![Page 1: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/1.jpg)
Tricarboxylic Acid Cycle (TCA), Krebs Cycle
Occurs totally in mitochondria Pyruvate (actually acetate) from
glycolysis is degraded to CO2 Some ATP is produced More NADH is made NADH goes on to make more ATP in
electron transport and oxidative phosphorylation
Traffic circle, comp. entering & leaving
![Page 2: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/2.jpg)
Tricarboxylic Acid Cycle (TCA),
![Page 3: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/3.jpg)
Oxidative Decarboxylation of Pyruvate
Pyr. from aerobic glycolysis is transported to cross inner mitochondrial membrane by specific transporter. In the matrix, pyr. is irreversibly decarboxylated by a multienzyme complex Five coenzyme’re needed See figure
![Page 4: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/4.jpg)
Oxidative Decarboxylation of Pyruvate
Pyr is converted to acetyl CoA by pyr dehydrogenase (pyr DH) complex , which is a multienzyme complex.
pyr dehydrogenase complex is not part of TCA cycle proper, but is a mojor source of acetyl CoA.
The irreversibility of the reaction explains why glucose can not be formed from acetyl CoA in gluconeogenesis.
![Page 5: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/5.jpg)
Oxidative Decarboxylation of Pyruvate
pyr dehydrogenase complex is composed of three enzymes – pyr decarboxylase (E1) - dihydrolipoyl transacylase (E2) - dihydrolipoyl dehydrogenase (E3)
Each catalyzed a part of the overall reaction In addition to two regulatory enzymes
protein kinase and phosphoprotein phosphatase.
![Page 6: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/6.jpg)
Oxidative Decarboxylation of Pyruvate
Coenzymes: Pyr DH complex contains 5 coenzyme which act as a carriers or oxidant for intermediates.
(1) Thiamine pyrophosphate(2)Lipoic acid(3) CoA(4) FAD(5) NAD
![Page 7: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/7.jpg)
Mechanism of Pyr. decarboxylase
![Page 8: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/8.jpg)
Regulation of Pyr. Dehydrogenase
Complex Allosteric activation of kinase & Phosphatase:- Cyclic AMP-independent protein kinase
( activated)activates phosphorylated E1 ( inactive ) & inhibits dephosphorylated ( active ) inhibit Pyr DH.
- protein kinase allosterically activated by ATP, acetyl CoA, NADH ( high energy signals) inhibit Pyr DH (turned off).
- protein kinase allosterically inactivated by NAD+ CoA, ( low energy signals) activate Pyr DH (turned ).
- Pyr is a potent inhibitor of kinase, if pyr concentration is elevated so E1 is active
- Ca+ is strong activator of Phosphatase, stimulating E1 activity ( skeletat muscle contraction)
![Page 9: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/9.jpg)
Regulation of Pyr. Dehydrogenase Complex
![Page 10: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/10.jpg)
![Page 11: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/11.jpg)
![Page 12: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/12.jpg)
Reactions of TCA Synthesis of citrate from acetyl CoA and
oxaloacetate (OAA): Irreversible, catalyzed by citrate
synthase. Aldol condensation reaction. citrate synthase is inhibited by ATP,
NADH, succinyl CoA & fatty acyle CoA. Function of citrate: It provides a source
of acetyl CoA for fatty acid synthesis & it inhibits PFK1
![Page 13: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/13.jpg)
Reactions of TCA (3) Isomerisation of citrate: to isocitrate by
aconitase ( reversible reaction), It is inhibited by fluroacetate, a compound used for rat poisoning(fluroacetate is converted to flurocitrate which is a potent inhibitor for aconitase)
(4) Oxidative Decarboxylation of isocitrate: irreversible oxidative phosphorylation, by isocitrate DH to give -Ketoglutarate, NADH & CO2
-It is rate limiting step-isocitrate DH is activated by ADP and Ca +2 &
inhibited by ATP, NADH
![Page 14: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/14.jpg)
Reactions of TCA (5) Oxidative Decarboxylation of -
Ketoglutarate: by -Ketoglutarate DH to give succinyle CoA (similar to pyr DH),
Release of 2nd NADH & CO2
-Ketoglutarate DH need coenzymes TPP,NAD,FAD,CoA& lipoic acid.
-Ketoglutarate DH is inhibited by ATP,NADH, GTP& succinyle CoA. And activated by Ca +2 .
However it is not regulated by the phosphorylation and de phosphorylation reaction that describe in Pyr DH
![Page 15: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/15.jpg)
Reactions of TCA (5) Cleavage of succinyle CoA: Cleavage of
(high-energy thioester dound) succinyle CoA to succinate by succinate thiokinase.
It is coupled by release of GTPwhich inter-converted by nucleoside diphosphate kinase reaction
Substrate –level phosphorylation. succinyle CoA can be produced from
Proponyle CoA ( metabolism of fatty acids)
![Page 16: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/16.jpg)
Reactions of TCA
(6) Oxidation of succinate: to fumarate by succinate DH, producing FADH2
(7) Hydration of fumarate: to malate by fumarase
(8)Oxidation of malate: By malate DH
To OAA & 3nd NADH.
![Page 17: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/17.jpg)
Regulation of TCA Cycle
![Page 18: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/18.jpg)
Intermediates for Biosynthesis -Ketoglutarate is transaminated to
make glutamate, which can be used to make purine nucleotides, Arg and Pro
Succinyl-CoA can be used to make porphyrins
Fumarate and oxaloacetate can be used to make several amino acids and also pyrimidine nucleotides
mitochondrial citrate can be exported to be a cytoplasmic source of acetyl-CoA (F.A in fed state) and oxaloacetate glucose in fast state
![Page 19: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/19.jpg)
Biosynthetic & Anaplerotic reactions
![Page 20: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/20.jpg)
![Page 21: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/21.jpg)
Anaplerotic Reactions (filling up reactions)
PEP carboxylase - converts PEP to oxaloacetate
Pyruvate carboxylase - converts pyruvate to oxaloacetate
Malic enzyme converts pyruvate to malate
See fig. Reactions from1-5 is anaplerotic i.e. filling up reactions
![Page 22: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/22.jpg)
Membrane Transport System The inner mitochondrial membrane is
impermeable to the most charged and hydrophilic substances. However it contains numerous transport proteins that permit the passage of specific molecules.
1- ATP-ADP transport, see oxid-phospho, Transporter for ADP & Pi from cytosol into
mitochondria by specialized carriers ( adenine nucleotide carrier) which transport ADP from cytosol into mitochondria, while exporting ATP from matrix back into the cytosol .
![Page 23: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/23.jpg)
Membrane Transport System Transport of reducing equivalents from cytosol
into mitochondria using: The inner mitochondrial membrane lacks an NADH transport proteins, NADH produced in cytosol cannot directly penetrate into mitochondria. However two electron of NADH ( called reducing equivalents) are transported by using shuttle.
1. glycerophosphate shuttle ( results in synthesis of 2 ATP for each cytosolic NADH oxidized )
2. malate-aspartate shuttle ( results in synthesis of 3 ATP in the mitochondrial matrix for each cytosolic NADH oxidized )
![Page 24: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/24.jpg)
Membrane Transport System
![Page 25: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/25.jpg)
![Page 26: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/26.jpg)
Pyruvate DH deficiency. Pyruvate DH deficiency is the most
common biochemical cause of congenital lactic acidosis.
Pyruvate cannot to acetyl CoA but to lactate
The most sever form cause neonatal death.
The moderate form cause psychomotor retardation with damage in cerebral cortx, basal ganglia and brain stem and death.
The third form cause episodic ataxia.
![Page 27: Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is](https://reader036.vdocument.in/reader036/viewer/2022062518/56649e905503460f94b94ba7/html5/thumbnails/27.jpg)
Energy produced from TCA