L10- Galactose, Fructose & Ethanol Metabolism

Question 1

LO1: List the major dietary sources of galactose and fructose

Answer 1

Galactose: dairy +dairy products, baby formulas
Fructose: fruit, table sugar (sucrose), high fructose corn syrup, honey

Question 2

LO2: Name four biologically important compounds whose synthesis requires galactose

Answer 2

Activated galactose=UDP-gal, used by galactosyltransferase to make:

1. Glycoproteins
2. Glycolipids
3. Proteoglycans

In lactating mammary gland, UDP-gal required for:
4. Lactose synthesis

Question 3

LO3: Name three enzymes unique to galactose metabolism, the reaction that each enzyme catalyzes, and indicate the tissue in which these enzymes are expressed

Answer 3

Enzymes all expressed in liver
Galactokinase: transfers phosphate from ATP to the C-1 of galactose to generate galactose-1-phosphate

Uridyl transferase: catalyzes an exchange reaction in which galactose-1-phosphate is exchanged for the glucose-1-phosphate moiety of UDP-glucose, forming glucose-1-phosphate and UDP-gal

UDP-Glu-4-Epimerase: alters configuration of UDP-gal to form UDP-glu using an internal oxidation-reduction reaction to complete epimerization

Question 4

LO4: Name two enzymes whose deficiencies result in galactosemia and how you would distinguish between the two

Answer 4

URIDYL TRANSFERASE: (most common) deficiency causes galactose-1-phosphate to accumulate in the cell, and galactose to accumulate in the blood

      - symptoms include vomiting, diarrhea, enlarged liver, jaundice, cataracts (galactose glycalates lens proteins, creating galactitol which alters osmotic pressure)
      - will see increased galactose-1-phosphate levels in plasma/RBC lysate

GALACTOKINASE (rare) defiency causes galactose to accumulate in the cell (not galactose-1-phosphate)

      - symptoms are milder and usually only include early cataract formation/vision loss in few weeks of life
       - plasma/RBC lysate does not show increased galactose-1-phosphate levels

Treatment for both: limit galactose intake

Question 5

LO5: Explain how a mother who is homozygous for galactosemia and therefore can’t digest dietary galactose is able to produce lactose in her milk

Answer 5

Mammary gland tissue can use D-glucose as the acceptor molecule in the galactosyltransferase reaction (galactosyltransferase gets modified by alpha-lactalbumin in order to do so) to make lactose from D-glucose

(UDP-gal can also be epimerized by UDP-glu-4-epimerase if body is still synthesizing galactose)

Question 6

LO6: Describe a reaction that contributes to galactose toxicity (seen in galactosemias)

Answer 6

Galactose can be reduced at C-1 to form galactitol, which cannot leave the cell and whose accumulation alters the osmotic pressure of the cell

• catalyzed by aldol reductase, which is non-specific and can reduce the carbonyl group of most aldoses
• occurs most often in the lens of the eye, as aldol reductase is present in [high] here

Question 7

LO7: Name three enzymes unique to fructose metabolism, the reaction that each enzyme catalyzes, and indicate the tissue in which these enzymes are expressed

Answer 7

Enzymes all expressed in liver
Fructokinase: catalyzes transfer of a phosphate group from ATP to fructose in first step of its utilization

Aldolase B (different isozyme of aldolase used in glycolysis): metabolizes fructose-1-phosphate (formed by fructokinase) into glyceraldehyde and DHAP

Glyceraldehyde kinase (triose kinase, triokinase): converts glyceraldehyde to glyceraldehyde-3-phosphate utilizing a phosphate group from ATP

Question 8

LO8: Describe the causes of essential fructosuria and hereditary fructose intolerance

Answer 8

ESSENTIAL FRUCTOSURIA

• fructokinase deficiency
• fructose accumulates in the blood and spills over into urine
• benign; [fructose] in the blood is abnormally high enough that it is taken up by extrahepatic tissues and converted to fructose-6-phosphate by hexokinase

HEREDITARY FRUCTOSE INTOLERANCE

• aldolase B deficiency
• fructose-1-phosphate accumulates, resulting in depletion of ATP as it can’t be regenerated because phosphate is trapped in fructose-1-phosphate
• adenine nucleotides get degraded since ATP is not regenerated (hyperuricemia/increased uric acid)
• hepatic gluconeogenesis also impaired due to lack of ATP
• deficiency in phopshate also impairs glucose liberation from glycogen by glycogen phosphorylase (hypoglycemia)
• lack of ATP eventually leads to cell death
• fructose must be elimited from diet (as well as its precursors: sucrose and sorbitol)

Question 9

LO9: Why does HFI result in hypoglycemia even when glycogen is present in the liver?

Answer 9

• there isn’t enough phosphate (trapped in fructose-1-phosphate) to liberate glucose from glycogen stores by glycogen phosphorylase
  - glycogen phosphorylase must be phosphorylated to be active

Question 10

LO10: List the enzymes needed to metabolize ethanol; what’s the toxic intermediate in this pathway?

Answer 10

1. alcohol dehydrogenase
2. acetaldehyde dehydrogenase

acetaldehyde=toxic intermediate

Question 11

LO11: Describe the use and mechanisms of action of disulfiram and fomepizole

Answer 11

disulfiram (Antabuse): competitive inhibitor of ALDH; leads to accumulation of acetaldehyde and increased unpleasant effects from ethanol consumption to deter drinking

fomepizole (Antizol): competitive inhibitor of ADH: to inhibit metabolism of ethanol, or more commonly, ethylene glycol in accidental poisoning