Carbohydrate Metabolism

A. Glycolysis : Glycolysis is a metabolic pathway that breaks down glucose into

two molecules of pyruvate, generating energy in the form of ATP and NADH. It
occurs in the cytoplasm and does not require oxygen, making it an anaerobic
process.
• Reactions of Glycolysis :

• Fates of Pyruvates :
➢ Aerobic respiration

When oxygen is available, pyruvate is transported to the mitochondria and converted to

acetyl-CoA. This process produces ATP.
 ➢ Anaerobic glycolysis

When oxygen is not available, pyruvate is converted to lactate. This process regenerates
NAD+.

➢ Conversion to alanine

Pyruvate is converted to alanine during periods of amino acid biosynthesis and

translation.

➢ Fermentation

Pyruvate is converted to alcohol and carbon dioxide during fermentation. This process
occurs in bacteria and yeast.

• Feeder Pathway of Glycolysis : The feeder pathways of glycolysis refer to

various metabolic routes through which different carbohydrates and
biomolecules enter the glycolytic pathway. These pathways allow the
body to utilize a variety of sugars besides glucose, ensuring efficient
energy production.
➢ Glycogen and Starch Breakdown

Glycogenolysis: Glycogen (stored in the liver and muscles) is broken down into
glucose-1-phosphate by glycogen phosphorylase, which is then converted to glucose-6-
phosphate by phosphoglucomutase, feeding into glycolysis.

Starch Degradation: Ingested starch is broken down by amylase and other enzymes to
produce glucose, which enters glycolysis.

➢ Fructose Metabolism :

In the Liver: Fructose is converted to fructose-1-phosphate by fructokinase, then

cleaved into glyceraldehyde and dihydroxyacetone phosphate (DHAP), both of which
enter glycolysis.

In Muscle and Adipose Tissue: Fructose is directly phosphorylated to fructose-6-

phosphate by hexokinase, entering glycolysis.
 ➢ Mannose Metabolism :

Mannose is phosphorylated by hexokinase to form mannose-6-phosphate, which is

then converted to fructose-6-phosphate by phosphomannose isomerase, entering
glycolysis.

➢ Glycerol Metabolism :

Glycerol, derived from triglycerides, is phosphorylated by glycerol kinase to form

glycerol-3-phosphate, which is then oxidized to DHAP (dihydroxyacetone phosphate),
feeding into glycolysis.

• Energetics of Glycolysis :

➢ Energy Investment Phase (Preparatory Phase)

In this phase, ATP is consumed to phosphorylate glucose and prepare it for subsequent
breakdown.

1. Glucose → Glucose-6-phosphate (catalyzed by hexokinase/glucokinase)

ATP used: 1
2. Fructose-6-phosphate → Fructose-1,6-bisphosphate (catalyzed by
phosphofructokinase-1 (PFK-1))
ATP used: 1
➢ Total ATP consumed: 2 ATP

➢ Energy Payoff Phase (Payoff Phase)

In this phase, ATP and NADH are produced by substrate-level phosphorylation and
redox reactions.
 1. Glyceraldehyde-3-phosphate → 1,3-bisphosphoglycerate

NAD⁺ is reduced to NADH

NADH produced : 2 (1 per molecule, 2 per glucose)

2. 1,3-bisphosphoglycerate → 3-phosphoglycerate (catalyzed by phosphoglycerate

kinase)
2 ATP produced

3. Phosphoenolpyruvate → Pyruvate (catalyzed by pyruvate kinase)

2 ATP produced

Total ATP produced: 4 ATP

Total NADH produced: 2 NADH

➢ Glycolysis Energetics :
1. ATP Used: 2
2. ATP Produced: 4
3. Net ATP Yield: 2
4. NADH Produced: 2 (yields ~5-6 ATP in aerobic respiration)

• Cori Cycle : The Cori cycle is a metabolic pathway that describes the
movement of lactate between the muscles and the liver. It plays a crucial
role in maintaining energy balance during anaerobic (low oxygen)
conditions, such as intense exercise.

• Steps of the Cori Cycle:

➢ Glycolysis in Muscles:

During intense activity, muscles break down

glucose to produce ATP through anaerobic
glycolysis, generating lactate as a by
product.

Lactate accumulates in the muscles,

leading to fatigue.

➢ Lactate Transport to Liver:

Lactate is transported via the bloodstream to the liver.

 ➢ Gluconeogenesis in Liver: In the liver, lactate is converted back into
glucose via gluconeogenesis.This process requires ATP and occurs when
oxygen is readily available.
➢ Glucose Return to Muscles:

The newly synthesized glucose is released back into the bloodstream and transported
to the muscles to provide energy, completing the cycle.

o Significance of the Cori Cycle:

Helps remove lactate from muscles, preventing acidosis.Allows continued energy

production under anaerobic conditions.Supports glucose homeostasis, especially
during prolonged physical activity.However, it is energetically expensive, as the liver
consumes more ATP to regenerate glucose than is produced in glycolysis.

• Galactosemia : Galactosemia is a rare genetic metabolic disorder

characterized by the body’s inability to properly process galactose, a sugar found
in milk and dairy products. This condition results from a deficiency in enzymes
required to metabolize galactose, leading to toxic accumulation in the body.

• Types of Galactosemia and Enzyme Deficiencies:

o Classic Galactosemia (Type I) –

o Most severe form Caused by deficiency of the enzyme galactose-1-
phosphate uridylyltransferase (GALT)
o Leads to accumulation of galactose-1-phosphate, which can
damage the liver, kidneys, brain, and eyes.

o Galactokinase Deficiency (Type II) :

o Caused by deficiency of the enzyme galactokinase (GALK)
o Leads mainly to cataracts, as galactitol accumulates in the lens of the
eye.

o Epimerase Deficiency (Type III)

o Caused by deficiency of the enzyme UDP-galactose-4-epimerase (GALE)
o Can present in mild or severe forms, affecting multiple organs.
 • Symptoms of Galactosemia: Symptoms typically appear soon after birth,
especially after consuming breast milk or formula containing lactose (which
breaks down into glucose and galactose).

❖ Common symptoms include :

• Poor feeding and failure to thrive

• Jaundice (yellowing of skin and eyes)
• Vomiting and diarrhea
• Lethargy and irritability
• Enlarged liver (hepatomegaly)
• Cataracts
• Developmental delays
• Risk of sepsis (especially due to E. Coli infections)

o Diagnosis:
o Newborn screening: Blood tests measure galactose levels and enzyme
activity.
o Genetic testing: Confirms the specific enzyme deficiency.
o Urine tests: Detect reducing substances (galactose)

o Treatment:

The primary treatment for galactosemia is a galactose-free diet, which includes:

o Avoiding milk, dairy products, and any food containing lactose/galactose.

o Using soy-based or lactose-free formulas for infants.

o Long-term management:

Even with dietary restrictions, some complications (e.g., learning disabilities, speech
issues, or hormonal imbalances) may still occur, requiring lifelong monitoring and
support from healthcare professionals.

o Complications if Untreated:

If left untreated, galactosemia can lead to:

o Liver damage or cirrhosis

o Developmental and cognitive impairments
o Kidney failure
o Cataracts
o Death in severe cases

• Regulation of Glycolysis :
Regulation of glycolysis is crucial to ensure efficient energy production and
metabolic balance in response to the cell’s energy demands. Glycolysis is
regulated at multiple levels, primarily by controlling the activity of key enzymes
through allosteric regulation, hormonal signals, and substrate availability.

o Key Regulatory Enzymes of Glycolysis:

Glycolysis is primarily regulated at three irreversible steps, catalyzed by the

following enzymes:

1. Hexokinase/Glucokinase (Step 1: Glucose → Glucose-6-phosphate)

Regulation:

Inhibited by: Glucose-6-phosphate (feedback inhibition in most tissues)

Liver-specific regulation: Glucokinase (liver isoform) is regulated by insulin and

the glucokinase regulatory protein (GKRP), which sequesters glucokinase in the
nucleus when glucose levels are low.

Purpose: Prevents excess glucose phosphorylation when not needed.

2. Phosphofructokinase-1 (PFK-1) (Step 3: Fructose-6-phosphate →

Fructose-1,6-bisphosphate)

Regulation:

o Inhibited by: ATP, citrate (signals sufficient energy and TCA cycle
intermediates)
o Activated by: AMP, ADP (indicates low energy levels), and fructose-2,6-
bisphosphate (produced by PFK-2, under hormonal control)
o Purpose: Acts as the main rate-limiting step of glycolysis.
 3. Pyruvate Kinase (Step 10: Phosphoenolpyruvate → Pyruvate)

Regulation:

o Inhibited by: ATP, acetyl-CoA (signals energy abundance)

o Activated by: Fructose-1,6-bisphosphate (feed-forward activation)
o Hormonal regulation: Glucagon (via phosphorylation by PKA) inhibits
pyruvate kinase in the liver, preventing glycolysis when blood glucose is
low.
o Purpose: Ensures glycolysis proceeds when energy demand is high.

Hormonal Regulation of Glycolysis:

Hormones help regulate glycolysis in response to metabolic needs, primarily

through control of PFK-1 activity via fructose-2,6-bisphosphate levels.

1. Insulin (promotes glycolysis):

o Increases glucose uptake (via GLUT4 in muscle and adipose tissue).

o Activates PFK-2, increasing fructose-2,6-bisphosphate, which activates

PFK-1.

o Promotes dephosphorylation of pyruvate kinase, making it active.

2. Glucagon (inhibits glycolysis, promotes gluconeogenesis):

o Decreases fructose-2,6-bisphosphate, reducing PFK-1 activity.

o Inhibits pyruvate kinase via phosphorylation by protein kinase A (PKA).

o Promotes glucose release into the bloodstream.

3. Energy Charge Regulation:

o High ATP levels inhibit glycolysis to conserve energy.

 o High AMP/ADP levels activate glycolysis to generate ATP when energy is
low.

4. Substrate Availability:

o Glycolysis is influenced by the availability of glucose.

o If glucose is abundant, glycolysis proceeds; if scarce, gluconeogenesis

takes precedence.

4. pH Regulation:

A drop in pH (due to lactate production) inhibits PFK-1 to prevent excessive

acidification of the cell, which can be detrimental.

5. Regulation in Different Tissues:

o Liver: Focuses on maintaining blood glucose levels; regulated by insulin

and glucagon.

o Muscles: Respond to energy demand (ATP/AMP ratio); glycolysis

increases during exercise.

o Brain: Continuous glycolysis to meet constant energy demands.

• Regulation of Gluconeogenesis : Regulation of gluconeogenesis ensures that

glucose is synthesized only when necessary, such as during fasting, exercise, or
low carbohydrate intake. The process primarily occurs in the liver (and to a lesser
extent in the kidneys), and is tightly regulated to balance blood glucose levels
with energy demands.

Key Regulatory Enzymes of Gluconeogenesis:

Gluconeogenesis is regulated at key irreversible steps that bypass glycolysis. These

enzymes are:

1. Pyruvate Carboxylase (Pyruvate → Oxaloacetate)

o Activated by: Acetyl-CoA (signals sufficient energy availability for glucose
production).
 o Inhibited by: ADP (indicates low energy, favoring glycolysis instead).
2. Phosphoenolpyruvate Carboxykinase (PEPCK) (Oxaloacetate →
Phosphoenolpyruvate)
o Activated by: Glucagon (via cAMP and PKA signaling), cortisol.
o Inhibited by: Insulin, ADP.

3. Fructose-1,6-bisphosphatase (F-1,6-BPase) (Fructose-1,6-bisphosphate →

Fructose-6-phosphate)

o Inhibited by: AMP (signals low energy) and fructose-2,6-bisphosphate (which

promotes glycolysis).
o Activated by: ATP, citrate (indicating energy surplus and TCA cycle abundance).

4. Glucose-6-phosphatase (Glucose-6-phosphate → Glucose)

o Regulated by substrate availability: Present only in the liver and kidneys to
release free glucose into the bloodstream.
o Inhibited by: Insulin.

• Hormonal Regulation of Gluconeogenesis:

1. Glucagon (stimulates gluconeogenesis):

o Increases cAMP → activates protein kinase A (PKA), which:

Phosphorylates and inhibits PFK-2, lowering fructose-2,6-bisphosphate levels (thus

activating F-1,6-BPase and inhibiting glycolysis).

o Induces expression of PEPCK and glucose-6-phosphatase.

2. Insulin (inhibits gluconeogenesis):

Activates protein phosphatases that:

o Decrease PKA activity.

o Increase fructose-2,6-bisphosphate, favoring glycolysis by stimulating
PFK-1.
o Suppresses expression of gluconeogenic enzymes (PEPCK, glucose-6-
phosphatase).

3. Cortisol (stimulates gluconeogenesis):

o Enhances transcription of key gluconeogenic enzymes (PEPCK and glucose-6-
phosphatase).
o Ensures glucose availability during prolonged stress or fasting.
 4. Epinephrine (stimulates gluconeogenesis):

Works via similar pathways as glucagon during stress and fasting to increase glucose
production.

Allosteric Regulation:

1. Energy status (AMP/ATP ratio):

High AMP: Inhibits gluconeogenesis (low energy state).

High ATP and citrate: Activate gluconeogenesis (high energy availability).

2. Fructose-2,6-bisphosphate (F-2,6-BP):

Low levels favor gluconeogenesis (inhibited by glucagon).

High levels favor glycolysis (stimulated by insulin).

3. Acetyl-CoA levels:

High levels activate pyruvate carboxylase, driving oxaloacetate production for

gluconeogenesis.

Low levels favor conversion of pyruvate into energy (via TCA cycle).

o Substrate Availability Regulation:

Amino acids: Serve as gluconeogenic precursors during fasting.

Glycerol: Released from adipose tissue during lipolysis and used for glucose synthesis.

Lactate: Converted to glucose via the Cori cycle.

o Key Takeaways:

Gluconeogenesis is activated by:

Glucagon, cortisol, epinephrine, ATP, acetyl-CoA, fasting.

Gluconeogenesis is inhibited by:

Insulin, AMP, fructose-2,6-bisphosphate, high glucose availability.

• Glycogen Storage Disease : Glycogen storage diseases are a group of rare

inherited conditions that can cause frequent low blood sugar, muscle weakness
and liver damage. There are several different types based on which enzyme is
 missing, and each one affects you differently. Most types are manageable with
treatment.

• Diagnosis of Glycogen Storage Diseases:

1. Blood Tests:
o Hypoglycemia, lactic acidosis (Type I), elevated liver enzymes.
o Elevated creatine kinase (CK) in muscle GSDs.

2. Genetic Testing:

o Identifies mutations in genes related to the deficient enzyme.

 3. Biopsy (Liver/Muscle):

o Shows excessive glycogen storage and structural abnormalities.

4. Enzyme Assay:

o Measures activity of the specific enzyme in tissue samples.

5. Exercise Testing (for muscle GSDs):

o Evaluates exercise intolerance and muscle fatigue.

• Treatment Approaches for GSDs:

➢ Dietary Management:

o Frequent carbohydrate-rich meals to prevent hypoglycemia.

o Cornstarch therapy (slow-release glucose, Type I).
o High-protein diet to support gluconeogenesis (Type III, VI).

➢ Medications:

o Allopurinol for hyperuricemia (Type I).

o Lipid-lowering drugs for hyperlipidemia (Type I).
o Enzyme replacement therapy (for Pompe’s disease).

➢ Exercise Management:

o Avoid strenuous exercise in muscle GSDs.

o Carbohydrate loading before activity (McArdle’s disease).

➢ Liver Transplantation:

o Considered in severe hepatic forms, such as Type IV (Andersen’s).

• Prognosis:

Mild forms (Type VI, IX): Good prognosis with lifestyle modifications.

Severe forms (Type I, II, IV): Can result in life-threatening complications if untreated.

With proper management, many individuals with GSDs can lead relatively normal
lives.