T03 - Carbohydrate Metabolism II

Question 1

The allosteric mode of regulation acts on what order of time?

Answer 1

milliseconds

Question 2

The protein localization mode of regulation acts on what order of time?

Answer 2

seconds-minutes

Question 3

The covalent modification mode of regulation acts on what order of time?

Answer 3

minutes

Question 4

The gene expression mode of regulation acts on what order of time?

Answer 4

hours

Question 5

Describe how the liver responds to high blood [glucose] levels.

Answer 5

liver uses GLUT2 transporter + glucokinase to detect and then stores excess glucose as glycogen

Question 6

Describe how pancreatic beta cells respond to high blood [glucose] levels.

Answer 6

pancreatic beta cells use GLUT2 transporter to detect and then release insulin to lower blood [glucose]

Question 7

Describe the interplay between insulin and glucagon in type 1 diabetes and the resulting effect.

Answer 7

insulin lacking and therefore glucagon chronically high, causing hyperglycemia

Question 8

Describe the interplay between insulin and glucagon in type 2 diabetes and the resulting effect.

Answer 8

insulin signaling lacking (i.e. defect in receptor) and glucagon action is chronically high

Question 9

What is the effect of glucagon?

Answer 9

raises blood [glucose]

Question 10

(T/F) Glucose levels fluctuate significantly over the course of a day.

Answer 10

False. Glucose levels actually remain relatively constant, with fluctuations maxing at 5 mM.

Question 11

(T/F) GLUT3 is only expressed in the brain.

Answer 11

False. It is expressed in most tissues, but is the predominant transporter in neurons, which is why it is designated as the “brain” glucose transporter.

Question 12

Which of the four GLUT transporters are NOT expressed in all tissues?

Answer 12

GLUT2 (expressed in liver and pancreatic beta cells); GLUT4 (expressed in muscle and fat)

Question 13

Which of the four GLUT transporters are insulin-dependent for activation?

Answer 13

GLUT4 only

Question 14

Does glucose-6-phosphate inhibit hexokinase IV/glucokinase?

Answer 14

No.

Question 15

Glucokinase is highly expressed in which tissues? (2)

Answer 15

liver; pancreatic beta cells

Question 16

What is the significance of hexokinases I-III lacking a GK-RP form of regulation?

Answer 16

lack of GKRP-type regulation means that organs such as brain and muscle can use glucose even at low blood [glucose]

Question 17

What are the key three reactions within glycolysis that are highly regulated?

Answer 17

glucose → G6P [hexokinase]

F6P → F-1,6-bP [PFK]

PEP → pyruvate [pyruvate kinase]

Question 18

What is the major site of expression for hexokinase I?

Answer 18

brain (and many other tissues)

Question 19

What is the major site of expression of hexokinase II? (2)

Answer 19

fat

muscle

Question 20

What is the major site of expression of hexokinase III?

Answer 20

lung

Question 21

What is the major site of expression of hexokinase IV? (2)

Answer 21

liver

islet beta cells of pancreas

Question 22

Draw a graph that shows relative enzyme activity for hexokinase and glucokinase.

Answer 22

Question 23

Which enzyme is thought to be the most important regulatory point for glycolysis?

Answer 23

PFK

Question 24

Why does H⁺ inhibit PFK?

Answer 24

H⁺ is associated with lactate production, which is a signal that there is already enough energy

Question 25

Which molecule is the _most_ important regulator of PFK?

Answer 25

F-2,6-bP

Question 26

What are the two mechanisms by which F-2,6-bP upregulates PFK activity?

Answer 26

(1) F-2,6-bP antagonizes ATP inhibition of PFK (2) lowers K_m of enzyme for F6P, the PFK substrate (i.e. increases affinity)

Question 27

What is a bifunctional protein/enzyme? In what context is it used?

Answer 27

contains both kinase and phosphatase domains used to interconvert F6P and F-2,6-bP

Question 28

How does the fasting state affect the bifunctional protein?

Answer 28

activates phosphatase function, which reduces F-2,6-bP and slows down glycolytic flux

Question 29

How does the feeding state affect the bifunctional protein?

Answer 29

activates kinase domain, which increases F-2,6-bP and increases glycolytic flux

Question 30

What are the activators and inhibitors of pyruvate kinase?

Answer 30

activated by F-1,6-bP inhibited by ATP and alanine

Question 31

Describe the activity of HIF in normoxic conditions.

Answer 31

HIF is turned over as quickly as it's made, mediated by binding of VHL (and is ultimately degraded by proteosome)

Question 32

Describe the activity of HIF in hypoxic conditions and the resulting effect on glycolysis.

Answer 32

HIF forms active heterodimer with ARNT and avoids degradation → HIF target genes are glycolytic enzymes (since glycosis doesn't require O₂) in short, hypoxia means activation of glycolysis

Question 33

Describe the activity of HIF in cancer cells.

Answer 33

HIF is always active in many cancer cells (Warburg effect — cancer cells are highly glycolytic)

Question 34

What are the inhibitors of fructose-1,6-bisphosphatase?

Answer 34

F-2,6-bP AMP

Question 35

What are the activators of fructose-1,6-bisphosphatase?

Answer 35

citrate

Question 36

What are the activators of the pyruvate kinase reaction?

Answer 36

F-1,6-bP

Question 37

What are the inhibitors of the pyruvate kinase reaction?

Answer 37

ATP alanine

Question 38

What are the inhibitors of the PEP carboxykinase reaction?

Answer 38

ADP

Question 39

What are the activators of the pyruvate carboxylase reaction?

Answer 39

acetyl CoA

Question 40

What are the inhibitors of the pyruvate carboxylase reaction?

Answer 40

ADP

Question 41

Draw a diagram illustrating the reciprocal regulation of glycolysis and gluconeogenesis.

Answer 41

Question 42

What is the relationship between glucagon and PEP carboxykinase?

Answer 42

glucagon **promotes transcription** of PEP carboxykinase

Question 43

Draw a diagram showing how the phosphorylation/dephosphorylation of PFK works in normoglycemic and hypoglycemic conditions.

Answer 43

Question 44

What specific component of the HIF system is mutated in cancer cells that exhibit the Warburg effect?

Answer 44

prolyl hydroxylase is mutated → it can't bind HIF → HIF accumulates → cell thinks it's in hypoxia and therefore drives glycolysis

Question 45

HIF does not regulate the normal bifunctional enzyme. Describe how one of the isoforms of the bifunctional enzyme is regulated by HIF.

Answer 45

HIF regulates an isoform (iPFK-2) that has a mutation in the phosphatase domain → kinase domain always on → constitutive production of F-2,6-bP → high glycolytic rate as F-2,6-bP is an activator of PFK