TCA Cycle
-
Upload
ansil-p-n -
Category
Health & Medicine
-
view
592 -
download
1
Transcript of TCA Cycle
![Page 1: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/1.jpg)
CITRIC ACID CYCLE
IntroductionSitePathwayEnergeticsRegulationClinical importance
![Page 2: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/2.jpg)
Glycolysis
Link reaction
Kreb’s cycle
Oxidative Phosphorylation (ETC)
![Page 3: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/3.jpg)
INTRODUCTION
Citric acid cycle
Krebs cycle (1937; NP-1953)
Tricarboxylic acid cycle
Reduced co-enzymes are produced – act as substrate for for ETC
Most important ATP producing pathway
About 65-70% ATP synthesized Sir Hans Krebs [1900-
1981] – on his bike!
![Page 4: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/4.jpg)
Takes place in the matrix of the mitochondria.
It happens once for every pyruvate molecule in glycolysis….
Purpose
• Conversion of Acetyl-CoA to
CO2
• Generates reducing equivalents (NADH + H+, FADH2) & GTP to be oxidized in the respiratory chain to generate ATP
![Page 5: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/5.jpg)
OVERVIEW
![Page 6: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/6.jpg)
STEPS INVOLVED IN TCA CYCLE
![Page 7: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/7.jpg)
Succinate thiokinase
![Page 8: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/8.jpg)
![Page 9: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/9.jpg)
Let’s have a short break
![Page 10: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/10.jpg)
TIPS TO LEARN BIOCHEMISTRY
• Do not rely on passive reading and highlighting/underlining of the textbook.
• Do not sit and stare at the handouts
• Do not try to read 50 review books. (Make your own review book instead!)
• Do focus on identifying key concepts
• Do actively draw and redraw pathways and connections
• Do learn to identify relevant information
![Page 11: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/11.jpg)
Do prioritize:
• What is the purpose of a pathway?
• What are the starting and ending molecules?
• Where is the pathway (in the cell, in a tissue, in an organ system)?
• How does the pathway connect to other pathways?
• What metabolic conditions turn the pathway on and off?
• What are the control points for regulating the pathway?
• reactants, products and enzyme name of each regulatory step
• additional regulatory molecules involved (vitamins, cofactors)
• make sure you know every step that makes or uses ATP
• What specific drugs or diseases associated with the pathway?
![Page 12: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/12.jpg)
![Page 13: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/13.jpg)
TCA cycle is an open cycle
Operates only under aerobic conditions
This is the Final common pathway of oxidative metabolism
Two carbon dioxide molecules are released as a waste product of respiration
GTP+ H+
![Page 14: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/14.jpg)
Energetics : 2 Acetyl CoA from 2 Pyruvate
1NADH+H+ = 3/2.5 ATP
1FADH2 = 2/1.5 ATP
1GTP = 1 ATP
Acetyl-CoA + 3 NAD+ + [FAD] + GDP + Pi + 2 H2O CoASH + 3 NADH+3 H + +[FADH2] + GTP + 2 CO2
×2=24
![Page 15: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/15.jpg)
![Page 16: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/16.jpg)
ATP generation during oxidation of Glucose
Net ATP production depends on shuttle used for the transfer of
reducing equivalents from cytosol to mitochondria.
8 / 76 / 5
24 / 2038 / 32
![Page 17: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/17.jpg)
SIGNIFICANCE OF TCA CYCLE:
1. Complete oxidation of Acetyl CoA
2. As provider of energy
3. Final common oxidative pathway
4. Integration of major metabolic pathways
5. Fat is burned on the wick of carbohydrates
6. Excess carbohydrates are converted to Neutral fat
7. No net synthesis of carbohydrates from fat
8. Amino acids enters TCA cycle
9. Amphibolic pathway
10. Anaplerotic role
![Page 18: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/18.jpg)
1.Complete oxidation of Acetyl CoA
2. ATP generation
12/10 ATP are generated via substrate level phosphorylation and ETC
Oxaloacetate
Citrate
Isocitrate
α-ketogluterate
![Page 19: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/19.jpg)
3. Final common oxidative pathway
![Page 20: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/20.jpg)
4. Integration of major metabolic pathways
![Page 21: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/21.jpg)
![Page 22: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/22.jpg)
5.Fat is burned on the wick of carbohydrates
For complete oxidation of acetyl CoA , it needs the help of oxaloacetate
The major source of oxaloacetate is pyruvate, derived from carbohydrate
6. Excess carbohydrates are converted to Neutral fat
Glucose Pyruvate Acetyl CoA Fatty Acid
PDH is irreversible – fat can not be converted to glucose.
![Page 23: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/23.jpg)
Participation of TCA cycle in fatty acid synthesis from glucose
![Page 24: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/24.jpg)
7.No net synthesis of carbohydrates from fat
• Acetyl CoA entering in the cycle is completely oxidized to
CO2 by the time the cycle reaches Succinyl CoA.
• So acetyl CoA can not be used for the synthesis of
carbohydrates.
![Page 25: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/25.jpg)
8. Amino acids finally enters the TCA cycle
![Page 26: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/26.jpg)
9. Amphibolic Pathway
• Both anabolic and catabolic
• Metabolic traffic cycle
![Page 27: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/27.jpg)
10. Anaplerotic role of TCA cycle
“Filling up” reactions or “influx” reactions or
“replenishing” reactions
• Pyruvate Oxaloacetate
• Glutamate α-KG
• Aspartate Oxaloacetate
• Pyruvate Malate
![Page 28: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/28.jpg)
![Page 29: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/29.jpg)
Regulation of TCA cycle
Indicator molecules of higher energy state i.e. ATP, NADH, citrate, Acetyl CoA – inhibit TCA cycle
Indicator molecules of low energy state i.e. ADP, AMP, NAD+ – stimulate TCA cycle
*
*
*
*
![Page 30: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/30.jpg)
INHIBITORS OF TCA CYCLE
1. Fluoroacetate
Condensation FluoroacetylCoA with Oxaloacetate
Fluorocitrate inhibit Aconitase enzyme accumulation
of citrate
Fluoroacetate pesticide
2. Malonate Succinate dehydrogenase enzyme
3. Arsenite α-ketoglutarate dehydrogenase enzyme
![Page 31: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/31.jpg)
METABOLIC DEFECTS
• Extremely rare1. Defect in PDH - Lactic acidosis - Neurologycal dosorders
2. Defect In Pyruvate carboxylase - Oxaloacetate - Hyperammonemia - Lactic acidosis - Hyperalaninemia.
![Page 32: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/32.jpg)
SUMMARY
• Pyruvate is converted to acetyl-CoA by the action of p yruvate dehydrogenase complex, a huge enzyme complex.
• Acetyl-CoA is converted to 2 CO2 via the eight-step citric acid cycle, generating three NADH, one FADH2, and one ATP (by
substrate-level phophorylation).
![Page 33: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/33.jpg)
• Intermediates of citric acid cycle are also used as biosynthetic precursors for many other biomolecules, including fatty acids, steroids, amino acids, heme, pyrimidines, and glucose.
• Oxaloacetate can get replenished from pyruvate, via a carboxylation reaction catalyzed by the biotin-containing pyruvate carboxylase.
![Page 34: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/34.jpg)
QUESTIONS?
• TCA cycle is the final common metabolic pathway for the oxidation of food stuffs. – Justify
• Conversion of Pyruvate to Acetyl CoA
• Energetics of citric acid cycle
![Page 35: TCA Cycle](https://reader036.fdocuments.us/reader036/viewer/2022070514/5881bf851a28abdd268b4c93/html5/thumbnails/35.jpg)
THANK YOU