Mod+12+Reading+Guide

__**Module 12 Reading Guide**__

Mod 12 Summary: Chapter 24 covers many cellular process such as beta-oxidation, transamination, and lipogenesis that break down fatty acids and proteins into usable and safe products such as citric acid cycle intermediates, urea, and ketone bodies in the body.

__**24.1 Digestion of Triacylglycerols**__ Summary: Fat cells called **adipocytes** store triacylglycerols in adipose tissues. The energy stored in a "typical" person is 135,000 kcal from fat, 24,000 kcal as protein, 720 kcal as glycogen, and 80 kcal as blood glucose. A process called **emulsification** uses bile salts (made in the gallbladder) to break down fat globules into smaller **micelles**. Then lipases from the pancreas hydrolyze the triaclglycerols in the micelles to yield monoacylglycerols and free fatty acids. **Chylomicrons** transport triacylglycerols through the lymph system and into the bloodstream. Fatty acids oxidized to acetyl CoA for ATP synthesis are the preferred fuel for the heart, and glucose and glycogn are the only source of energy for the brain and red blood cells. **Fat** **mobilization** breaks down triacylglycerols to fatty acids and glycerol. This mobilization occurs when the hormones glucagon or epinephrine are secreted into the bloodstream and bind to adipose cells' receptors. First the fatty acid is hydrolyzed from C1 or C3. C2 is hydrolyzed after the other two. Most glycerol goes into the liver where it is converted to glucose. Overall, in the liver glycerol is converted to dihydroxyacetone phosphate by converting ATP into ADP and then AMP. Then the dihydroxyacetone phosphate can be used for glycolysis or gluconeogenesis. The reaction for the metabolism of glycerol is: glycerol + ATP + NAD+ --> dihydroxyacetone phosphate + ADP + NADH + H+. In the small intestine, triaclyglycerols are converted to glycerol, and in the liver glycerol is converted into a useable form.

Struggling Topic 1: The alpha carbon is the 2nd carbon from the CoA group on a fatty acid, and the beta carbon is the 3rd carbon from the CoA group, right? The bond between A and B carbon is the one that is broken in B-oxidation, right?

Struggling Topic 2: It appears as though most digestion happens outside of the stomach. Where does the idea that digestion occurs in the stomach come from?

Summary: In the matrix of the mitochondria **beta oxidation** removes two-carbon segments from fatty acids one at a time. Each cycle in B-oxidation produces acetyl CoA and a fatty acid that is shorter by 2 carbons. Fatty acids are converted into acetyl CoA that enters the citric acid cycle. ATP spends 2 P groups to activate the fatty acid outside the mitochondria. Fatty acyl CoA cannot cross the inner mitochondrial membrane without bonding to **carnitine**. This transport process regulates the oxidation and synthesis of fatty acids. While fatty acids are being synthesized in the cytosol, the transport of fatty acyl CoA into the matrix is blocked to prevent fatty acid degradation. The four reactions in B-oxidation are 1. Oxidation of fatty acyl CoA forming FADH2, 2. Hydration of trans-enoyl CoA adding an OH to the B-carbon, 3. Oxidation Dehydrogenation of B-hydroxyacyl CoA forming an NADH, and 4. Cleavage of Acetyl CoA splits the A-carbon and the B-carbon to form an acetyl CoA and a fatty acyl that is 2 carbons shorter than the original fatty acid. The number of carbon atoms determines the number of times B-oxidation can happen. The final time the B-oxidation happens produces 2, 2-carbon Acetyl CoAs, so the number of B-oxidation cycles is one less than the total number of Acetyl CoAs produced. The number of acetyl CoAs produced is half the number of C-atoms in the original fatty acid. B-oxidation of trans unsaturated fatty acids produces slightly less energy than saturated fatty acid oxidation because it skils the step that produces FADH2.
 * __24.2 Oxidation of Fatty Acids__**

Struggling Topic 1: What happens to cis unsaturated fatty acids? Are these converted into trans unsaturated fatty acids by an isomerase? Does this also produce similar amounts of energy as a saturated fatty acid (except the FADH2)?

Struggling Topic 2: How many of these steps to beta-oxidation should we have memorized? It seems like having a chart of complex reactions like this would be more beneficial than memorizing all these steps.

Summary: Each B-oxidation cycle requires 2 ATP for activation and then produces 1 Acetyl CoA, 1 FADH2, and 1 NADH. 12 ATP are produced in the citric acid cycle from each Acetyl CoA. 2 ATP are produced in electron transport from FADH2, and 3 ATP are produced in electron transport from NADH. So, the total ATP produced for a fatty acid of n-carbon length = n/2 * 12 ATP(Acetyl CoA) + n/2 * 2 ATP(FADH2) + n/2 *3 ATP(NADH) - 2 ATP. This equation gives us the ratio of how many moles of ATP are produced per mole of fatty acid. This can be used as a conversion factor. 1 gram of fat produces more than double the number of nutritional calories than 1 g of carbohydrate.
 * __24.3 ATP and Fatty Acid Oxidation__**

Struggling Topic 1: Does the activation of the B-oxidation cycle always require 2 ATP, or does this change depending upon the size of the fatty acid?

Struggling Topic 2: How did we come up with the values 4 kcal/g carbohydrate and 9 kcal/g fat?

Summary: When too much acetyl CoA has built up in the liver, the acetyl CoA combines to form compounds called **ketone bodies** in a chemical process called **ketogenesis**. This process produces acetone and B-hydroxybutyrate. If ketone bodies accumulate they cannot be completely metabolized by the body and lead to **ketosis** which is found in severe diabetes, starvation, and diets that are high in fat and low in carbohydrates. Because two ketone bodies are acids, they lower blood pH below 7.4 causing **acidosis**, a drop in blood pH. This drop in blood pH interferes with the blood's ability to transport oxygen throughout the body and causes breathing difficulties.
 * __24.4 Ketogenesis and Ketone Bodies__**

Struggling Topic 1: How severe must diabetes be to induce ketosis? It doesn't seem like most diabetic fatalities occur because of acidosis.

Struggling Topic 2: How does acetyl CoA build up? Would this mean that too much ATP is present for the citric acid cycle to use up acetyl CoA? Would simply a high fat/low carb diet cause this?

Summary: **Lipogenesis** is a series of chemical reactions that links 2-carbon acetyl units together to form the fatty acid, palmitic acid (16 carbons long). Lipogenesis uses a different set of enzymes than fatty acid oxidation, and lipogenesis happens in the cytosol while fatty acid oxidation occurs in the mitochondria. Thirdly, NADPH is used in lipogenesis instead of NADH. In fatty acid synthesis an acyl carrier protein (ACP-SH) is used before CoA is involved. When Acetyl CoA combines with bicarbonate and forms malonyl CoA (3 carbon compount), ATP is hydrolyzed, and fatty acid synthesis begins. Four reactions occur in a cycel that adds two-carbon acetyl groups to a carbon chain: 1. Condensation of acetyl ACP and molonyl ACP, 2. Reduction of the ketone group on the Beta carbon using NADPH, 3. Dehydration of OH from the B-carbon, 4. Reduction by of the double bond to a single bond using NADPH forming a saturated four-carbon compound. This cycle repeats as the chain continues to get 2 carbons longer until C-16 palmitoyl-ACP is hydrolyzed to yield palmitate and HSACP. Overall, 8 acetyl CoA + 14 NADPH + 14 H+ + 7 ATP --> palmitate + 8 CoA + 14 NADP+ + 7 H2O + 7 ADP + 7 Phosphate groups. Fatty acid synthesis usually happens in the adipose tissue, and insulin stimulates fatty acid synthesis when blood glucose levels are high. Overall, Beta oxidation removes 2-carbon units using oxidation and hydration, CoA FAD, NAD+, when glucagon is activated by low blood glucose, and fatty acid synthesis adds 2-carbon units using reduction and dehydration, ACP, NADPH when insulin is activated by high blood glucose.
 * __24.5 Fatty Acid Synthesis__**

Struggling TOpic 1: Is it true that the body prioritizes energy storage beginning with blood glucose, glycogen, and then lipids?

Struggling Topic 2: What difference does NADPH have in function compared to NADH? Does the P make the molecule specific to lipogenesis and not to glycolysis/gluconeogenesis?

__**24.6 Digestion of Proteins**__ Summary: Digestion of protein begins in the stomach where HCl (pH 2) denatures protein and activates enzymes like pepsin that hydrolyze peptide bonds. In the small intestine, polypeptides are broken into amino acids that are absorbed into the blood stream through the intestinal wall. **Protein turnover** is the process where proteins are constantly synthesized and broken down in the body. For example, insulin lasts only 10 minutes in its active form in the cells. The body does not store nitrogen, so a high protein diet results in excess urea to remove nitrogen. Under normal circumstances, only about 10% of our energy is supplied by amino acids. In fasting or starving conditions, amino acids provide a much larger source of energy, and the breakdown of body proteins leads to loss of essential body tissue eventually.

Struggling Topic 1: Compared to the amount of fat and carbohydrate that is oxidized in the small intestine and elsewhere in the digestive system, how much protein is broken down in the stomach?

Struggling Topic 2: Does this amount of constant protein turnover account for the idea that digestion occurs mainly in the stomach? How realistic is this belief?

Summary: Degradation of amino acids occurs mostly in the liver. **Transamination** reactions transfer a-amino groups from an amino acid to an a-keto acid. This process can be used to yield pyruvate. **Oxidative deamination** is a process where the amino group is removed as NH4+ by the enzyme gluatamate dehydrogenase and the coenzyme NAD+ or NADP+. Thus any amino acid may be deaminated to produce glutamate while the NH4+ is converted to urea.
 * __24.7 Degradation of Amino Acids__**

Struggling Topic 1: Is there a use for NH4+ ions in the body other than protein?

Struggling Topic 2: How is kidney failure and dialysis related to ketosis? It seems like diabetes often causes problems with kidney function. Is this related to the ketosis we learned about previously?

Summary: NH4+ is toxic if it accumulates. In the liver, the **urea cycle** is a process that detoxifies ammonium ions by converting them to urea that can be processed by the kidneys to form urine. The typical adult may excrete about 25-30 g of urea in the urine per day. This amount may increase with a high protein diet. Renal disease is detected by measuring the amount of urea nitrogen in the blood (BUN levels). If the BUN is high, then protein intake is reduced or dialysis may be used to remove nitrogen waste from the blood. Before the urea cycle can happen, the NH4 ion reacts with CO2 and 2 ATP to form carbomoyl phosphate. The four steps of the urea cycle are: 1. transfer of carbomoyl group - in the mitochondria, carbamoyl phosphate loses a phosphate bond to move citrulline across the mitochondrial membrane into the cytosol; 2. condensation with aspartate - in the cytosol, citrulline condenses with aspartate to form argininosuccinate; ATP is hydrolyzed to AMP to provide the energy for this reaction; the nitrogen atom in aspartate becomes the other nitrogen atom in urea that is produced later; 3. cleavage of fumarate - argininosuccinate is cleaved to yield fumarate (from the citric acid cycle) and arginine. 4 - hydrolysis to form urea - the hydrolysis of arginine yields urea and ornithine (see step 1). Overall, NH4+ + CO2 + 3ATP + aspartate (other N atom) + 2H20 --> urea + 2ADP + AMP + 4 P + fumarate (citric acid cycle intermediate).
 * __24.8 Urea Cycle__**

Struggling TOpic 1: How essential is it to have the steps of the urea cycle memorized? It seems like a basic understanding with an additional chart or table would be sufficient for this cycle.

Struggling Topic 2: Does the fumarate produced from the urea cycle enter the citric acid cycle? How is aspartate replenished?

Summary: Carbon atoms from transamination of amino acids can be used as intermediates of the citric acid cycle or other metabolic reactions. This is determined by how many carbon atoms are in those intermediates. Amino acids with 3 Cs or that are converted into 3 C molecules are converted to pyruvate, 4 C molecules are converted to oxaloacetate, and the 5 C molecules become alpha-ketoglutarate. Some amino acids can enter metabolic processes in more than one path. **Glucogenic amino acids** generate pyruvate or oxaloacetate which are converted to glucose by gluconeogenesis. **Ketogenic amino acids** produce acetoacetyl CoA or acetyl CoA which enter ketogenesis to form ketone bodies or fatty acids.
 * __24.9 Fates of the Carbon Atoms from Amino Acids__**

Struggling Topic 1: Is there a factor other than the number of carbon atoms that affects whether an amino acid will become glucogenic or ketogenic? It seemed like the number of carbon atoms was the main factor.

Struggling Topic 2: Is there variation between amino acids that could take more than one pathway towards pryuvate, oxaloacetate, acetoacetyl CoA, or acetyl CoA? What causes this variation if it is possible?

Summary: Humans can only synthesize 10 of the 20 amino acids found in their proteins. The **nonessential amino acids** are synthesized in the body while the **essential amino acids** must be obtained from the diet. Two amino acids, arginine and histidine, are essential for children but not for adults. Alpha-keto skeletons are obtained from the citric acid cycle or glycolysis and converted to amino acids by transamination. Simple transamination, like forming alanine, requires only the amino group from glutamate be transfered to pyruvate, a 3-C alpha keto acid.
 * __24.10 Synthesis of Amino Acids__**

Struggling Topic 1: Are amino acids constantly synthesized by the body, or is this only done when the body has a shortage of a given amino acid.

Struggling Topic 2: How specifically are the 10 essential amino acids found in foods in our diets?

__**Critique**__ A. specifics about how clearly the author communicated individual topics ->24.2, 24.5, 24.8 - The author's charts and descriptions of reactions in beta-oxidation, lipogenesis, and the urea cycle were very helpful for understanding the complex steps in the reactions.

B. specifics about the amount of content and whether it was sufficient to help learn the material (did you need more examples?) ->24 - Overall, this chapter seemed to cover a very broad range of topics. It seemed that we could have better covered this material in two separate chapters - one on lipids and the other on amino acids.

C. why did the author place this chapter where she did in the overall text? not later or earlier, transitions with previous chapter, with subsequent chapter(s), did this chapter seem out of place? -> 24.9 - it is good that we have already learned about the different amino acids before learning about the fate of their carbon atoms in the metabolic processes. It made for a good review to look at the different amino acids and compare how many C atoms each had.