Carbohydrate metabolism and the TCA cycle

The Pentose Phosphate Pathway (PPP):

• An alternative pathway (from glycolysis) of glucose oxidation generating NADPH and

ribose 5-phosphate (ribose 5-P).

• Enzymes reside in the cytosol similar to glycolysis.

 Carbohydrate metabolism and the TCA cycle

Fig 1. General scheme of the pentose phosphate pathway. From Lehninger Principles of Biochemistry 4th Ed.,
Nelson & Cox, W. H. Freeman and Company, 2004, Fig Fig 14-20
 Carbohydrate metabolism and the TCA cycle

Oxidative Phase
• NADPH Production:
• Glucose 6-P oxidized to ribulose 5-P, generating 2 NADPH per glucose 6-P.
• NADPH crucial for reductive detoxification and biosynthesis.

Ribose 5-Phosphate Generation:

• Ribulose 5-P isomerized to ribose 5-P for nucleotide synthesis or glycolytic
intermediates.
 Carbohydrate metabolism and the TCA cycle

Nonoxidative Phase
• Reversible Reactions:
• Interconversion of glycolytic intermediates (glyceraldehyde 3-P, fructose 6-P) and
five-carbon sugars.

• Ribose 5-P converted back to glucose 6-P if NADPH still needed.

 Carbohydrate metabolism and the TCA cycle

Conversion of Ribose 5-Phosphate to Glycolytic Intermediates

Series of rearrangement and transfer

reactions involving epimerase, isomerase,
Transketolase, and transaldolase.

Result: Formation of fructose 6-P and

glyceraldehyde 3-P for glycolysis.

Fig 2. Nonoxidative reactions of the pentose phosphate pathway. From Lehninger Principles of
Biochemistry 4th Ed., Nelson & Cox, W. H. Freeman and Company, 2004, Fig Fig 14-22
 Carbohydrate metabolism and the TCA cycle

Role of the PPP in NADPH Generation

• Major source of NADPH for biosynthetic reactions and defense against reactive oxygen species
(ROS).

• Crucial for fatty acid and cholesterol synthesis, cytochrome P450 hydroxylation, and phagocytic
cell function.

• Regulation: NADPH inhibits glucose-6-phosphate dehydrogenase

 Carbohydrate metabolism and the TCA cycle
Physiological Importance
Maintains membrane integrity in red blood cells and supports anabolic pathways.

Fig 3. Hemolysis caused by reactive oxygen species (ROS). From Marks’ basic medical biochemistry : a
clinical approach 4th Ed., Lieberman, Marks & Peet, Lippincott Williams & Wilkins, 2013, Fig 29.11
 Carbohydrate metabolism and the TCA cycle

Diseases related to the PPP

Disease or
Disorder
Glucose-6-phosphate (X-linked) Lack of glucose-6-phosphate dehydrogenase activity leads to
dehydrogenase hemolytic anemia in the presence of strong oxidizing agents.
deficiency
 Carbohydrate metabolism and the TCA cycle

Metabolism of Glycogen:

• Glycogen

Branched glucose polysaccharide that is composed of glucosyl units.

Glucosyl units are linked by α-1,4-glycosidic bonds and α-1,6-branches after every 8 to 12
residues.

Anomeric carbon at the beginning of the chain is attached to glycogenin. The other ends
are known as nonreducing ends.
 Carbohydrate metabolism and the TCA cycle

In the Skeletal Muscles

Glycogen is a reservoir for ATP generation from glycolysis. It is degraded (glycogenolyis) to
glucose 1-P, then to glucose 6-P to enter the glycolytic pathway.
Important during High ATP demand and anaerobic glycolysis.

In the Liver
A source of glucose for blood glucose maintenance. Glucose 6-P from glycogen
degradation converted to glucose.
Supplies glucose during decreased dietary intake or increased muscular demand.
Carbohydrate metabolism and the TCA cycle

Fig 1. Glycogenolysis in skeletal muscle and liver. From Marks’ basic medical biochemistry : a clinical approach
4th Ed., Lieberman, Marks & Peet, Lippincott Williams & Wilkins, 2013, Fig 28.2
 Carbohydrate metabolism and the TCA cycle
Glycogen synthesis
• Glucose phosphorylation to G6P.
• G6P converted to glucose 1-phosphate by
phosphoglucomutase.
• Formation of α-1,4-glycosidic bonds and
α-1,6-branches.
• Occurs through chain elongation of
preexisting glycogen molecule.
 Carbohydrate metabolism and the TCA cycle

Fig 2. Branch synthesis in glycogen. Modified From Lehninger Principles of Biochemistry 4th Ed., Nelson &
Cox, W. H. Freeman and Company, 2004, Fig Fig 15-9
 Carbohydrate metabolism and the TCA cycle
Glycogen degradation
• Glucose residues are removed by
glycogen phosphorylase and debrancher
enzyme.
• Glucose 1-P is released and converted to
glucose 6-P by phosphoglucomutase.
• Glucose 6 phosphatase remove inorganic
phosphate releasing free glucose.
 Carbohydrate metabolism and the TCA cycle

Fig 3. Glycogen breakdown. Modified From Lehninger

Principles of Biochemistry 4th Ed., Nelson & Cox, W. H.
Freeman and Company, 2004, Fig Fig 15-4
 Carbohydrate metabolism and the TCA cycle

Regulation of glycogen metabolism

Liver glycogen:
Primarily responds to systemic glucose needs, regulated by insulin/glucagon ratio.
Degradation activated by epinephrine during exercise, hypoglycemia, or stress.

Skeletal muscle glycogen:

Responsive to local energy demands during muscle contraction, regulated by AMP and Ca2+ levels.
Activation of glycogenolysis by epinephrine during exercise or stress.
 Carbohydrate metabolism and the TCA cycle

Conditions related to glycogen metabolism

Disease or
Disorder
Insulin overdose In the absence of carbohydrate intake, administration of insulin can
result in severe hypoglycemia.
Glycogen storage These include von Gierke’s disease, Pompe’s disease, Cori’s /Forbes’s,
diseases from genetic Andersen’s and McArdle’s diseases. They affect glycogen storage and
defect usage with varying consequences