Citric Acid Cycle

Characteristics

1-This cycle located in the mitochondria and occure in all body

cells, except for red blood cell RBC .
2- Also called tricarboxylic acid cycle, krebs cycle .
3-The final common oxidative pathway that oxidizes acetyl
CoA to CO2.
4-The link between catabolic and anabolic pathways
(amphibolic role).
5-acetyl Coenzyme A (acetyl CoA) condenses with OAA to
begin the cycle.
6-All the enzymes of citric acid cycle are located inside the
mitochondria.

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Reactions of the Cycle Preparatory Steps
Pyruvate derived from glycolysis can enter the mitochondria
from the cytoplasm and converted to acetyl CoA by the
pyruvate dehydrogenase (The pyruvate dehydrogenase reaction occurs
in the mitochondria )
This is the link between the TCA cycle and glycolysis.

 All the reactions of krebs cycle are summarized in the

next figure

Oxaloacetate as a Junction Point

Oxaloacetate may be viewed as a catalyst, which enters into
the reaction, causes complete oxidation of acetyl CoA and
comes out of it without any change.

ATP Generating Steps in TCA Cycle

There are 3 NADH molecules generated during one cycle, each
of them will give rise to 2 ½ ATPs on oxidation by electron
transport chain (ETC); so altogether they will give 3 × 2 ½ = 7
½ (7.5) high energy phosphates. The FADH2 will generate 1½
molecules of ATP. In addition,
one molecule of GTP (equivalent to one molecule of ATP) is
formed by substrate level phosphorylation. Hence, per turn of
the cycle, 10 high energy phosphates are produced.

Note: Recent work shows that in the electron transport chain,

NADH produces only 2.5 ATPs and FADH only 1.5 ATPs.

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 s

Notes

Excess Carbohydrates are Converted as Neutral Fat

Excess calories are deposited as fat in adipose tissue. The
pathway is glucose to pyruvate to acetyl CoA to fatty acid.
However, fat cannot be converted to glucose because
pyruvate dehydrogenase reaction (pyruvate to acetyl CoA) is
an absolutely irreversible step

GLYCOGEN METABOLISM
Functions of Glycogen
1. Glycogen is the storage form of carbohydrates in the human
body. The major sites of storage are liver and muscle. The major
function of liver glycogen is to provide glucose during fasting. The
glycogen content of liver (10 g/100 g tissue) is more than in the
skeletal muscle (1–2 g/100 g). But the total quantity of muscle
glycogen is more than liver glycogen because of the larger muscle
mass.

2. All the enzymes related to glycogen metabolism are

cytoplasmic.

3. The function of muscle glycogen is to act as reserve fuel for

muscle contraction.

4. When blood glucose level lowers, liver glycogen is broken down

and helps to maintain blood glucose level. After taking food,
blood sugar tends to rise, which causes glycogen deposition in
liver. About 5 hours after taking food, the blood sugar tends to
fall. But, glycogen is lyzed to glucose so that the energy needs are

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met. After about 18 hours fasting, most of the liver glycogen is
depleted, when depot fats are hydrolyzed and energy
requirement is met by fatty acid oxidation.
DEGRADATION OF GLYCOGEN
(GLYCOGENOLYSIS)

Glycogen Phosphorylase

i. Glycogen phosphorylase removes glucose as glucose- 1-

phosphate from glycogen (phosphorolysis) ,It contains pyridoxal
phosphate (PLP) as a prosthetic group. The alpha-1, 4 linkages in
the glycogen are cleaved.

ii. It removes glucose units one at a time. Enzyme sequentially

hydrolyzes alpha-1, 4 glycosidic linkages, till it reaches a glucose
residue, 3–4 glucose units away from a branch point. It cannot
attack the 1, 6 linkage at branch point.

iii. If glycogen phosphorylase alone acts on a glycogen molecule,

the final product is a highly branched molecule; it is called limit
dextrin.

Debranching by Bifunctional (Two) Enzymes

i. A block of 3 glucose residues (trisaccharide unit) are transferred

from the branching point to another branch. This enzyme is →
alpha-1, 4 glucan transferase.

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ii. Now the branch point is free. Then alpha-1, 6- glucosidase
(debranching enzyme) can hydrolyze the remaining glucose unit
held in alpha-1, 6 linkage at the branch point.

iii. This glucose residue is released as free glucose. At this stage,

the ratio of glucose-1-phosphate to free glucose is about 8:1.

iv. The transferase and alpha-1, 6-glucosidase will together

convert the branch point to a linear one. With the removal of the
branch point, phosphorylase enzyme can proceed with its action.

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Phosphoglucomutase

Phosphorylase reaction produces glucose-1-phosphate while

debranching enzyme releases glucose. The glucose- 1-phosphate
is converted to glucose-6-phosphate by phosphoglucomutase.

Glucose-6-phosphatase in Liver
Next, hepatic glucose-6-phosphatase hydrolyzes glucose- 6-
phosphate to glucose. The free glucose is released to the
bloodstream.

Muscle Lacks Glucose-6-phosphatase

Muscle will not release glucose to the bloodstream, because
muscle tissue does not contain the glucose-6-phosphatase.
Instead, in muscle, glucose-6-phosphate undergoes glycolysis to
produce ATP for muscle contraction.

Energetics
i. The energy yield from one glucose residue derived from
glycogen is 3 ATP molecules, because no ATP is required for initial
phosphorylation of glucose (step 1 of glycolysis).
ii. If glycolysis starts from free glucose only 2 ATPs are produced.

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GLYCOGEN SYNTHESIS (GLYCOGENESIS)
The glycogen synthesis occurs by a pathway distinctly different
from the reversal of glycogen breakdown, The steps are:

Activation of Glucose
Glycogen Synthase
In the next step, activated glucose units are sequentially added
by the enzyme glycogen synthase. The glucose unit is added to
form an alpha-1, 4 glycosidic linkage and UDP is liberated.

Branching Enzyme
i.The glycogen synthase can add glucose units only in alpha-1, 4
linkage. A branching enzyme is needed to create the alpha-1, 6
linkages.
ii. When the chain is lengthened to 11–12 glucose residues, the
branching enzyme will transfer a block of 6 to 8 glucose residues
from this chain to another site on the growing molecule. The
enzyme amylo-[1, 4]→[1, 6]-transglucosidase (branching
enzyme) forms this alpha-1, 6 linkage.
iii. To this newly created branch, further glucose units can be
added in alpha-1, 4 linkage by glycogen synthase.

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Regulation of Glycogen Metabolism
i. The key enzyme for glycogenolysis is phosphorylase,
which is activated by glucagon and epinephrine, under the
stimulus of hypoglycemia.
ii. The key enzyme for glycogen synthesis is glycogen
synthase, the activity of which is decreased by glucagon and
epinephrine but is enhanced by insulin, under the stimulus of
hyperglycemia
* Insulin and glucagon are the major regulatory hormones,
although epinephrine has stimulatory effect on glycogenolysis
in both liver and muscle.

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