Citric acid cycle TCA Cycle

1. Citric Acid cycle
Dr Anurag Yadav
MBBS, MD
Assistant Professor
Department of Biochemistry
Instagram page –biochem365
Email: dranurag.y.m@gmail.com
MNR MEDICAL COLLEGE & HOSPITAL

2. • Also know as Krebs Cycle.
• Krebs proposed the original name TCA
(Tricarboxylic acid)

3. Functions of the Citric acid cycle
1. The final common oxidative pathway that
oxidizes acetyl CoA to CO2.
2. The source of reduced co-enzymes that provide
the substrate for the respiratory chain.
3. The link between catabolic and anabolic
pathways (amphibolic role).
4. Provides precursors for synthesis of amino acids
and nucleotides.
5. Components of the cycle have a direct or indirect
controlling effects on key enzymes of other
pathways.

4. Significance of Citric acid cycle
1. Complete oxidation of acetyl CoA
2. ATP generation
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 as neutral fat
7. No net synthesis of carbohydrates from fat
8. Carbon skeletons of amino acids finally enter the citric acid cycle
9. Amphibolic pathway
10. Anaplerotic role.

5. STEPS of CITRIC ACID CYCLE
• Location: Mitochondrial matrix
• Krebs cycle basically involves the combination
of a two carbon acetyl CoA with a four carbon
oxaloacetate to produce a six carbon
tricarboxylic acid, citrate.

6. • In the reactions that follow, the two carbons
are oxidized to CO2 and oxaloacetate is
regenerated and recycled.
• Oxaloacetate is considered to play a catalytic
role in citric acid cycle.

8. Reactions of the cycle preparatory
step
• Acetyl CoA enters the cycle, and is completely
oxidized.
• All the enzymes of citric acid cycle are located
inside the mitochondria.

10. Reactions of citric acid cycle
Formation of citrate
Citrate is isomerized to isocitrate
Formation of alpha-ketoglutarate
Conversion of alpha-ketoglutarate to succinyl CoA
Formation of Succinate
Conversion of succinate to fumarate
Formation of malate
Conversion of malate to oxaloacetate

12. Steps
• starts with the condensation of acetyl
CoA and oxaloacetate, catalysed by
the enzyme citrate synthase.
formation of
citrate:
• by enzyme aconitase.
2 & 3. citrate is
isomerized to
isocitrate
• Isocitrate dehydrogenase catalyses
the conversion of isocitrate to
oxalosuccinate and then to alpha-
ketoglutarate.
4 & 5.
Formation of
alpha-
ketoglutarate:

13. • Occurs through oxidative
decarboxylation, catalysed by
alpha-ketoglutarate
dehydrogenase complex.
• This enzyme is dependent on
five cofactors—TPP,
lipoamide, NAD+, FAD and
CoA.
6. Conversion
of alpha-
ketoglutarate
to succinyl
CoA:

14. • succinyl CoA is converted to
succinate by succinate thiokinase.
• this is substrate level
phosphorylation
7.
Formation
of succinate:
• succinate is oxidized by succinate
dehydrogenase to dumarate
• result in production of FADH2
8.
Conversion
of succinate
to fumarate:

15. • fumarase catalyses the conversion
of fumarate to malate
9. Formation
of malate:
• malate is oxidized to oxaloacetate
by malate dehydrogenase.
• third and final synthesis of NADH
occurs at this stage.
• Oxaloacetate is regenerated
10.
Conversion of
malate to
oxaloacetate:

16. ATP Generating steps in TCA Cycle
3 NADH generated
3 * 2.5 = 7.5 ATP
1 FADH2 generated
1 * 1.5 = 1.5 ATP
1 GTP generated
= 1 ATP
Per turn of cycle = 10 ATP are generated

18. Role of Vitamins in TCA cycle
• Coenzyme for alpha-ketoglutarate
dehydrogenase
Thiamine (TPP)
• Coenzyme for succinate
dehydrogenase
Riboflavin
(FAD)
• electron acceptor for isocitrate
dehydrogenase, alpha ketoglutarate
dehydrogenase, malate
dehydrogenase
Niacin (NAD+)
• Acetyl CoA and Succinyl CoA
Pantothenic
acid

19. Regulation of Citric Acid cycle
• Inhibited by ATP, NADH, Acetyl
CoA and Succinyl CoA
Citrate synthase
• Activated by ADP, and inhibited by
ATP and NADH
Isocitrate
dehydrogenase
• Inhibited by succinyl CoA and
NADH
Alpha-ketoglutarate
dehydrogenase
Availability of ADP

20. Integration of Major Metabolic
Pathway
1. carbohydrates: are metabolized through
glycolytic pathway to pyruvate, then converted
to acetyl CoA which enters TCA.
2. Fatty acids: through beta oxidation, are broken
down to acetyl CoA and then enters this cycle.
3. Glucogenic amino acids after transamination
enter at some or other points in this cycle.
• Ketogenic amino acids are converted into acetyl
CoA.

21. Fat is burned on the wick of
carbohydrates
• The oil in a lamp by itself cannot be lighted;
the flame needs a wick
• Oxidation of fat need the help of oxaloacetate.
• Major source of oxaloacetate is pyruvate
(Carb)

22. Excess Carb are converted to Neutral
fat
• Excess calories are deposited as fat in adipose tissue.
• The pathway is glucose to pyruvate to acetyl CoA to
fatty acid.
• fat cannot be converted to glucose because pyruvate
dehydrogenase reaction (pyruvate to acetyl CoA) is an
absolutely irreversible step.
• No Net synthesis of Carbohydrate from Fat

23. Amphibolic nature of TCA cycle
• TCA cycle is both catabolic and analbolic.
• TCA is termed as Metabolic Traffic Circle

24. Important anabolic reactions
• Oxaloacetate is the precursor of aspartate
• Alpha ketogutarate can be made into
glutamate
• Succinyl CoA is used for synthesis of heme
• Mitochondrial citrate is transported to
cytoplasm, where it is cleaved into acetyl
CoA, which then is the starting point of
fatty acid synthesis.

25. Efflux of TCA cycle intermediates

26. Influx of TCA cycle intermediates

27. Anaplerotic Role of TCA cycle
• Greek word : Fill up
• The synthetic reactions depletes the
intermediates of TCA cycle.
• Cycle will ease to operate unless the
intermediates are replenished.

28. • The reactions concerned to replenish or to fill
up the intermediated of citric acid cycle are
called anaplerotic reactions or anaplerosis.

31. Inhibitors of TCA cycle
• Inhibited by Fluoro-acetate
Aconitase
• Inhibited by Arsenite
Alpha
ketoglutarate
dehydrogenase
• Inhibited by Malonate
Succinate
dehydrogenase

32. Metabolic Defects Related to Krebs
Cycle
• Though rare.
• Some of the defects are found to affect the
operation of TCA cycle

33. • Pyruvate to acetyl CoA
• Lactic acidosis, Neurological disorders
Pyruvate
dehdrogenase
• Fatty acyl CoA to Alpha, beta unsaturated
fatty acyl CoA
• Organic aciduria, glutaric aciduria,
acidosis, hypoglycemia
Acyl CoA
dehydrogenase
• Pyruvate to oxaloacetate
• Oxaloacetate needed for sparking TCA
cycle is deficient. Lactic acidosis,
hyperammonemia and hyperalaninemia
Pyruvate
carboxylase

34. Dr Anurag Yadav
MBBS, MD
Assistant Professor
Department of Biochemistry
Instagram page –biochem365
YouTube – Dr Biochem365
Email: dranurag.y.m@gmail.com