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![Why Does Atkins Diet Appear to Work?
CHO H2O retention (short term)
long term: wt loss = caloric balance
high CHO
high fat
Any healthy diet will do
Main argument against Atkins
= unhealthy diet
weight
time
Why Does Atkins Diet Appear to Work?
CHO H2O retention (short term)
long term: wt loss = caloric balance
high CHO
high fat
Any healthy diet will do
Main argument against Atkins
= unhealthy diet
weight
time
Low carbohydrate versus low fat diets will be covered in more detail in lecture.
________________________________________________________________________
Key Points about the Citric Acid Cycle
1. Cofactors for the pyruvate dehydrogenase reaction and their corresponding
vitamins.
thiamine pyrophosphate thiamin
lipoic acid
coenzyme A pantothenic acid
FADH2 riboflavin
NAD niacin
2. Regulation of C.A.C.
When O2 limiting it causes an increase in [NADH] which causes inhibition
(NADH = direct end product C.A.C.).](https://image.slidesharecdn.com/citricacidcycle-150801072856-lva1-app6891/85/Citric-acid-cycle-9-320.jpg)
![When cell has more energy than it needs the concentration of [ATP]
increases, which causes inhibition.
ATP = end product C.A.C. and ox. phos.
This diverts pyruvate, acetyl CoA and amino acids to other pathways
3. C.A.C. and Other Pathways
It is the final step for conversion of all foods to CO2 and H2O.
It is the central pathway that interconnects all others.
CHO can be converted to protein or fat.
Some protein can be converted to CHO or fat.
Fat cannot be converted to CHO or protein.
OAA is needed to keep the C.A.C. going.
________________________________________________________________________
SAMPLE QUESTIONS
Each of the following questions has one correct answer.
1. The overall reaction of the pyruvate dehydrogenase complex produces: NADH,
H+, CO2, and
a. lactate
b. oxaloacetate
c. citrate
d. ATP
e. Acetyl CoA
2. The citric acid cycle and oxidative phosphorylation both occur in the:
a. lysosomes
b. nucleus
c. zymogen granules
d. cytoplasm
e. mitochondrion](https://image.slidesharecdn.com/citricacidcycle-150801072856-lva1-app6891/85/Citric-acid-cycle-10-320.jpg)
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Citric acid cycle
- 1. CITRIC ACID (KREB’S,TCA) CYCLE Date: September 2, 2005 * Time: 10:40 am- 11:30 am * Room: G-202 Biomolecular Building Lecturer: Steve Chaney 515A Mary Ellen Jones Building stephen_chaney@med.unc.edu 966-3286 *Please consult the online schedule for this course for the definitive date and time for this lecture. Office Hours: by appointment Assigned Reading: This syllabus. Key Concepts vs Supplementary Information: Because this syllabus is meant to replace the need for a Biochemistry textbook, it contains a mixture of information that is critical for you to know and information that serves to illustrate and explain the key points. I have attempted to emphasize important terms, definitions and concepts in red, and have listed key points after each section of the syllabus. Illustrative and supplementary information is indicated in italics. Overall Objectives for Carbohydrate Metabolism: By the end of this course, you should: 1) understand how carbohydrate metabolism normally responds in the fed state, the fasting state, and during exercise. 2) understand how carbohydrate metabolism is altered by diabetes and the metabolic response to trauma and surgery. 3) understand the relationship between obesity, exercise, insulin resistance, and diabetes. 4) understand basic priciples of diet composition and weight management. Lecture Objectives: At the conclusion of this lecture you should: 1) know the vitamins and cofactors that are required by the citric acid cycle (especially for the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase reactions). 2) know how the citric acid cycle is regulated. 3) know the role that the citric acid cycle plays in carbohydrate, amino acid, and fat metabolism. 4) know the role that the citric acid cycle plays in the interconversion of carbohydrates, amino acids, and fats.
- 2. Important concepts: 1. Allfuel molecules are oxidized to citric acid cycle intermediates. 2. The citric acid cycle is important for the biosynthesis of glucose, lipids, and some amino acids. The citric acid cycle breaks down a 6 carbon compound (citrate) to a 4 carbon compound (oxaloacetate). The high energy electrons are transferred to co-enzyme carriers (NAD+ and FAD) and destined for oxidative phosphorylation. The carbons are removed as CO2, and the H+ will follow with the electrons to O2 to form H2O. The citric acid cycle enzymes are located in the mitochondria, but they are mostly soluble enzymes located in the mitochondrial matrix. A. Pyruvate dehydrogenase complex (PDH) Pyruvate dehydrogenase is a large enzyme complex in the mitochondrion consisting of 3 different types of enzyme subunits. It is the enzyme that connects the glycolytic pathway to the citric acid cycle. Note that 4 of the coenzymes used in this reaction are derived from substances that must be obtained in the diet. thiamine or vitamin B1 - thiamine pyrophosphate (TPP) pantothenic acid - coenzyme A (CoASH) riboflavin – FADH2 niacin - NADH Connects Glycolysis to C.A.C. pyruvate acetyl CoA CoASH NADH CO2CH3 C O CO2 - SCoA CH3 C O NAD+
- 3. pyruvate acetyl CoA The citricacid cycle contains a cyclic sequence of 8 enzymes that are so arranged that they perform molecular rearrangements of intermediate metabolic compounds to prepare them for decarboxylation and dehydrogenation. .Selected Enzymatic Steps 1. Citrate synthase: this is a 2 step reaction: an aldol condensation of oxaloacetate and acetyl CoA, followed by hydrolysis to yield citrate and free CoA. The hydrolysis step is not easily reversible. pyruvate dehydrogenase COO C O CH3 - SCoA C O CH3 CoASH NADH CO2 CoASH CO2 - CH2 C CO2 - HO CH2 CO2 - citric acid CO2 - CH2 CH2 C CO2 -O αKG succinyl CoA CO2 - CH2 CH2 CO2 - succinate CO2 - CHOH CH2 CO2 - malate CO2 - C CH2 CO2 - O OAA CO2 NADH CO2 CoASH NADH CoASH GTP FADH2 NADH B. Overview of the Citric Acid Cycle Citrate synthase αKG dehydrogenase CH2 CH2 C SCoA O CO2 - Succinyl CoA synthetase Malate dehydrogenase acetyl CoA SCoA C O CH3 CoASH CO2 - CH2 C CO2 - HO CH2 CO2 - citric acid CO2 - C CH2 CO2 - O Citrate synthase
- 4. 2. α-ketoglutarate dehydrogenase:a multi-enzyme complex very similar to pyruvate dehydrogenase. This step is irreversible. It also produces NADH. CO2 - CH2 CH2 C CO2 -O αKG succinyl CoA CO2 NADH CH2 CH2 C SCoA O CO2 - αKG dehydrogenase CoASH 3. succinyl CoA synthetase: succinyl CoA has a high negative ΔG°' of hydrolysis, and can, therefore, be coupled to the direct phosphorylation of GDP → GTP (which is equivalent to ATP); this reaction is fairly reversible. This is an example of substrate level phosphorylation. Succinyl CoA synthetase succinyl CoA CO2 - CH2 CH2 CO2 - succinate CoASH GTP CH2 CH2 C SCoA O CO2 - 4. malate dehydrogenase: this is a good example of a reaction that has a net flow opposite to an unfavorable Keq. That is the oxidation of malate by NAD+ to produce oxaloacetate + NADH + H+ has a ∆G°' of + 7 kcal/mole. CO2 - CHOH CH2 CO2 - malate CO2 - C CH2 CO2 - O OAA NADH Malate dehydrogenase Question: What can you deduce from the above direction of this reaction about the respective physiological concentrations of malate and oxaloacetate?
- 5. Net Energy Yieldof the Citric Acid Cycle For each acetyl group used up, the cycle produces: 3 NADH + 1 FADH2 + 1 GTP + 2 CO2 Since each NADH can result in 3 ATP, and each FADH2 can result in 2 ATP, the net high energy production is 12 ATP. Therefore, the total energy from 1 glucose is: 1 glucose → 2 pyruvate: 2 ATP + 2 NADH (= 4 ATP) 2 pyruvate → 2 acetyl CoA: 2 NADH 2 acetyl CoA → 4 CO2 : 2 x 12 ATP 6 ATP 6 ATP 24 ATP - 6 in cytosol - 30 in mitochondria 36 ATP It should be self-evident why the 36 ATP that result from the complete oxidation of glucose are far preferable to the 2 ATP that are derived by glycolysis alone. C. Regulation of the Citric Acid Cycle The citric acid cycle is regulated at multiple points. However, in general it is safe to say that it is inhibited by ATP and NADH. The inhibition by NADH keeps it tightly regulated by oxygen supply, since NADH is converted to NAD+ by oxidative phosphorylation. The inhibition by ATP keeps the citric acid cycle in balance with energy supply. When ATP (energy supply) is high, the citric acid cycle is inhibited and precursors to the citric acid cycle (pyruvate, acetyl CoA and amino acids) are diverted into other pathways. Acetyl CoA, citrate, and succinylCoA are the end products of individual steps in the citric acid cycle and their accumulation inhibits the step involved in their production. That, of course, results in inhibition of the cycle as a whole. Finally, Ca++ stimulates the citric acid cycle at several points. This is important because electrical stimulation of the muscle causes an increase in intracellular calcium levels. Thus, during exercise the citric acid cycle will be maximally stimulated in muscle. The regulation of the citric acid cycle is summarized below.
- 6. Pyruvate Ca2+ Acetyl-CoA Citrate Isocitrate α-Ketoglutarate Ca2+ Ca2+ Succinyl-CoAGTP Regulation of theCitric Acid Cycle (animation available in PowerPoint) D. Relationship Between the Citric Acid Cycle and Other Metabolic Pathways 1. Acetyl CoA is both the final product of fatty acid degradation and the first building block for fatty acid synthesis. 2. Several citric acid cycle intermediates can be converted to amino acids by simple transamination reactions (see below). Thus, the citric acid cycle can be involved in amino acid synthesis, degradation, or conversion to oxaloacetate for gluconeogenesis. ATP Succinate Fumarate Malate Oxaloacetate NADH - + - - + - + e- e- e- Ox Phos
- 7. αKG + AspGlu + OAA + α-Ketoglutarate Aspartate Glutamate + Oxaloacetate CO2 - CH2 CH2 C O CO2 - CH2 CH CO2 - CO2 - Interconversions of the Citric Acid Cycle (animation available in PowerPoint) C.A.C. and Other Pathways Glucose PEP pyruvate acetyl CoA fatty acids fats CO2 CO2 Alanine a.a.’s protein citrate (C6) αKG (C5) glutamate urea cycle a.a.’s protein succinate (C4) porphyrins hemoglobin Val, Ile protein NADH + FADH2 ATP protein a.a.’s Asp OAA (C4) CO2 C.A.C. and Other Pathways Glucose PEP pyruvate Alanine a.a.’s protein citrate (C6) αKG (C5) glutamate urea cycle a.a.’s protein succinate (C4) porphyrins hemoglobin Val, Ile protein NADH + FADH2 ATP protein a.a.’s Asp OAA (C4) acetyl CoA fatty acids fats CO2 CO2 CO2 NH3 + CO2 - CH2 CH2 CH CO2 - CO2 - CH2 C O CO2 -NH3 +
- 8. Thus, the citricacid cycle: 1. is the final step in the conversion of all foods to CO2 and H2O. 2. is the major source of reducing equivalents (NADH and FADH2) used by the cell to generate ATP (via oxidative phosphorylation). 3. is the central pathway that interconnects all others. a. Excess carbohydrate can be converted to protein* and fat. b. Excess protein can be converted to carbohydrate or fat. c. However, net conversion of fatty acids to carbohydrate and most amino acids is not possible. *Note: Some amino acids cannot be synthesized by the body and are, therefore, essential components of the diet. In the absence of these essential amino acids, net conversion of carbohydrate to complete proteins is impossible. 4. The citric acid cycle requires a constant supply of oxaloacetate to keep going. (What enzyme supplies oxaloacetate when we break down carbohydrate?) (Why is this enzyme activated by acetyl CoA?) 5. Since oxaloacetate is depleted by gluconeogenesis, Dr. Atkins has postulated that fat calories won’t be utilized in the absence of carbohydrate. Based on what you now know about the citric acid cycle, what is the basic falacy of this hypothesis? (Where does oxaloacetate come from when we break down protein?)
- 9. Why Does AtkinsDiet Appear to Work? CHO H2O retention (short term) long term: wt loss = caloric balance high CHO high fat Any healthy diet will do Main argument against Atkins = unhealthy diet weight time Why Does Atkins Diet Appear to Work? CHO H2O retention (short term) long term: wt loss = caloric balance high CHO high fat Any healthy diet will do Main argument against Atkins = unhealthy diet weight time Low carbohydrate versus low fat diets will be covered in more detail in lecture. ________________________________________________________________________ Key Points about the Citric Acid Cycle 1. Cofactors for the pyruvate dehydrogenase reaction and their corresponding vitamins. thiamine pyrophosphate thiamin lipoic acid coenzyme A pantothenic acid FADH2 riboflavin NAD niacin 2. Regulation of C.A.C. When O2 limiting it causes an increase in [NADH] which causes inhibition (NADH = direct end product C.A.C.).
- 10. When cell hasmore energy than it needs the concentration of [ATP] increases, which causes inhibition. ATP = end product C.A.C. and ox. phos. This diverts pyruvate, acetyl CoA and amino acids to other pathways 3. C.A.C. and Other Pathways It is the final step for conversion of all foods to CO2 and H2O. It is the central pathway that interconnects all others. CHO can be converted to protein or fat. Some protein can be converted to CHO or fat. Fat cannot be converted to CHO or protein. OAA is needed to keep the C.A.C. going. ________________________________________________________________________ SAMPLE QUESTIONS Each of the following questions has one correct answer. 1. The overall reaction of the pyruvate dehydrogenase complex produces: NADH, H+, CO2, and a. lactate b. oxaloacetate c. citrate d. ATP e. Acetyl CoA 2. The citric acid cycle and oxidative phosphorylation both occur in the: a. lysosomes b. nucleus c. zymogen granules d. cytoplasm e. mitochondrion
- 11. 3. The citricacid cycle "begins" with citrate synthase catalyzing the formation of citrate from: a. succinyl CoA + pyruvate b. acetyl CoA + pyruvate c. acetyl CoA + oxaloacetate d. furmarate + oxaloacetate e. pyruvate + lactate
- 12. Answers 1. e 2. e 3.c Comments 1. Pyruvate dehydrogenase is a key enzyme. You are, therefore, asked to remember that it converts pyruvate to acetylCoA. 2. You need to know the location of metabolic pathways. e is correct. 3. Again this is a key enzyme. You are asked to remember the substrates.