L30: Galactose and Glycogen Metabolism

Question 1

Lactose structure

Answer 1

disaccharide (galactose + glucose with a β 1,4 glycosidic bond)

Question 2

Lactose metabolism

Answer 2

Lactose is not absorbed from the intestine

Digested using the enzyme lactase, which catalyzes the hydrolysis of lactose to galactose and glucose

Question 3

What happens when you cannot metabolize lactose? When does this tend to happen in mammals?

Answer 3

Many mammals after breastfeeding have a reduction in lactase
Insufficient lactase activity causes lactose intolerance in which intestinal bacteria metabolize lactose to acids and carbon dioxide → bloating, diarrhea, dehydration

Question 4

Where does galactose come from?

Answer 4

Galactose is obtained from lactose in the diet.

Question 5

Galactokinase function

Answer 5

phosphorylates galactose at the 1 position

Question 6

How is UDP-Glucose formed?

Answer 6

Two ways to make UDP-Glucose:
Note: Glucose and Galactose are epimers (differ at carbon 4 chiral center)
Glucose 1-P + UTP → (UDP-Glucose pyrophosphorylase) UDP Glucose
UDP Galactose → (UDP-Hexose 4-epimerase) UDP Glucose

Question 7

Why is UDP-Galactose important?

Answer 7

UDP-Galactose = important precursor to making lactose in mammary glands
Also important for making other glyco-compounds:
Glycolipids
Glycoproteins
Glycosaminoglycans

Question 8

What happens if you are deficient in galactokinase? What are the hereditary diseases due to this?

Answer 8

galactose builds up in the blood → type of galactosemia

• Galactokinase Deficiency
• Classic Galactosemia

Question 9

Galactokinase Deficiency

Answer 9

Leads to elevated galactose = substrate for the enzyme aldose reductase
Rare autosomal recessive disorder
Aldose reductase = high Km (low affinity)
High enough levels of galactose → can get reduction of galactose to form galactitol
Galactose + NADPH + H+ → Galactitol + NADP+
Elevated galactitol causes cataracts
Tx: Dietary adjustment- remove galactose and galactitol from diet

Question 10

Classic Galactosemia

Answer 10

Autosomal recessive disorder
Able to produce galactose 1-P, but impaired metabolism
Similar to galactokinase deficiency: galactose build up will lead to formation of galactitol → cataracts
Build up of Galactose 1-P will change metabolic pathways and lead to metabolic retardation, liver cirrhosis, liver failure, etc.
Important to diagnose neonatally to provide formula without lactose
Prenatal diagnosis: chorionic villus sampling
Despite adequate tx, at risk for developmental delays and, in females, premature ovarian failure

Question 11

Glycogen Structure/Size

Answer 11

A polysaccharide of glycosyl residues joined by glycosidic links
Major linkages: α1,4
Less common linkage: α1,6 → forms branch points
Branches make molecule more soluble
Occur at an average spacing of 8-12 α1,4 links
(Ratio of α1,6:α1,4 = 1:10)
Glycogen changes size (not fixed) depending on metabolic requirements

Question 12

How are the α1,4 bonds formed in glycogen?

Answer 12

Formed by glycogen synthase (catalyzes the transfer of glucose from UDP-glucose to glycogen)
Attaches at the non-reducing end of growing glycogen (-OH group at C4)

Question 13

How are the α1,6 bonds formed in glycogen?

Answer 13

Formed by glycogen branching enzyme (amylo 1,4-1,6 transglycosylase)
Two roles: breaks α1,4 linkage and rejoins new α1,6 bond
Branches make molecule more soluble

Question 14

How is glycogen synthesized? (What are the 3 things you need?)

Answer 14

1. Glucose 6-phosphate ↔ Glucose 1-phosphate
   Enzyme: Phosphoglucomutase
   Reversible rxn!
2. Glucose 1-phosphate + UTP → UDP-glucose + pyrophosphate
   Enzyme: Pyrophosphorylase
3. Need glycogenin to begin synthesis of glycogen
   Mixture of UDP-glucose and glycogen synthase does not create glycogen. Glycogen synthase requires a primer to function.
   Glycogenin is a protein with a tyrosine residue (-OH) at the end. It is the site at which the first glucose will be added.
   Some enzymatic activity: transfer glucose from UDP-glucose to tyrosine and form a short primer so that glycogen synthase can begin adding glucose units

Question 15

How is glycogen broken down?

Answer 15

First breakdown α1,4 links via phosphorolytic cleavage
Phosphorolytic cleavage breaks bonds by adding an inorganic phosphate group and produces glucose 1-phosphate
Enzyme: Glycogen phosphorylase
Breakdown of α1,6 branch points
Close to the branch point, glycogen phosphorylase stops working and leaves a short oligosaccharide chain
Enzyme: Glycogen debranching enzyme
Transferase & hydrolase activity
Transfers short oligosaccharide chain and adds it the other chain
Hydrolyzes α1,6 with the addition of water to produce free glucose

Question 16

What is the function and location of glycogen?

Answer 16

Storage form of carbohydrate

The glycogen content of tissues varies with dietary changes and also from tissue to tissue. (liver, muscle, brain)

Question 17

What is the function of glycogen in the liver?

Answer 17

Highest concentration in the body, but also the most readily depleted- “labile reserve”
24-48 hour fast: Glycogen depleted for maintenance of blood glucose levels
Maintenance of blood glucose levels:
- Gluconeogenesis
- Glycogenolysis

Question 18

What is the function of glycogen in muscle?

Answer 18

Concentration is lower than the liver, but more glycogen in the muscle overall because more muscle in the body
Not as easily influenced by nutritional changes (stable)
Will be depleted with exercise!
Breakdown of glycogen for energy:
Glycolysis→ TCA→ ATP
Resting muscle: mostly oxidizing fatty acids

Question 19

What is the function of glycogen in the brain?

Answer 19

Very low glycogen concentration
Largely dependent upon circulating glucose for the carbohydrate that it requires (need a continuing supply of glucose)
Hypoglycemia→ brain malfunction, coma & death