 and H2O
h) lipid to protein
Alcohol Metabolism Effects
(Adapted from C.S. Lieber, Sci. Am. 234(3), 25(1976)
Alcohol is the favorite mood-altering drug in the United States and its effects, both pleasant and unpleasant, are well-known. What may not be well known is the fact that alcohol is a toxic drug that produces pathological changes (cirrhosis) in liver tissue and can cause death.
Alcohol is readily absorbed from the gastrointestinal tract; however, alcohol cannot be stored and therefore, the body must oxidize it to get rid of it. Alcohol can only be oxidized in the liver, where enzymes are found to initiate the process.
In addition, alcohol directly contributes to malnutrition since a pint of 86 proof alcohol (not an unusual daily intake for an alcoholic) represents about half of the daily energy requirement. However, ethanol does not have any minerals, vitamins, carbohydrates, fats or protein associated with it. Alcohol causes inflammation of the stomach, pancreas, and intestines which impairs the digestion of food and absorption into blood. Moreover, the acetaldehyde (the oxidation product) can interfere with the activation of vitamins.
The first step in the metabolism of alcohol is the oxidation of ethanol to acetaldehyde catalyzed by alcohol/dehydrogenase containing the coenzyme NAD+. The acetaldehyde is further oxidized to acetic acid and finally CO2 and water through the citric acid cycle. A number of metabolic effects from alcohol are directly linked to the production of an excess of both NADH and acetaldehyde.
CH3CH2OH + NAD+ ---> CH3CH=O + NADH + H+
Metabolic Fates of NADH:
The metabolic pathways for the disposal of excess NADH and the consequent blocking of other normal metabolic pathways is shown in the graphic on the left.
1. Pyruvic Acid to Lactic Acid:
The conversion of pyruvic acid to lactic acid requires NADH:
Pyruvic Acid + NADH + H+ ---> Lactic Acid + NAD+
This pyruvic acid normally made by transamination of amino acids, is intended for conversion into glucose by gluconeogenesis. This pathway is inhibited by low concentrations of pyruvic acid, since it has been converted to lactic acid. The final result may be acidosis from lactic acid build-up and hypoglycemia from lack of glucose synthesis.
2. Synthesis of Lipids:
Excess NADH may be used as a reducing agent in two pathways--one to synthesize glycerol (from a glycolysis intermediate) and the other to synthesis fatty acids. As a result, heavy drinkers may initially be overweight.
3. Electron Transport Chain:
The NADH may be used directly in the electron transport chain to synthesize ATP as a source of energy. This reaction has the direct effect of inhibiting the normal oxidation of fats in the fatty acid spiral and citric acid cycle. Fats may accumulate or acetyl CoA may accumulate with the resulting production of ketone bodies. Accumulation of fat in the liver can be alleviated by secreting lipids into the blood stream. The higher lipid levels in the blood may be responsible for heart attacks.