Detailed Lecture Notes on Galactose and Fructose Metabolism

To succeed in this course, students must be able to provide detailed answers to the following questions:

What specific reactions and enzymes participate in fructose metabolism within the liver?
What is the biochemical basis and the associated symptoms of fructose intolerance?
What reactions and enzymes participate in galactose metabolism?
What is the biochemical basis and the symptoms of classic galactosemia?
What is the biochemical basis and symptoms of lactose intolerance?

Glucose Sources: Derived from the diet or via gluconeogenesis (primarily in the liver) from amino acids and lactate.
Central Intermediate: Glucose-6-phosphate ( $Glucose\text{-}6P$ ).
Metabolic Fates of Glucose-6-phosphate:
- Glycolysis: Conversion into pyruvate (producing $2ATP + 2NADH$ ).
  - Anaerobic conditions: Pyruvate is converted to Lactate (regenerating $NADH$ ), which can lead to acidosis in circulation.
  - Aerobic conditions: Pyruvate enters the mitochondrion, is converted to Acetyl-CoA (releasing $CO_2$ ), and enters the Krebs cycle for Oxidative Phosphorylation ( $ATP$ production).
- Pentose Phosphate Pathway: Production of $NADPH$ and Ribose for synthesis of $NTPs$ , $DNA$ , and $RNA$ .
- Glycogen Synthesis: Storage of glucose in the liver.
Relationship with Other Sugars: Fructose and Galactose enter this central metabolic pathway at specific points, primarily in the liver.

In the Liver: Fructose is metabolized via the fructose 1-phosphate pathway.
In Other Tissues (e.g., Adipose Tissue): Fructose is directly phosphorylated by hexokinase to enter glycolysis.

PFK Bypass: Fructose processing in the liver bypasses phosphofructokinase (PFK), which is the key regulatory and rate-limiting enzyme of glycolysis.
Fat Synthesis: Because the regulatory step is bypassed, excess Acetyl-CoA is synthesized. This excess Acetyl-CoA is subsequently converted into fatty acids and fats.
Health Implications: Overconsumption of fructose instead of glucose is linked to:
- Obesity.
- Fatty liver disease.
- Development of Type 2 diabetes.

Fructose Intolerance (Hereditary):
- Biochemical Basis: Deficiency of the enzyme aldolase (specifically Fructose-1-phosphate aldolase) in the liver.
- Mechanism of Pathology: Consumption of fructose leads to the accumulation of fructose 1-phosphate. This causes a depletion of inorganic phosphate ( $P_i$ ) and $ATP$ .
- Consequences: Liver cell dysfunction and destruction.
Fructosuria: Mentioned as a related clinical condition of fructose metabolism.

Entry Point: Galactose is converted into glucose 6-phosphate to enter glycolysis.
Step-by-Step Reaction:
1. Phosphorylation: Galactose is phosphorylated by galactokinase.
2. Uridyl Transfer: Facilitated by uridyl transferase.
3. Epimerization: Facilitated by epimerase.
4. Isomerization: Glucose 1-phosphate is converted to glucose 6-phosphate by the enzyme phosphoglucomutase.
Summation of the Pathway Reaction:
- $Galactose + ATP \rightarrow Glucose\,1\text{-phosphate} + ADP + H^+$
Synthesized Products: Galactose is also used in the synthesis of complex polysaccharides and glycoproteins.

Galactosemia (Classic):
- Biochemical Basis: Deficiency of the enzyme galactose 1-phosphate uridyl transferase.
- Clinical Presentation upon Milk Consumption:
  - Vomiting and diarrhea.
  - Liver damage and jaundice.
  - Cataracts.
  - Mental retardation.
- Mechanism of Cataracts: The conversion of galactose to galactitol in the lens of the eye. Accumulation of galactitol causes an influx of water due to osmosis, resulting in clouding of the lens (infantile cataracts).
- Detection: Identified through neonatal mass presymptomatic screening.
- Treatment: Strict diet involving no galactose consumption.
- Prognosis Note: Even with treatment, Central Nervous System (CNS) dysfunction and ovarian failure may persist.

Biochemical Basis: A deficiency of the enzyme lactase in the small intestine, which is required to degrade lactose (disaccharide).
Mechanism of Symptoms:
- Undigested lactose reaches the large intestine where it is fermented by intestinal bacteria (e.g., Lactobacillus).
- Fermentation Products: Lactate, methane ( $CH_4$ ), and hydrogen ( $H_2$ ).
- Pathophysiology: These products cause "bloating" (discomfort). The presence of undigested sugar causes water entry into the intestine via osmosis, leading to diarrhea.
Epidemiology and Evolution:
- Lactose intolerance is normal for the majority of the adult world population.
- Lactose Tolerance: Result of a relatively recent mutation occurring approximately $5,000$ years ago.
- This mutation prevents the natural decline of lactase activity after weaning.
- The mutation prevailed in populations with developed dairy farming, particularly among Northern Europeans.

Tymoczko, Berg, Stryer: Biochemistry, a Short Course, 4th edition, Chapter 16.
Berg, Tymoczko, Stryer: Biochemistry, 8th Edition, Chapter 16.
Ferrier: Lippincott, Biochemistry, Chapter 12.

Question: Fructose intolerance is due to:
- A. Phosphofructokinase deficiency.
- B. Intestinal enzyme deficiency.
- C. Excessive milk consumption.
- D. Glyceraldehyde accumulation.
- E. Fructose-1-phosphate aldolase deficiency. (Correct Answer)
Question: Which is incorrect about galactosemia?
- A. It causes mental retardation.
- B. It is due to aldolase deficiency. (Correct Answer - it is due to uridyl transferase deficiency).
- C. It is detected during neonatal mass screening.
- D. It is associated with milk consumption.
- E. It causes cataracts.