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Metabolism > Carbohydrate metabolism (midterm) > Flashcards

Carbohydrate metabolism (midterm) Flashcards

1
Q

What is the name of the class of enzymes that digest glycosidic bonds?

A

Glycosidases (glycoside hydrolases)

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2
Q

How are carbohydrates digested in the mouth?

A

Salivary α-amylase hydrolyzes random α(1→4) bonds in dietary starch and glycogen, producing oligosaccharides known as dextrins

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3
Q

How are carbohydrates digested in the duodenum?

A

Pancreatic α-amylase hydrolyzes glycosidic bonds, similarly to salivary α-amylase

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4
Q

What are examples of enzymes of the upper jejunal mucosal lining (brush border) that digest carbohydrates?

A
  • Isomaltase: digests isomaltose; α(1→6)
  • Maltase: digests maltose; α(1→4)
  • Sucrase: digests sucrose; α(1→2)
  • Lactase: digests lactose; β(1→4)
  • Trehalase: digests trehalose (a Glc disaccharide found in fungi); α(1→1)
  • Glucoamylase (exoglycosidase): digests starch; α(1→6) and α(1→4)
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5
Q

What is the structure of isomaltose?

A

Glc-α(1→6)-Glc

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6
Q

What is the structure of trehalose?

A

Glc-α(1→1)-Glc

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7
Q

What are the structural features of the sucrase–isomaltase complex?

A
  • Transmembrane protein with a single transmembrane α-helix
  • Glycosylated
  • Two luminal subunits: a sucrase and an isomaltase–maltase
  • The two subunits are held together by noncovalent interactions
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8
Q

What is the function of the sucrase–isomaltase complex?

A
  • About 100% of intestinal sucrase activity
  • Almost all of intestinal α(1→6) hydrolysis
  • 80% of intestinal maltase activity
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9
Q

What are the causes of sucrase–isomaltase complex deficiency?

A
  • Genetics
  • Variety of intestinal diseases (e.g. Crohn disease, ulcerative colitis, celiac disease)
  • Malnutrition
  • Injury of the mucosa (e.g. by chemotherapy)
  • Severe diarrhea
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10
Q

What is the result of sucrase–isomaltase complex deficiency?

A

Intolerance of ingested sucrose

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11
Q

How is sucrase–isomaltase complex deficiency treated?

A
  • Dietary restriction of sucrose
  • Enzyme replacement therapy
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12
Q

What are the structural features of glucoamylase (exoglycosidase)?

A
  • Transmembrane protein
  • Forms two domains: a maltase and an exoglycosidase
  • There is no split of subunits, as in the sucrase–isomaltase complex
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13
Q

What is the function of glucoamylase (exoglycosidase)?

A
  • Maltase activity
  • Exoglycosidase activity
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14
Q

What intestinal enzyme digests isomaltose?

A

Isomaltase (in the sucrase–isomaltase complex)

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15
Q

What intestinal enzymes digest maltose?

A
  • Maltase in the sucrase–isomaltase complex
  • Maltase in glucoamylase (exoglycosidase)
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16
Q

What intestinal enzyme digests sucrose?

A

Sucrase (in the sucrase–isomaltase complex)

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17
Q

What intestinal enzyme digests lactose?

A

Lactase

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18
Q

What intestinal enzyme digests trehalose?

A

Trehalase

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19
Q

What is the structure of lactose?

A

Gal-β(1→4)-Glc

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20
Q

What is the structure of sucrose?

A

Glc-β(1→2)-Frc

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21
Q

What is the prevalance and distribution of lactose intolerance?

A
  • More than 75% of the world’s population are lactose intolerant
  • Up to 90% of African and Asian adults are lactase-deficient
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22
Q

What is thought to be the cause of lactose intolerance?

A

Small variations in the DNA sequence on chromosome 2 that controls expression of the lactase gene

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23
Q

When does lactose intolerance usually begin?

A

Ages 5–7, leading to lactose levels 10% of those in infants

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24
Q

How are carbohydrates absorbed into the intestinal mucosa?

A
  • Sodium-independent facilitated diffusion (GLUT carriers)
  • Sodium-dependent cotransporters (SGLTs)
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25
Q

In what direction do GLUT transporters move glucose?

A

Either direction, depending on the concentration gradient

In intestinal mucosae, the transport is generally from the lumen to the cytosol

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26
Q

Where is GLUT 1 found?

A
  • RBCs
  • Blood–brain barrier
  • Blood–retinal barrier
  • Blood–placental barrier
  • Blood–testis barrier
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27
Q

What are the functional features of GLUT 1?

A
  • High affinity, low efficiency
  • Low Km
  • Low Vmax
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28
Q

Where is GLUT 2 found?

A
  • Liver
  • Kidney
  • Pancreatic β-cells
  • Serosal surface of intestinal mucosal cells
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29
Q

What are the functional features of GLUT 2?

A
  • Low affinity
  • High efficiency
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30
Q

Where is GLUT 3 found?

A
  • Neurons of the brain
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31
Q

What are the functional features of GLUT 3?

A
  • Major transporter in the CNS
  • High affinity
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32
Q

Where is GLUT 4 found?

A
  • Adipose tissue
  • Skeletal muscle
  • Heart muscle
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33
Q

What are the functional features of GLUT 4?

A
  • High efficiency
  • Sensitive to insulin: ↑insulin leads to increase in number of GLUT 4 transporters on the cell surface
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34
Q

Where is GLUT 5 found?

A
  • Intestinal epithelium
  • Spermatozoa
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35
Q

What does GLUT 5 transport?

A

Fructose

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36
Q

What does GLUT 2 transport?

A
  • Glucose
  • Fructose
  • Galactose
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37
Q

Which GLUT carriers transport sugars other than glucose?

A
  • GLUT 2: Glc, Frc, Gal
  • GLUT 5: Frc only
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38
Q

Where is GLUT 7 found?

A

Glucogenic tissues (tissues where gluconeogenesis occurs)—in the ER membrane

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39
Q

How do GLUT proteins function?

A
  • Facilitated (saturable) diffusion of glucose
  • They alter between two conformational states (open to the cytosol or open to the outside)
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40
Q

Which GLUT carrier is sensitive to insulin?

A

GLUT 4

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41
Q

Where are sodium-dependent glucose transporters (SGLTs) found?

A
  • Proximal convoluted tubules of nephrons
  • Small intestine mucosa
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42
Q

How do SGLTs function?

A

Secondary active transport (cotransport) of glucose using the concentration gradient of Na+

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43
Q

What is the structure of the cAMP-dependent protein kinase (A)?

A
  • Two catalytic subunits
  • Two regulatory subunits
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44
Q

How does protein kinase A respond to cAMP?

A
  • cAMP molecules bind to the 2 binding sites on each regulatory subunit
  • The two catalytic subunits are activated and released (separately)
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45
Q

How many reactions are there in glycolysis?

A

10

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46
Q

What are the net products of glycolysis (per molecule of glucose)?

A
  • 2 ATP
  • 2 NADH
  • 2 pyruvate
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47
Q

What is step 1 of glycolysis?

A

glucose + ATP → glucose-6-phosphate + ADP
Catalyzed by hexokinase or glucokinase

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48
Q

What are the irreversible steps of glycolysis?

A
  • Step 1 (glucose phosphorylation)
  • Step 3 (fructose-6P phosphorylation)
  • Step 10 (pyruvate formation)
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49
Q

What are the isozymes that catalyze the first step of glycolysis?

A
  • Hexokinase: found in most tissues. Low Km, low Vmax. Allosterically regulated
  • Glucokinase: found in hepatocytes and pancreatic β cells. Higher Km, very high Vmax. Hormonally regulated
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50
Q

What are the features of hexokinase?

A
  • Found in most tissues
  • Broad substrate specificity: it can phosphorylate other hexoses
  • Low Km, allowing for some activity at low [glucose]
  • Low Vmax, so it cannot trap more glucose than the cell needs
  • Affected by feedback inhibition
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51
Q

What are the features of glucokinase?

A
  • Found in hepatocytes and pancreatic β cells
  • Specific to glucose
  • Higher Km: it only functions at > 100 mg dL–1
  • Very high Vmax, so it sequesters glucose in the cell
  • Activity induced by presence of glucose or insulin
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52
Q

What is step 2 of glycolysis?

A

glucose-6-phosphate ⇌ fructose-6-phosphate
Catalyzed by phosphoglucose isomerase

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53
Q

What is step 3 of glycolysis?

A

fructose-6-phosphate + ATP → fructose-1,6-bisphosphate + ADP
Catalyzed by phosphofructokinase-1

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54
Q

What is the committed step of glycolysis?

A

Step 3 (fructose-6P phosphorylation)

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55
Q

What is the rate-determining (slow) step of glycolysis?

A

Step 3 (fructose-6P phosphorylation)

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56
Q

What is step 4 of glycolysis?

A

glucose-6-phosphate ⇌ glyceraldehyde-3-phosphate + dihydroxyacetone phosphate
Catalyzed by aldolase

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57
Q

What is step 5 of glycolysis?

A

dihydroxyacetone phosphate ⇌ glyceraldehyde-3-phosphate
Catalyzed by triose phosphate isomerase

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58
Q

The reaction interconverting dihydroxyacetone phosphate and glyceraldehyde-3-phosphate is reversible. What ensures that GAP is formed?

A

GAP is consumed by the later steps of glycolysis, pulling the equilibrium in favor of its production

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59
Q

What is step 6 of glycolysis?

A

glyceraldehyde-3-phosphate + Pi + NAD+ + 2H+ ⇌ 1,3-bisphosphoglycerate + NADH + H+
Catalyzed by glyceraldehyde-3-phosphate dehydrogenase

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60
Q

In step 6 of glycolysis, glyceraldehyde-3-phosphate is phosphorylated to 1,3-bisphosphoglycerate, but no ATP (or other NTP) is consumed. How does this take place?

A

The oxidation of glyceraldehyde to glycerate releases enough energy for the addition of a phosphate

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61
Q

What is the fate of the 2 NADH produced in glycolysis

A
  • Used for cellular metabolism (including the glycerol-3-phosphate shuttle)
  • “Transported” to the mitochondria via the malate–aspartate shuttle
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62
Q

What is step 7 of glycolysis?

A

1,3-bisphosphoglycerate + ADP + Pi ⇌ 3-phosphoglycerate + ATP
Catalyzed by phosphoglycerate kinase

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63
Q

In which step is the first ATP of glycolysis produced?

64
Q

What is step 8 of glycolysis?

A

3-phosphoglycerate ⇌ 2-phosphoglycerate
Catalyzed by phosphoglycerate mutase

65
Q

What is step 9 of glycolysis?

A

2-phosphoglycerate ⇌ H2O + phosphoenolpyruvate
Catalyzed by enolase

66
Q

What is step 10 of glycolysis?

A

phosphoenolpyruvate + ADP + Pi → pyruvate + ATP
Catalyzed by pyruvate kinase

67
Q

How is glycolysis modified in RBCs?

A

Instead of step 7 (first ATP production):

  • Bisphosphoglycerate mutase isomerizes 1,3-BPG to 2,3-BPG
  • A phosphatase converts 2,3-BPG to 3-phosphoglycerate, releasing pyruvate using water
  • 3-PG re-enters glycolysis at step 8
68
Q

What is the effect of 2,3-bisphosphoglycerate in RBCs?

A
  • 2,3-BPG binds to deoxy-hemoglobin more strongly than O2, preventing O2 from rebinding
  • In the systemic circulation, this promotes oxygen delivery by preventing it from rebinding to hemoglobin
69
Q

How is pyruvate reduced to ethanol in yeasts and other microorganisms?

A
  • pyruvate → acetaldehyde + CO2, using TPP as a coenzyme
  • acetaldehyde + NADH → ethanol + NAD+

The entire reaction is catalyzed by pyruvate decarboxylase

70
Q

How is pyruvate converted to lactate?

A

pyruvate + NADH ⇌ lactate + NAD+
Catalyzed by lactate dehydrogenase

71
Q

When and where is pyruvate converted to lactate?

A
  • In exercising skeletal muscle, as NADH is formed by catabolism and there is not enough NAD+ for glycolysis
  • As a coping mechanism for brief periods of hypoxia
  • In cells with low energy demands
72
Q

What are the causes of lactic acidosis?

A
  • Decreased lactate utilization
  • Increased lactate production
  • Collapse of the circulatory system, leading to impaired O2 transport (as in respiratory failure, uncontrolled hemorrhage, myocardial infarction)
  • Decreased pyruvate utilization (shifting equilibrium to lactate formation), as in lowered gluconeogenesis (pyruvate carboxylase) or TCA (pyruvate dehydrogenase) activity
  • Alcohol intoxication: buildup of NADH; lactate dehydrogenase is used to regenerate NAD+
73
Q

Which enzymes in glycolysis are regulated?

A
  • Hexokinase/glucokinase
  • Phosphofructokinase-1
  • Pyruvate kinase
74
Q

How is phosphofructokinase-1 regulated?

A

Activators

  • AMP
  • Fructose-2,6-bisphosphate
  • Insulin

Inhibitors

  • ATP
  • citrate
  • H+
  • Glucagon
75
Q

How is pyruvate kinase regulated?

A

Activators

  • Fructose-1,6-bisphosphate (feedforward activation)
  • Insulin

Inhibitors

  • ATP
  • Alanine
  • Glucagon (by phosphorylating the enzyme via protein kinase A)
76
Q

How is hexokinase regulated?

A

Inhibitors

  • Glucose-6-phosphate (feedback inhibition)
77
Q

How is glucokinase non-hormonally regulated?

A

Glucokinase can be sequestered (inactivated) in the nucleus by binding to glucokinase regulatory protein (GKRP)

GKcyt ⇌ GK–GKRPnuc

  • Glucose activates the reverse reaction (liberation/activation)
  • Fructose-6-phosphate activates the forward reaction (sequestration/inactivation)
78
Q

ATP is an inhibitor of PFK-1, while AMP and fructose-2,6-bisphopshate are activators. How do AMP and F-2,6-BP affect inhibition by ATP?

A
  • Increasing [ATP] past a certain point usually causes steep, immediate inhibition of PFK-1
  • AMP and F-2,6-BP slow down the inhibiting effect of ATP
79
Q

What is the mechanism of insulin as a promoter of PFK-1?

A
  • High insulin:glucagon reduces [cAMP] and inactivates protein kinase A
  • Reduced protein kinase A activity favores dephosphorylation of the bifunctional enzyme PFK-2
  • Dephosphorylated PFK-2 functions as a kinase, producing fructose-2,6-bisphosphate
  • F-2,6-BP is an activator of PFK-1
80
Q

What is the mechanism of glucagon as an inhibitor of PFK-1?

A
  • Low insulin:glucagon increases [cAMP] and activates protein kinase A
  • Activated protein kinase A phosphorylates the bifunctional enzyme PFK-2
  • Phosphorylated PFK-2 functions as a phosphatase, degrading fructose-2,6-bisphosphate
  • F-2,6-BP is an activator of PFK-1, so its decreased concentration removes the activation of PFK-1
81
Q

What tissues/organs require a continuous supply of glucose as a metabolic fuel?

A
  • Brain
  • RBCs
  • Kidney medulla
  • Lens of the eye
  • Cornea of the eye
  • Testes
  • Exercising muscle
82
Q

What are the sources of blood glucose in the fasting state?

A
  • Glycogenolysis in the liver
  • Gluconeogenesis in the liver and kidneys
83
Q

Where does gluconeogenesis occur?

A
  • Liver (90% in an overnight fast, 60% in prolonged fasting)
  • Kidneys (10% in an overnight fast, 40% in prolonged fasting)
84
Q

What is gluconeogenesis?

A

The synthesis of glucose from non-carbohydrate sources

85
Q

What are the substrates that can enter gluconeogenesis?

A
  • As pyruvate: some glucogenic amino acids; lactate
  • As oxaloacetate: some glucogenic amino acids; propionate (propanoate)
  • As triose phosphates: glycerol (from triacylglycerols or otherwise)
86
Q

How do glucogenic amino acids contribute to gluconeogenesis?

A
  • They are converted to α-ketoacids, e.g. α-ketoglutarate
  • The α-ketoacids enter the Krebs cycle and form oxaloacetate
  • Oxaloacetate is an intermediate of gluconeogenesis
87
Q

How does glycerol contribute to gluconeogenesis?

A
  • Glycerol is phosphorylated by glycerol kinase to glycerol-3-phosphate
  • Glycerol-3-phosphate is oxidized by glycerol-3P dehydrogenase to dihydroxyacetone phosphate, an intermediate of glycolysis and gluconeogenesis
88
Q

Give the opposite process of each of the following:

  • Glycolysis
  • Glycogenolysis
A
  • Gluconeogenesis
  • Glycogenesis
89
Q

Give the opposite process of each of the following:

  • Gluconeogenesis
  • Glycogenesis
A
  • Glycolysis
  • Glycogenolysis
90
Q

How many reactions of gluconeogenesis are unique (i.e. not shared by glycolysis)?

A

Four (steps 1, 2, 9, and 11)

91
Q

How many steps are there in gluconeogenesis?

92
Q

What is the energy investment of gluconeogenesis (per one molecule of glucose synthesized)?

A

2 GTP + 4 ATP (⇒ 6 NTP total)

93
Q

Why is gluconeogenesis not the exact opposite of glycolysis in mechanism?

A

Glycolysis has three irreversible steps which must be reversed via other mechanisms

94
Q

What is the first unique step of gluconeogenesis (step 1 overall)?

A

pyruvate + CO2 + ATP → oxaloacetate + ADP + Pi
Catalyzed by pyruvate carboxylase; biotin as a coenzyme

95
Q

In step 1 of gluconeogenesis, pyruvate is combined with CO2. What is ATP used for?

A

Activating the CO2 and binding it to biotin. No phosphorylation takes place

96
Q

What is the second unique step of gluconeogenesis (step 2 overall)?

A

oxaloacetate + GTP → phosphoenolpyruvate + CO2 + GDP
Catalyzed by PEP-carboxykinase

97
Q

The second step of gluconeogenesis (formation of phosphoenolpyruvate) must occur in the cytosol, but some of the oxaloacetate for this reaction is found in the mitochondria. How is this oxaloacetate transported to the cytosol?

A
  • In the mitochondrion, oxaloacetate is reduced to malate by malate dehydrogenasemit
  • Malate can be transported to the cytosol by a specific translocase
  • In the cytosol, malate is oxidized back to oxaloacetate by malate dehydrogenasecyt

oxaloacetate + NADH ⇌ malate + NAD+

98
Q

Biotin participates in the first step of gluconeogenesis. How is biotin associated with the enzyme (pyruvate carboxylase)?

A

Covalently bound to the ε-amino group of a Lys residue in the enzyme

99
Q

What is the third unique step of gluconeogenesis (step 9 overall)?

A

fructose-1,6-bisphosphate + H2O → fructose-6-phosphate + Pi
Catalyzed by fructose-1,6-bisphosphatase

100
Q

What is the fourth unique step of gluconeogenesis (step 11 overall)?

A

glucose-6-phosphate + H2O → glucose + Pi
Catalyzed by glucose-6-phosphatase

101
Q

The final step of glycolysis, liberation of free glucose, occurs in the endoplasmic reticulum. How are the substrates and products transported?

A
  • Glucose-6-phosphate translocase transports G-6P into the ER
  • GLUT-7 transports glucose out of the ER
102
Q

What enzymes of gluconeogenesis are regulated?

A
  • Pyruvate carboxylase
  • Fructose-1,6-bisphosphatase
103
Q

How is pyruvate carboxylase regulated?

A

Allosteric activators

  • Elevated acetyl CoA levels

Allosteric inhibitors

  • Low acetyl CoA levels
104
Q

How is fructose-1,6-bisphosphatase regulated?

A

Inhibitors

  • Fructose-2,6-bisphosphate

Activators

  • Glucagon (by affecting formation of F-2,6-BP)
105
Q

What is the mechanism of glucagon as an activator of fructose-1,6-bisphosphatase?

A
  • Low insulin:glucagon increases [cAMP] and activates protein kinase A
  • Activated protein kinase A phosphorylates the bifunctional enzyme PFK-2
  • Phosphorylated PFK-2 functions as a phosphatase, degrading fructose-2,6-bisphosphate
  • F-2,6-BP is an inhibitor of F-1,6-bisphosphatase, so its decreased concentration removes the activation of F-1,6-bisphosphatase
106
Q

How does glucagon function in the overall regulation of gluconeogenesis?

A
  • Decreasing inhibition of fructose-1,6-bisphosphatase
  • Inhibition of pyruvate kinase, which slows glycolysis, allowing gluconeogenesis to predominate
  • Induction of the synthesis of the gene for PEP-carboxykinase
107
Q

Why is glycogenolysis preferred over gluconeogenesis as an immediate source of glucose in the fasting state?

A

Glycogenolysis is more rapid than gluconeogenesis

108
Q

What is the structure of glycogen

A
  • A homopolysaccharide of glucose
  • Each chain is formed of α(1→4) glycosidic bonds
  • Every 8–10 glucosyl residues, there is a branch, formed by a single α(1→6) glycosidic bond
  • A single glycogen molecule can contain hundreds of thousands of glucosyl residues, up to 108 Da
109
Q

Where are the primary stores of glycogen?

A
  • 400 g in resting skeletal muscle (1–2% of fresh weight)
  • 100 g in the well-fed adult liver (10% of fresh weight)
110
Q

How are the stores of glycogen affected by fasting?

A
  • Liver glycogen: depleted during a fast
  • Skeletal muscle glycogen: not affected by short fasts (a few days), moderately decreased in prolonged fasts (weeks)
111
Q

What is the result of glycogenolysis, as it occurs in both skeletal muscle and the liver?

A
  • Glucose-1-phosphate from breaking α(1→4) bonds
  • Free glucose from breaking each α(1→6) bond
112
Q

How are the straight chains of glycogen shortened in glycogenolysis?

A
  • Glycogen phosphorylase removes a glucosyl residue from the nonreducing ends by simple phosphorolysis (in the absence of ATP), breaking a α(1→4) glycosidic bond
  • The glucose residue is liberated as glucose-1-phosphate
  • This continues until there are 4 glucosyl units before the branching point—this is the limit dextrin
113
Q

What is the structure of a limit dextrin?

A

Four glucosyl residues (with a nonreducing end) before a branching point

114
Q

How does debranching occur in glycogenolysis?

A
  • The branch is shortened to 4 residues, including the one attached to the main chain
  • A bifunctional debranching enzyme removes the outer 3 residues (breaking an α(1→4) bond) and attaches them to the nonreducing end of the main chain (forming an α(1→4) bond). This is 4:4 transferase activity
  • The same bifunctional debranching enzyme breaks the remaining α(1→6) bond, liberating the last residue of the branch as free glucose. This is α(1→6)-glucosidase activity
115
Q

What are the two functions of the bifunctional debranching enzyme in glycogenolysis?

A
  • 4:4 transferase: the enzyme moves the 3 outer residues of a branch to the main chain, breaking and reforming an α(1→4) bond
  • α(1→6)-glucosidase: the enzyme breaks the α(1→6) bond joining the last branch residue to the branching point of the main chain, releasing free glucose
116
Q

What is the fate of glucose-1-phosphate formed in glycogenolysis?

A

glucose-1-phosphate → glucose-6-phosphate
Catalyzed by phosphoglucomutase, in the cytosol

117
Q

How does glycogenolysis differ in liver and skeletal muscle cells?

A

Liver

  • Glucose-6-phosphate is transported into the ER by glucose-6P translocase, where it is dephosphorylated by glucose-6-phosphatase
  • Free glucose is released from the ER by GLUT 7

Skeletal muscle

  • Lacks glucose-6-phosphatase, so free glucose is never produced. Instead G-6P can enter glycolysis
  • This is why skeletal muscle cannot release glucose into the blood
118
Q

What is glycogen synthesized from in glycogenesis?

A
  • α-ᴅ-glucose attached to UDP
  • A glycogen fragment or the protein glycogenin
119
Q

How is UDP-glucose formed for use in glycogenesis?

A

glucose-1-phosphate + UTP ⇌ UDP–glucose + PPi
Catalyzed by UDP-glucose pyrophosphorylase

The PPi is released from UTP. The phosphate group in glucose-1P is preserved

120
Q

What is the fate of the the pyrophosphate (PPi) produced in the formation of UDP-glucose?

A

PPi → 2Pi

  • Catalyzed by pyrophosphatase
  • This is necessary to keep the equilibrium of the UDP-glucose phosphorylase reaction in favor of UDP-glucose formation
121
Q

What is the main enzyme responsible for synthesizing glycogen?

A

Glycogen synthase

122
Q

What acts as the acceptor of UDP-glucose in glycogenolysis?

A
  • A glycogen fragment
  • Glycogenin, in the absence of a glycogen fragment
123
Q

How does glycogenin facilitate the formation of a glycogen fragment?

A
  • The –OH of a Tyr residue accepts a glucose residue from UDP-glucose (catalyzed by glycogenin itself via autoglucosylation)
  • Glycogenin catalyzes the transfer of the next few molecules of glucose from UDP-glucose, until a short chain is formed
124
Q

How is a glycogen chain elongated?

A

UDP-glucose + glycogen(n) ⇌ glycogen(n+1) + UDP
Catalyzed by glycogen synthase, forming an α(1→4) bond

125
Q

How are branches created in a glycogen molecule?

A
  • A branching enzyme removes 6–8 glucosyl residues from the nonreducing end of the main glycogen branch, breaking an α(1→4) bond
  • The branching enzyme adds the 6–8 residues to a non-terminal glucosyl residue, creating an α(1→6) bond
  • This is 4:6 transferase activity
  • Both of the nonreducing ends formed are elongated by glycogen synthase
126
Q

What are the general properties of glycogen storage diseases?

A
  • Genetic diseases
  • Cause a defect or deficiency in an enzyme required for glycogen synthesis or degradation
  • Cause accumulation of excessive amounts of normal glycogen (if degradation is affected) or abnormal glycogen (if synthesis is affected)
  • Can affect one or more tissue
  • Range in severity from fatal in infancy to mild disorder throughout life
127
Q

What are the types of glycogen storage diseases?

A
  • Type Ia: von Gierke disease (glucose-6-phosphatase deficiency)
  • Type Ib: glucose-6-phosphate translocase deficiency
  • Tye II: Pompe disease (lysosomal α(1→4)-glucosidase deficiency)
  • Type V: McArdle syndrome (muscle glycogen phosphorylase deficiency)
128
Q

Which type of glycogen storage disease is a lysosomal storage disease?

A

Type II (Pompe disease)

129
Q

How is glycogen degraded other than by glycogenolysis in the cytosol?

A

1–3% is degraded in lysosomes by lysosomal α(1→4)-glucosidase (acid maltase)

130
Q

What is the biochemical cause of type Ia glycogen storage disease (von Gierke disease)?

A

Deficiency in glucose-6-phosphatase prevents liberation of free glucose in the liver, kidneys, and intestines

131
Q

What is the cause of type Ib glycogen disease?

A

Deficiency in glucose-6-phosphate translocase prevents liberation of free glucose in the liver, kidneys, and intestines

132
Q

What are the clinical manifestations of type I glycogen storage diseases?

A
  • Affect the liver, kidneys, and intestine
  • Cause severe fasting hypoglycemia
  • Fatty liver, hepatomegaly, renomegaly
  • Progressive renal disease
  • Growth retardation and delayed puberty
  • Normal glycogen structure, but excess glycogen storage
133
Q

What is the biochemical cause of type V glycogen storage disease (McArdle syndrome)?

A

Deficiency of glycogen phosphorylase in skeletal muscle

134
Q

What are the clinical manifestations of type V glycogen storage disease?

A
  • Only skeletal muscle cells are affected
  • Weakness and cramping of the muscle after exercise
  • No increase in lactate levels during exercise
135
Q

What is the biochemical cause of type II glycogen storage disease (Pompe disease)?

A

Deficiency in lysosomal α(1→4)-glucosidase

136
Q

What are the clinical manifestations of type II glycogen storage disease?

A
  • Affects liver, muscle, and heart
  • Excessive glycogen found in abnormal vacuoles in the lysosomes
  • Normal blood sugar levels
  • Normal glycogen structure
  • Massive cardiomegaly
  • Early death from heart failure
137
Q

How is glycogenolysis hormonally regulated?

A

Activators

  • Glucagon
  • Epinephrine

Inhibitors

  • Insulin
138
Q

What is the mechanism of glucagon/epinephrine as activators of glycogenolysis?

A
  • Glucagon/epinephrine activate Gαs, increasing [cAMP]
  • cAMP activates protein kinase A
  • Protein kinase A phosphorylates glycogen phosphorylase to glycogen phosphorylase a
  • Glycogen phosphorylase a is active, so glycogen is degraded
139
Q

What is the mechanism of insulin as an inhibitor of glycogenolysis?

A
  • Insulin activates phosphodiesterase, decreasing [cAMP], so protein kinase A is gradually inactivated
  • Insulin activates protein phosphatase 1, which dephosphorylates glycogen phosphorylase to glycogen phosphorylase b
  • Glycogen phosphorylase b is inactive, so glycogen is not degraded
140
Q

How is glycogenesis hormonally regulated?

A

Activators

  • Insulin

Inhibitors

  • Glucagon
  • Epinephrine
141
Q

What is the mechanism of glycogen and epinephrine as inhibitors of glycogenesis?

A
  • Glucagon/epinephrine activate Gαs, increasing [cAMP]
  • cAMP activates protein kinase A
  • Protein kinase A phosphorylates glycogen synthase to glycogen synthase b
  • Glycogen synthase b is inactive, so glycogen is not synthesized
142
Q

What is the mechanism of insulin as an activator of glycogenesis?

A
  • Insulin activates phosphodiesterase, decreasing [cAMP], so protein kinase A is gradually inactivated
  • Insulin activates protein phosphatase 1, which dephosphorylates glycogen synthase to glycogen synthase a
  • Glycogen synthase a is active, so glycogen is synthesized
143
Q

How is glycogen phosphorylase allosterically regulated?

A

Activators

  • AMP (in muscle only)

Inhibitors

  • Glucose-6-phosphate
  • ATP
  • Glucose (in liver only)
144
Q

How is glycogen synthase allosterically regulated?

A

Activators

  • Glucose-6-phosphate (in well-fed state only)
145
Q

What is the role of calcium in regulation of glycogen metabolism?

A

Calmodulin

  • Ca2+ is released from the ER in response to hormones or neurotransmitters
  • Ca2+ binds to calmodulin, forming the calmodulin-Ca2+ complex
  • The calmodulin-Ca2+ complex activates phosphorylase kinase (without phosphorylation), which activates glycogen phosphorylase
  • The calmodulin-Ca2+ complex activates a calmodulin-dependent protein kinase, which inactivates glycogen synthase

PKC

  • Binding of a hormone/neurotransmitter (e.g. epinephrine) to its GPCR stimulates Gαq, which activates phospholipase C
  • Phospholipase C leads to formation of DAG in the membrane and release of IP3
  • IP3 leads to release of Ca2+ from the ER
  • Ca2+ and DAG activate protein kinase C
  • Protein kinase C inactivates glycogen synthase
146
Q

Where is alcohol metabolized?

147
Q

What are the pathways of alcohol oxidation?

A
  • The ADH/ALDH pathway, producing acetaldehyde or acetate
  • Microsomal ethanol oxidizing system (MEOS), producing acetaldehyde
  • Catalase-dependent oxidation, producing acetaldehyde (in the peroxisome)
148
Q

What is step 1 of the main process of alcohol oxidation in the liver?

A

ethanol + NAD+ → acetaldehyde + NADH

  • Catalyzed by alcohol dehydrogenase (ADH)
  • Acetaldehyde is toxic
149
Q

What is step 2 of the main process of alcohol oxidation in the liver?

A

acetaldehyde + NAD+ → acetate + NADH

  • Catalyzed by acetaldehyde dehydrogenase (ALDH)
  • 90% of acetaldehyde is oxidized this way
150
Q

What is the fate of acetate in the liver produced by ALDH

A

Activated to acetyl CoA for use in the Krebs cycle or fatty acid synthesis

151
Q

What is the major fate of acetate produced by ALDH?

A
  • Transport in the blood to the heart and skeletal muscle
  • acetate + ATP + CoA-SH → acetyl CoA + AMP + PPi
  • Catalyzed by acetyl-CoA synthetase
152
Q

What happens when a large amount of alcohol is oxidized?

A

High ratio of NADH to NAD+, leading to:

  • Inhibition of gluconeogenesis
  • Lactic acidosis
  • Inhibition of fatty acid oxidation
153
Q

What is the microsomal ethanol oxidizing system (MEOS)?

A

ethanol + NADPH + H+ + O2 → acetaldehyde + NADP+ + 2H2O

  • Catalyzed by cytochrome P450 2E1 (CYP2E1), a high Km enzyme inducible by alcohol
  • CYP2E1 is a major cause of oxidative stress by producing ROS like H2O2, HER∙, O2∙–
154
Q

What is the alcohol–catalase mechanism?

A

ethanol + H2O2 → acetaldehyde + H2O

  • Catalyzed by peroxisomal catalase
  • Catalase is found in all tissues, but is dependent on cellular levels of hydrogen peroxide
  • Catalase is also found in cells of the normal flora, leading to acetaldehyde production in the lower GI tract
155
Q

What is the genetic variation in the enzymes involved in alcohol metabolism?

A
  • ADH, ALDH, and CYP2E1 exist as families of isozymes
  • ADH exists as 5 isozymes, each produced in a different tissue (e.g. liver, lung, stomach, esophagus)
  • People inherit different sets of ADH isozymes. E.g. African Americans have an isoform with a high Vmax

Metabolism (6 decks)

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