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3 TCA cycle- complete oxidation of glucose

Fate of pyruvate and TCA cycle. Its regulation and clinical significance. Metabolic events associated with it. Fate of Acetyl CoA

Health & Medicine◦
Related topics:
Citric Acid Cycle•
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TCA CYCLE / CITRIC ACID CYCLE/ KREB’S CYCLE DR. VIYATPRAJNA ACHARYA MD, PhD
Metabolic fate of Pyruvate
3 fates :  1. Conversion to ethanol- yeast & microbes  2. Pyruvate → Lactate  3. Pyruvate → Acetyl CoA
Pyruvate → Acetyl CoA  Site : mitochondria  Transport: Pyruvate transporter (H+ symport);  It crosses the outer mitochondrial membrane freely through porin (VDAC) channels  Pyruvate crosses the inner mitochondrial membrane via the Mitochondrial Pyruvate Carrier (MPC).  Oxidative decarboxylation  1st c atom lost in the form of CO2  PDH complex- Multi-enzyme complex  3 enzymes & 5 Co-enzymes
Oxidative decarboxylation
Enzymes & Co-enzymes Enzymes: 1. Pyruvate decarboxylase 2. Dihydrolipoate transacetylase 3. Dihydrolipoate dehydrogenase Co-enzymes: 1. TPP 2. Lipoate 3. CoASH 4. FAD
3 processes  Decarboxylation  Oxidation  Transfer of acetyl group
Regulation  Feedback inhibition by acetyl CoA  Allosteric inhibitors- ATP, Acetyl CoA and NADH  Covalent modifications: Phosphorylation converts active enzyme to inactive enzyme  Arsenide & Mercury- inhibit PDH complex Insulin, Ca2+ + ATP, Acetyl CoA, NADH + ADP, Pyruvate, Ca2+ -
Significance  Links the glycolytic pathway to TCA cycle  Acetyl CoA is also an important intermediate in lipid metabolism, Cholesterol biosynthesis, acetylation reaction  Alcohol→ ↓Thiamine absorption → ↓TPP → Lactic acidosis Dextrose drip → lactic acidosis → Death  Inherited deficiency of PDH → Lactic acidosis
Fate of Acetyl CoA
TCA CYCLE
We are here Sir Hans Krebs
A R A O D OD SLP O H O
1. 1ST PRODUCT- CITRATE Condensation reaction
2. Dehydration - Fluoroacetate
3. Formation of Isocitrate Rehydration
4. Oxidation
5. Decarboxylation Cytoplasmic IDH- NADP+ dependent
6. Oxidative decarboxylation •Similar to PDH complex •Same co-enzymes •2nd NADH produced
7. SLP Only 1 ATP generated Where else SLP??? GTP- when Gluconeogenesis takes place Liver & Kidney
8. Oxidation •Reversible dehydrogenation •Succinate dehydrogenase- bound to inner surface of inner mitochondrial membrane •FAD- 1.5 ATP generated •Malonate –
9. Hydration Malate is fully permeable to the mitochondrial membrane
10. Oxidation 3rd synthesis of NADH
A R A O D OD SLP O H O
Bioenergetics  3 NADH- 32.5 = 7.5  1 FADH2-1 1.5= 1.5  1 SLP = 1 10 1 glucose- 2 pyruvate Net ATP generation – 7 + (2 2.5) + (2 10) = 32
Significance of TCA cycle  Provides energy  Final common pathway for oxidation of carbohydrates, lipids & protein  Fat is burnt on the wick of carbohydrates  Oxaloacetate acts a catalyst  Amphibolic process  Anaplerotic role  Anabolic reactions- Gluconeogenesis transamination FA synthesis Porphyrin synthesis
Aspire intensely, but without impatience
Role of Vitamins as coenzymes  Thiamine  Riboflavin  Pantothenic acid  Lipoic acid  Niacin  Biotin (B7)- Indirect; Pyruvate→ OA  B12- Indirect; Propionyl CoA Succinyl → CoA
REGULATION  PDH  Citrate synthase  IDH  α- ketoglutarate dehydrogenase All dehydrogenases- activated by Ca2+ High ratios of ATP/ADP, NADH/NAD+ , Acetyl CoA/CoA – inhibits TCA cycle ↑Succinyl CoA – inhibits citrate synthase & α KGD
Excess carbohydrates converted to neutral fat  The vice versa is not true  Pyruvate→ Acetyl CoA is the irreversible step
ANAPLEROTIC REACTIONS Anaplerosis = to fill up  TCA intermediates move out for different metabolic processes- 4C compounds  Rate of TCA cycle declines  Special reactions (Anaplerotic reactions)- replenish the TCA intermediates
Efflux of TCA intermediates
Influx of TCA intermediates Urea cycle
Major Anaplerotic reactions  Pyruvate Oxaloacetate  Transamination of Asp & Glu to OA & α KG respectively  Deamination of glutamate to α KG  VIM, Thr, Propionyl CoA- Succinyl CoA  C skeleton of AA is converted to propionyl CoA→ succinyl CoA Pyruvate Carboxylase
 Cytoplasmic Malic enzyme: Pyruvate → Malate  All TCA intermediates can replenish OA
Clinical Significance  PDH deficiency (Mutation in E1-alpha subunit of PDH complex)- Lactic acidosis, neurological disorders  Pyruvate carboxylase deficiency- OA ↓ ↓ Lactic acidosis, hypoglycemia, hyperammonemia and hyperalaninemia  Alcoholism- Thiamine deficiency- Lactic acidosis
www.drvpacharya.com For more PPT on Medical Biochemistry