Diseases assc w Metabolic Pathways

Question 1

hexokinase

Answer 1

traps glucose in cell by phosphorylating glucose to glucose-6P. Uses ATP. First step of glycolysis

Question 2

PFK-1

Answer 2

rate limiting enzyme of glycolysis; uses ATP to convert fructose-6P to fructose-1,6BP. Regulates what goes into glycolysis.

• Activated by AMP, Fructose-2,6-BP.
• Inhibited by ATP, Citrate from TCA

Question 3

glyceraldehyde-3P dehydrogenase

Answer 3

uses NAD+ to convert glyceraldehyde 3P to 1,3-BPG

Question 4

phosphoglycerate kinase

Answer 4

generates 2 ATP by converting 1,3-BPG into 3-phosphoglycerate

Question 5

pyruvate kinase

Answer 5

bottleneck enzyme of glycolysis, controls rate of exit of glycolysis by generating pyruvate; also generates 2 ATP.

• Activated by F-1,6-BP (if PFK1 is moving faster than PK, F-1,6BP will build up and bind to PK to stimulate)
• Inhibited by ATP, Acetyl-CoA from TCA

Question 6

PFK2

Answer 6

enzyme that converts fructose-6P to fructose-2,6-BP, which stimulates PFK-1. Allows glycolysis to bypass inhibition by citrate/acetyl coA.

Question 7

lactate dehydrogenase

Answer 7

enzyme that converts pyruvate to lactate using NADH. There is an increased amt of lactic acid during hypoxic conditions - symptoms = muscle cramps, exhaustion, nausea, malaise

Question 8

hemolytic anemia

Answer 8

defective glycolysis causes RBCs to not be able to use energy from ATP to pump Na+ ions back out of the cell. Leads to the cell swelling up and exploding –> echinocytes, hemolysis. Leads to lactic acidosis if anemia is severe enough because lack of RBCs to carry O2 makes for worsening hypoxic conditions.

Question 9

other role of glycolysis in RBCs

Answer 9

Rapoport-Luebering glycolytic bypass - unique to RBCs. Uses BPG mutase to convert 1,3BPG to DPG.

DPG binds hemoglobin and stabilizes its low O2 affinity state. This helps hemoglobin deliver O2 to tissues.

Question 10

too much DPG leads to

Answer 10

right shift of Hb curve, poor loading of O2 onto RBCs

Question 11

too little DPG leads to

Answer 11

left shift of Hb curve, poor offloading of O2 to tissues

Question 12

fetal hemoglobin

Answer 12

does not respond to DPG, thus always has a high affinity for O2

Question 13

defect in hexokinase or PFK-1

Answer 13

not enough DPG, left shift of Hb curve = poor offloading

More severe, treat with blood transfusions.

Question 14

defect in pyruvate kinase

Answer 14

too much DPG, right shift in Hb curve = poor onloading

Milder, treat with oxygen therapy.

Question 15

fasting state

Answer 15

high glucagon/insulin ratio, liver releases glucose (glycogenolysis)

Question 16

fed state

Answer 16

high insulin/glucagon ratio, liver stores glucose (glycogenesis)

Question 17

prolonged fasting state

Answer 17

high glucagon/insulin ratio, body switches from glycogenolysis to gluconeogenesis after about 24 hours

Question 18

glucokinase

Answer 18

the liver expresses this to capture dietary carbs, has lower affinity (higher Km) for glucose than hexokinase 1 (found in all other cells)

Question 19

UDP glucose

Answer 19

glucose-6P is converted to UDP-glucose by UDP-Glucose-Pyrophosphorylase. UDP glucose is the substrate for glycogenesis as well as for glycoproteins and glycolipids.

Normal glucose is not reactive enough to be added onto glycogen, so must be energized by adding UDP.

Question 20

glycogenesis

Answer 20

1. glycogenin autoglycosylates itself with UDP-glucose.
2. glycogen synthase adds glucose monomers with a-1,4 bonds.
3. branching enzyme breaks an a-1,4 bond and transfers the chain after that point onto a branch formed by an a-1,6 bond.
4. Both chains can be elongated by glycogen synthase.

Question 21

glycogenolysis

Answer 21

1. phosphorylase breaks a-1,4 bonds to release glucose 1P but falls off at branching point.
2. debranching enzyme breaks the a-1,4 bond one monomer away from the branching point, then breaks the a-1,6 bond at the branching point, releasing the glucose.
3. phosphorylase can now return to original chain and continue breaking off monomers

Question 22

allosteric activation/inhibition of glycogenesis

Answer 22

High glucose = glucose 6-P builds up and activates glycogen synthase; glucose itself inhibits phosphorylase, preventing glycogenolysis

Question 23

glucagon

Answer 23

“glucose in the blood is low”

Receptors found in liver only; causes increased glycogenolysis, gluconeogenesis

Question 24

insulin

Answer 24

“there is too much glucose in the blood”

Receptors found in liver and muscle; causes increased glycogenesis, decreased gluconeogenesis

Question 25

epinephrine

Answer 25

“we are going to need more glucose”

Receptors found in liver and muscle; causes increased glycogenolysis and increased gluconeogenesis

Question 26

How does epinephrine/glucagon tell the liver to increase glycogenolysis?

Answer 26

Using GPCR, cAMP, PKA pathway. PKA activates phosphorylase kinase and deactivates glycogen synthase. Activated phosphorylase kinase activates phosphorylase = glycogenolysis.

Question 27

How does insulin decrease glycogenolysis?

Answer 27

removes phosphate from glycogen machinery which inactivates the degrading enzymes and activates glycogen synthase

Question 28

Regulation of glycogenolyis in skeletal muscle

Answer 28

unique muscle-specific glycogen phosphorylase has an AMP allosteric activation site – is activated by contraction (influx of Ca2+) and energy need (increased AMP).
Activation of glycogenolysis and glycolysis is coupled in skeletal muscle by AMP.

Question 29

Cori and glucose-alanine cycles

Answer 29

1. Pyruvate may build up in a working muscle cell, will be converted into lactate and alanine and secreted into bloodstream.
2. Liver uptakes the lactate/alanine, converts back to pyruvate, and uses gluconeogenesis to turn it into glucose.

Question 30

defects in gluconeogenesis

Answer 30

The inability to convert lactic acid into glucose leads to hypoglycemia, lactatemia, and lactic acidosis.
Excessive consumption of alcohol can overwhelm the liver’s ability to use NAD+ to convert lactate to glucose = lactic acidosis.

Question 31

glycogen storage diseases

Answer 31

Abnormal synthesis or degradation of glycogen. Caused by mutation or altered expression of enzymes involved in the regulation of glycogen metabolism, symptoms can be mild to severe. Most of the diseases are due to decreased degradation.
Liver defect: inter-meal hypoglycemia and hepatomegaly
Muscle defect: normal blood glucose but exercise intolerance, muscle cramping, wasting

Question 32

Von Gierke’s

Answer 32

defect of liver glucose-6-phosphatase, dietary glucose builds up in the liver over time, cannot be released. Severe hepatomegaly, severe hypoglycemia.

Question 33

McArdle’s

Answer 33

defect of muscle phosphorylase; muscle cells unable to breakdown glycogen. Causes muscle pain with exercise, normal blood glucose levels.

Question 34

Hers’ disease

Answer 34

defect of liver phosphorylase, cannot degrade glycogen as well. Symptoms similar to Von Gierkes but milder.

Question 35

Cori’s disease

Answer 35

defect in debranching enzyme in muscle and liver; causes buildup of abnormal glycogen. Similar symptoms to Von Gierke’s but milder.

Question 36

Andersen’s disease

Answer 36

defect in branching enzyme in liver and spleen; causes normal amounts of glycogen but glycogen branches much longer. Causes progressive cirrhosis of the liver and death by age 2.

Question 37

Pompe’s disease

Answer 37

defect that causes abnormal glycogen storage in lysosomes in all organs. Caused cardiorespiratory failure by age 2 until myozyme hit the market.