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Krebs Cycle: PR DR Allan Lugaajju Makerere University College of Health Sciences

The Krebs cycle, also known as the citric acid cycle or TCA cycle, is the final pathway where the breakdown of carbohydrates, fats, and proteins converge to generate energy through the oxidation of acetyl CoA derived from these macromolecules. The cycle occurs in the mitochondria and uses oxygen as the final electron acceptor. It is tightly regulated by the levels of ATP, acetyl CoA, and NADH to prevent excessive breakdown of fuels when energy levels are already high. One turn of the cycle generates 11 ATP directly from oxidation and one more from the electron transport chain, for a total of 12 ATP per acetyl CoA molecule that enters the cycle.

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Mwanja Moses
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78 views20 pages

Krebs Cycle: PR DR Allan Lugaajju Makerere University College of Health Sciences

The Krebs cycle, also known as the citric acid cycle or TCA cycle, is the final pathway where the breakdown of carbohydrates, fats, and proteins converge to generate energy through the oxidation of acetyl CoA derived from these macromolecules. The cycle occurs in the mitochondria and uses oxygen as the final electron acceptor. It is tightly regulated by the levels of ATP, acetyl CoA, and NADH to prevent excessive breakdown of fuels when energy levels are already high. One turn of the cycle generates 11 ATP directly from oxidation and one more from the electron transport chain, for a total of 12 ATP per acetyl CoA molecule that enters the cycle.

Uploaded by

Mwanja Moses
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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1

KREBS CYCLE
PR DR ALLAN LUGAAJJU
MAKERERE UNIVERSITY
COLLEGE OF HEALTH SCIENCES
SCHOOL OF BIOMEDICAL SCIENCES
32

TRI CARBOXYLIC CYCLE (TCA)


33

TCA
• also called the Krebs cycle or the citric acid cycle
• It is the final pathway where the oxidative
metabolism of carbohydrates, amino acids, and
fatty acids converge, their carbon skeletons
being converted to CO2
• The cycle occurs totally in the mitochondria and
is, therefore, in close proximity to the reactions
of electron transport
• The TCA cycle is an aerobic pathway, because O2
is required as the final electron acceptor
34

• Reactions such as the catabolism of some A.A


generate intermediates of the cycle and are
called anaplerotic reactions
• TCA also participates in a number of important
synthetic reactions. E.g, the cycle functions in
the formation of Glc from the carbon skeletons
of some amino acids
• and it provides building blocks for the synthesis
of some amino acids and heme
35

Oxidative decarboxylation of pyruvate


• Pyruvate, the endproduct of aerobic glycolysis,
must be transported into the mitochondrion
before it can enter the TCA cycle.
• This is accomplished by a specific pyruvate
transporter that helps pyruvate cross the inner
mitochondrial membrane
• Once in the matrix, pyruvate is converted to
acetyl CoA by the pyruvate dehydrogenase
complex, which is a multienzyme complex
36

Component enzymes
• The PDH complex is a multimolecular aggregate
of three enzymes;
• Pyruvate dehydrogenase (E1, also called a
decarboxylase),
• Dihydrolipoyl transacetylase (E2), and
• Dihydrolipoyl dehydrogenase (E3).
37

• the complex also contains 2 tightly bound


regulatory enzymes,PDH kinase & PDH
phosphatase.
• The PDH complex contains five coenzymes;
• E1 requires thiamine pyrophosphate,
• E2 requires lipoic acid and CoA, and
• E3 requires FAD and NAD+.
38

Regulation of the PDH complex

• The two regulatory enzymes that are part of the


complex alternately activate and inactivate E1.

• The cyclic AMP-independent PDH kinase


phosphorylates and, thereby, inhibits E1
whereas PDH phosphatase activates E1
39

Py+ CoA-SH+NAD+-------CO2+Acetyl COA+NADH+H+


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• The kinase is allosterically activated by ATP,


acetyl CoA, and NADH.

• Therefore, in the presence of these high-energy


signals, the pyruvate dehydrogenase complex is
turned off.
41

Pyruvate dehydrogenase deficiency


• A deficiency in the E1 component of the pyruvate
dehydrogenase complex is the most common
biochemical cause of CLA

• This enzyme deficiency results in an inability to


convert pyruvate to acetyl CoA, causing pyruvate
to be shunted to lactic acid via lactate
dehydrogenase
42

• This causes particular problems for the brain,


which relies on the TCA cycle for most of its
energy, and is particularly sensitive to acidosis.

• The defect is classified as X-linked dominant.

• There is no proven treatment for pyruvate


dehydrogenase complex deficiency
43

• Leigh syndrome
• - mutations in PDH complex, electron transport
chain, ATP synthase.
• Nuclear and mt DNA can be affected
• Arsenite, mercury and deficiency of thiamin inhibit
the enzyme leading to lactic acidosis
44

TCA cycle
45
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• ATP produced from one turn of the citric acid


cycle starting with NAD+ ETC
• Steps 4 = NAD+ = 3 ATP
Steps 6 = NAD+ = 3 ATP
Steps 10 = NAD+ = 3 ATP
NET ATP from = NAD+ = 9 ATP
Step 8 is another
oxidation involving the coenzyme FAD =2 ATP
• Net ATP = 11+1= 12
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48
49

Regulation of the TCA cycle


• At the PDH reaction

• Product inhibition; e.g


• citrate inhibits citrate synthase,
• α-ketoglutarate dehydrogenase is inhibited by
NADH and acetyl CoA.

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