1. Tricarboxylic Acid Cycle
Siti Annisa Devi Trusda
Biochemistry Department

3. Overview
final pathway where oxidative metabolism of CH, AA, FAcarbon skeleton : CO2 & H2O
provides energy (ATP)
occurs in mitochondriain close proximity to reactions of electron transport
AerobicO2 required as the final electron acceptor
Participates in synthetic rx/: formation of glucose from carbon skeleton of some AA
Intermediates of the TCA cycle can also be synthesized by the catabolism of some amino acids
a traffic circle with compounds entering and leaving as required

6. REACTION OF THE TCA CYCLE
Pyruvate, the product of glycolysis, is converted to acetyl-CoA, the starting material for the citric acid cycle, by the pyruvate dehydrogenase complex.
The PDH complex is composed of multiple copies of three enzymes:
pyruvate dehydrogenase, E1 (with its bound cofactor TPP);
dihydrolipoyl transacetylase, E2 (with its covalently bound lipoyl group)
dihydrolipoyl dehydrogenase, E3 (with its cofactors FAD and NAD).

7. E1 catalyzes the decarboxylation of pyruvate hydroxyethyl -TPP, then the oxidation of the hydroxyethyl group acetyl group.
E2 catalyzes the transfer of the acetyl group to coenzyme A, forming acetyl-CoA.
E3 catalyzes the regeneration of the disulfide(oxidized) form of lipoate; electrons pass first to FAD, then to NAD.

11. The Pyruvate Dehydrogenase Complex Requires Five Coenzymes
The combined dehydrogenation and decarboxylation of pyruvate to the acetyl group of acetyl-CoA requires the sequential action of
3 different enzymes
5 different coenzymes or prosthetic groups
thiamine pyrophosphate (TPP),
flavin adenine dinucleotide (FAD),
coenzyme A (CoA, sometimes denoted CoA-SH, to emphasize the role of the OSH group),
nicotinamide adenine dinucleotide (NAD)
lipoate.
4 different vitamins required in human nutrition are vital components of this system: thiamine (inTPP), riboflavin (in FAD), niacin (in NAD), and pantothenate (in CoA).

12. Pyruvate Dehydrogenase Deficiency
congenital lactic acidosis
inability to convert pyruvate to acetyl CoA
Pyruvate to be shunted to lactic acid via lactate dehydrogenase
Severe : Neonatal death
Moderate: psychomotor retardation w/ damage of cerebral cortex, basal ganglia, brainstemdeath in infancy
Third form: episodic ataxia induced by Ch rich meal
No treatment available ketogenic diet

13. Mechanism of Arsenic Poisoning
Arsenic inhibits enzymes that require lipoic acid as cofactor : pyruvate dehydrogenase, α-ketoglutarate dehydrogenase.
Arsenite forms a stable complex with the thiol (-SH) group of lipoic acidunavailable to serve as coenzyme
If it binds to lipoic acid in the pyruvate dehydrogenase complex, pyruvate (and lactate) accumulate ≈ pyruvate dehydrogenase complex deficiency neurologic distrubance - death

14. The Citric Acid Cycle Has 8 Steps 1. Formation of Citrate

15. 2. Formation of Isocitrate via cis-Aconitate

16. 3. Oxidation of isocitrate to α-ketoglutarate +CO2

17. 4. Oxidation of α-ketoglutarate to succinyl coA+ CO2

18. 5. Conversion of succinyl coA to succinate

19. 6. Oxidation of succinate to fumarate

20. 7. Hydration of fumarate to malate

21. 8.Oxidation of malate to oxaloacetate

23. Products of one turn of the citric acid cycle.
At each turn of the cycle(each molecule of acetyl coA), 3 NADH (9 ATP), 1 FADH2(2 ATP), 1GTP (1 ATP), and two CO2 are released in oxidative decarboxylation reactions 12 ATP

25. Citric Acid Cycle Components Are Important Biosynthetic Intermediates
The citric acid cycle is an amphibolic pathwayboth catabolic and anabolic processes.
Besides its role in the oxidative catabolism of carbohydrates, fatty acids, and amino acids, the cycle provides precursors for many biosynthetic pathways through reactions that served the same purpose in anaerobic ancestors.
α–Ketoglutarate and oxaloacetate can serve as precursors of the amino acids aspartate and glutamate by simple transamination

26. Oxaloacetate is converted to glucose in gluconeogenesis
Through aspartate and glutamate, the carbons of oxaloacetate and α–ketoglutarate are then used to build other amino acids, as well as purine and pyrimidine nucleotides.
Oxaloacetate is converted to glucose in gluconeogenesis
Succinyl-CoA is a central intermediate in the synthesis of the porphyrin ring of heme groups, which serve as
oxygen carriers (in hemoglobin and myoglobin)
electron carriers (in cytochromes)
Citrate produced in some organisms is used commercially for a variety of purposes

27. Regulation of the Citric Acid Cycle
The overall rate of the citric acid cycle is controlled by
rate of conversion of pyruvate acetyl-CoA
flux through citrate synthase, isocitrate dehydrogenase, & -ketoglutarate dehydrogenase.
These fluxes are largely determined by the concentrations of substrates and products:
the end products ATP and NADH are inhibitory
the substrates NAD and ADP are stimulatory.

28. The production of acetyl-CoA for the citric acid cycle by the PDH complex is :
inhibited allosterically by metabolites that signal a sufficiency of metabolic energy (ATP, acetyl-CoA, NADH, and fatty acids)
stimulated by metabolites that indicate a reduced energy supply (AMP, NAD, CoA).

29. Have a Nice ‘Cycling’ Time
HATURNUHUN….
Have a Nice
‘Cycling’ Time

30. LIKE ALWAYS, A SIMPLE QUIZ ;p
Reaksi pertama yang terjadi untuk masuk ke dalam siklus Krebs adalah perubahan…….. menjadi……..
Produk dari satu putaran siklus Krebs adalah….., ………, dan……….. dengan jumlah energi yang dihasilkan sebanyak……..
Defisiensi enzim piruvat dehidrogenase mengakibatkan penyakit……..
Berikan satu contoh komponen dalam siklus Krebs yang menjadi zat antara biosintesis zat lain!