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Metabolism > Carbohydrate metabolism (final exam) > Flashcards

Carbohydrate metabolism (final exam) Flashcards

Metabolism of monosaccharides and disaccharides, pentose-phosphate pathway

1
Q

What are the major sources of dietary fructose?

A
  • Sucrose
  • Free monosaccharide in many fruits, in honey, and in high-fructose corn syrup
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2
Q

What distinguishes uptake of fructose into cells from uptake of glucose?

A

It is not insulin-dependent

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3
Q

What is the major metabolic fate of fructose?

A

Conversion to DHAP, GA3P, and glyceraldehyde for use in glycolysis/gluconeogenesis, as well as other pathways

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4
Q

What is the first step of fructose metabolism?

A

(1) fructose + ATP → fructose-1-phosphate + ADP, OR
(2) fructose + ATP → fructose-6-phosphate + ADP

(1): catalyzed by fructokinase
(2): catalyzed by hexokinase

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5
Q

What are the two enzymes that catalyze the phosphorylation of fructose?

A
  • Hexokinase
  • Fructokinase
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6
Q

What are the differences between fructokinase and hexokinase in the phosphorylation of fructose?

A

Fructokinase

  • Produces fructose-1-phosphate
  • Found in the liver, kidney, and small intestinal mucosa

Hexokinase

  • Produces fructose-6-phosphate
  • Has a high Km, so it does not function unless intracellular fructose levels are high
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7
Q

What is the fate of fructose-1-phosphate?

A

fructose-1-phosphate ⇌ glyceraldehyde + dihydroxyacetone phosphate
Catalyzed by *aldolase B *

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8
Q

What is the fate of fructose-6-phosphate?

A

Continues through glycolysis normally

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9
Q

What are the different aldolases?

A
  • Aldolase A: found in most tissues; cleaves F-1,6-BP only
  • Aldolase B: found in the liver; cleaves F-1,6-BP AND F-1-P
  • Aldolase C: found in the brain; cleaves F-1,6-BP only
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10
Q

Which is faster: glycolysis, or fructose metabolism (which eventually merges with glycolysis)?

A

Fructose metabolism, because the trioses formed from fructose-1-phosphate bypass PFK-1, the rate-limiting step of glycolysis

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11
Q

What are the features of essential fructosuria?

A
  • Deficiency in fructokinase
  • Autosomal recessive
  • Benign condition
  • Fructose accumulates in the urine
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12
Q

Deficiency in which enzyme results in essential fructosuria?

A

Fructokinase

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13
Q

Deficiency in which enzyme results in hereditary fructose intolerance (HFI)?

A

Aldolase B

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14
Q

What are the features of hereditary fructose intolerance (HFI)?

A
  • Autosomal recessive
  • Absence of aldolase B
  • Symptoms begin when baby is weaned off milk and is fed food containing sucrose or fructose
  • F-1P begins to accumulate, resulting in a drop in levels of ATP and Pi
  • As ATP levels fall, AMP levels rise, and AMP is eventually degraded, resulting in hyperuricemia and lactic acidosis
  • Decreased availability of hepatic ATP affects gluconeogenesis and plasma protein synthesis and may lead to liver failure
  • Symptoms: severe hypoglycemia, vomiting, jaundice, hemorrhage, hepatomegaly, renal dysfunction, hyperuricemia, lacticacidemia
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15
Q

How is hereditary fructose intolerance treated?

A

Sucrose, sorbitol, and fructose must be removed from the diet to prevent liver failure

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16
Q

How is glucose converted to sorbitol?

A

glucose + NADPH + H+ → sorbitol + NADP+
Catalyzed by aldose reductase

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17
Q

Where in the body is sorbitol produced?

A
  • Lens
  • Retina
  • Schwann cells of peripheral nerves
  • Liver
  • Kidney
  • Placenta
  • RBCs
  • Ovaries and seminal vesicles
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18
Q

How is sorbitol converted to fructose?

A

sorbitol + NAD+ (or NADP+) → fructose + NADH (or NADPH)
Catalyzed by sorbitol dehydrogenase

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19
Q

Where in the body is sorbitol reduced to fructose?

A
  • Liver
  • Ovaries
  • Seminal vesicles
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20
Q

How is sorbitol implicated in cell swelling?

A
  • During hyperglycemia, glucose enters the cells containing aldose reductase freely, as they do not use the insulin-sensitive GLUT-4
  • High intracellular glucose levels accompanied with adequate NAPH/NADH cause aldose reductase to produce a high amount of sorbitol
  • Sorbitol cannot pass through cell membranes and is trapped inside the cell, causing uptake of whater by osmosis
  • Water retention occurs
  • This problem is exacerbated when the tissue does not contain sorbitol dehydrogenase, e.g. the lens, nerves, retina, and kidneys
  • Some of the pathologic changes in diabetes can be attributed to this phenomenon, e.g. cataracts, peripheral neuropathy, microvascular problems leading to nephropathy and retinopathy
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21
Q

What are the major sources of galactose?

A
  • Milk and milk products
  • Degradation of complex carbohydrates, e.g. glycoproteins and glycolipids in cell membranes
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22
Q

What is the first step of galactose metabolism?

A

galactose + ATP → galactose-1-phosphate + ADP
Catalyzed by galactokinase

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23
Q

How is galactose-1-phosphate converted to UDP-galactose?

A

UDP-glucose + galactose-1-phosphate ⇌ UDP-galactose + glucose-1-phosphate
Catalyzed by galactose-1-phosphate uridyltransferase (GALT)

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24
Q

What are the fates of UDP-galactose?

A
  • Converted to UDP-glucose by UDP-hexose 4-epimerase for use in glucose metabolism
  • Donor of galactose units in synthetic pathways of lactose, glycoproteins, glycolipids, and glycosaminoglycans
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25
Q

What are the disorders of fructose metabolism?

A
  • Essential fructosemia (fructokinase deficiency)
  • Hereditary fructose intolerance (aldolase B deficiency)
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26
Q

What are the disorders of galactose metabolism?

A
  • Galactokinase deficiency
  • Classic galactosemia (GALT deficiency)
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27
Q

What are the features of galactokinase deficiency?

A
  • Elevation of galactose in blood (galactosemia) and urine (galactosuria)
  • Causes galactitol accumulation if galactose is present in the diet, leading to cataracts
  • Treated by dietary restriction
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28
Q

What are the features of classic galactosemia?

A
  • GALT deficiency
  • Autosomal recessive
  • Causes galactosemia, galactosuria, vomiting, diarrhea, and jaundice
  • Accumulation of Gal-1P and galactitol in nerve, lens, liver, and kidney tissue causes liver damage, severe mental retardation, and cataracts
  • Treated by rapid diagnosis and removal of galactose (and therefore lacose) from the diet
  • Despite adequate treatment, patients are at risk for developmental delays and premature ovarian failure
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29
Q

What is the structure of lactose?

A

Gal-β(1→4)-Glc

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30
Q

Where in the cell is lactose synthesized?

A

Golgi apparatus

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31
Q

What is the enzyme that is used to synthesize lactose?

A

Lactose synthase (UDP-galactose:glucose galactosyltransferase), composed of:

  • Protein A (β-ᴅ-galactosyltransferase), an enzyme
  • Protein B (α-lactalbumin), which is not an enzyme
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32
Q

How is lactose synthesis confined to the mammary glands?

A

Synthesis of α-lactalbumin (protein B) only occurs in response to prolactin in the lactating mammary glands. Protein B forms a complex with the enzyme, protein A, changing the specificity of the transferase so lactose is synthesized instead of N-acetyllactosamine

33
Q

What is the activity of lactose synthase in tissues other than lactating mammary glands?

A

UDP-galactose + N-acetyl-ᴅ-glucosamine → N-acetyllactosamine + UDP

  • Contains the same β(1→4) bond
  • N-acetyllactosamine is a component of N-linked glycoproteins
34
Q

How is glucuronate produced?

A

(1) glucose-1-phosphate ⇌ UDP-glucose
(2) UDP-glucose + NAD+ → UDP-glucuronic acid + NADH

(1): catalyzed by pyrophosphorylase
(2): catalyzed by UDP-glucose dehydrogenase

35
Q

What is the fate of UDP-glucuronic acid?

A
  • Conversion to UDP-xylose for use in the pentose phosphate pathway
  • Precursor for glycosaminoglycans
36
Q

What are the main products of the pentose phosphate pathway?

A
  • NADPH for reductive biosynthesis
  • Ribose-5-phosphate for nucleic acid biosynthesis
  • Glycolytic intermediates (as byproducts)
37
Q

Where in the body is the irreversible, oxidative portion of the pentose phosphate pathway particularly important?

A
  • Liver, lactating mammary glands, adipose tissue: active in fatty acid biosynthesis
  • Testes, ovaries, placenta, adrenal cortex: active in biosynthesis of steroid hormones
  • Erythrocytes: use NADPH to keep glutathione reduced
38
Q

What is the first step of the pentose phosphate pathway?

A

glucose-6-phosphate + NADP+ + H2O ⇌ 6-phosphogluconate + NADPH + H+

Catalyzed by glucose-6-phosphate dehydrogenase (G6PD)

39
Q

What is the second step of the pentose phosphate pathway?

A

6-phosphogluconate + NADP+ ⇌ ribulose-5-phosphate + NADPH + H+ + CO2

Catalyzed by 6-phosphogluconate dehydrogenase

40
Q

What is the slow, rate-determining step of the pentose phosphate pathway?

A

The first step, catalyzed by G6PD (oxidation of glucose)

41
Q

How is glucose-6-phosphate dehydrogenase regulated?

A

Activators

Insulin: upregulates expression of G6PD in the well-fed state

Inhibitors

NADPH

42
Q

How does insulin function as an activator of the pentose phosphate pathway?

A

Upregulates expression of G6PD in the well-fed state

43
Q

How many molecules of glucose-6-phosphate are needed to complete the reversible, nonoxidative reactions of the pentose phosphate pathway?

A

Three:

  • One to produce ribose-5-phosphate for the first transfer reaction
  • One to produce xylulose-5-phosphate for the first transfer reaction
  • One to produce an additional xylulose-5-phosphate for the final transfer reaction
44
Q

What are the enzymes used in the reversible, nonoxidative reactions of the pentose phosphate pathway?

A
  • Transketolase: transfers 2-carbon units
  • Transaldolase: transfers 3-carbon units
  • A ribulose epimerase
  • A ribulose isomerase
45
Q

What is the sequence of transfer reactions in the reversible, nonoxidative phase of the pentose phosphate pathway?

A

[ketose + aldose ⇌ aldose + ketose] (number of carbons equals the position of the phosphate)

  • xylulose-5-phosphate + ribose-5-phosphate ⇌ glyceraldehyde-3-phosphate + sedoheptulose-7-phosphate (∆2C)
  • sedoheptulose-7-phosphate + glyceraldehyde-3-phosphate ⇌ erythrose-4-phosphate + fructose-6-phosphate (∆3C)
  • xylulose-5-phosphate + glyceraldehyde-3-phosphate ⇌ glyceraldehyde-3-phosphate + fructose-6-phosphate (∆2C)
46
Q

How is ribulose-5-phosphate modified in the pentose phosphate pathway?

A
  • Isomerized to ribose-5-phosphate by an isomerase
  • Epimerized to xylulose-5-phosphate (a C3 epimer) by an epimerase
47
Q

Using G6P to represent all hexose sugar units, what is the stoichiometry of the pentose phosphate pathway?

A

3G6P + 6NADP+ ⇌ 2G6P + GA3P + 6NADPH + 3CO2

If we progress through the reactions twice, we obtain:
6G6P + 12NADP+ ⇌ 4G6P + 2GA3P + 12NADPH + 6CO2

Two molecules of GA3P can be simplified to glucose (as would happen in gluconeogenesis), therefore:
6G6P + 12NADP+ ⇌ 5G6P + 12NADPH + 6CO2

tldr; for every 6 molecules of glucose, 5 are preserved as hexoses, and 1 is lost as 6CO2

48
Q

Where in the structure of NADPH is the phosphate?

A

2’ of the adenylyl ribose

49
Q

What is the ratio of NADP+ to NADPH in hepatocytes?

A

1:10 (0.1)

50
Q

What is the ratio of NAD+ to NADH in hepatocytes?

A

1000:1

51
Q

What are the uses of NADPH in the cell?

A
  • Reductive biosynthesis
  • Reduction of ROS
  • Coenzyme for cytochrome P450
  • Production of ROS in the oxidative burst of phagocytes
  • Synthesis of NO
52
Q

What are the sources of ROS in the cell?

A
  • Byproducts of aerobic metabolism:
    • Produced accidentally by CoQ in the ETC
    • Produced intentionally in the oxidative burst of phagocytes
    • Produced accidentally by the cytochrome P450 system
  • Ionizing radiation
53
Q

What kinds of ROS are produced by CoQ in the ETC?

A

O2∙–

54
Q

What kinds of ROS are produced in the oxidative burst?

A
  • O2∙–
  • H2O2
  • OH∙
  • HOCl
55
Q

What kinds of ROS are produced by ionizing radiation?

A

OH∙

56
Q

What kinds of molecules are damaged by ROS?

A
  • DNA
  • Proteins
  • Unsaturated lipids
57
Q

Which pathologic processes have ROS been implicated in?

A
  • Reperfusion injury
  • Cancer
  • Inflammatory disease
  • Aging
58
Q

What are the intracellular mechanisms of neutralizing ROS?

A
  • Glutathione peroxidase
  • Catalase
  • Superoxide dismutase
  • Antioxidant chemicals
59
Q

What is the structure of glutathione?

A

Gly-Cys-Glu

60
Q

How does glutathione neutralize ROS?

A

2G-SH + H2O2 → G-S–S-G + H2O
Catalyzed by glutathione peroxidase

61
Q

How is reduced glutathione regenerated after its oxidation?

A

G-S–S-G + NADPH → 2G-SH + NADP+
Catalyzed by glutathione reductase

62
Q

Which chemicals are antioxidants?

A
  • Ascorbate (vitamin C)
  • Vitamin E
  • Carotenoids
63
Q

What is the general reaction of cytochrome P450?

A

R-H + O2 + NADPH → R-OH + H2O + NADP+,
where R may be a steroid, drug, or other chemical

64
Q

What are the different cytochrome P450 systems?

A
  • Mitochondrial
  • Microsomal
65
Q

What is the function of the mitochondrial cytochrome P450 system?

A

Synthesis of steroids, bile acids, and the active forms of vitamin D

66
Q

What is the function of the microsomal cytochrome P450 system?

A
  • Detoxification of foreign compounds
  • Activation or inactivation of drugs
  • Solubilization for excretion in the urine or feces
67
Q

What are the enzymes used in the oxidative burst?

A
  • NADPH oxidase: produces superoxide
  • Superoxidase dismutase: produces hydrogen peroxide
  • Myeloperoxidase: uses hydrogen peroxide to produce HOCl
  • Nitric oxide synthase: produces NO for conversion to ONOO–
68
Q

What are the isozymes of NO synthase?

A
  • Endothelial (eNOS): constitutive in endothelial cells
  • Neural (nNOS): constitutive in neural tissue
  • Inducible (iNOS): induced in macrophages in response to cytokines or bacterial endotoxins
69
Q

How is NO synthesized?

A

ʟ-arginine + O2 + NADPH → ʟ-citrulline + NO + NADP+
Catalyzed by NO synthase

70
Q

What are the functions of NO?

A
  • Smooth muscle relaxant
  • Prevents platelet aggregation
  • Functions as a neurotransmitter in the brain
  • Medidates tumoricidal and bactericidal actions of macrophages
71
Q

How does NO relax smooth muscles?

A
  • NO is produced in the endothelial cells by eNOS
  • NO diffuses into vascular smooth muscle cells and activates cytosolic guanylyl cyclase
  • cGMP is produced
  • cGMP activates protein kinase G
  • Protein kinase G phosphorylates Ca2+ channels, causing decreased calcium entry
  • Decreased Ca2+ levels decrease smooth muscle contraction
72
Q

How is G6PD deficiency inherited?

A

X-linked

73
Q

What kind of mutation causes G6PD deficiency?

A
  • Usually a point mutation leading to missense
  • It is caused by one of more than 400 different mutations, not all of which lead to disease
74
Q

What is the epidemiology of G6PD deficiency?

A

200–400 million people are affected worldwide. Prevalent in:

  • Middle East
  • Tropical Africa
  • Southeast Asia
  • Mediterranean
75
Q

What are the symptoms of G6PD deficiency?

A
  • Hemolytic anemia
  • Resistance to falciparum malaria
76
Q

What are the precipitating factors in G6PD deficiency?

A
  • Oxidant drugs (AAA):
    • Antibiotics: e.g. sulfamethoxazole
    • Antimalarials: e.g. primaquine
    • Antipyretics: e.g. acetanilid
  • Favism due to vicine and covicine in fava beans (doesn’t affect all patients)
  • Infection and generation of an oxidative burst
  • Neonatal jaundice
77
Q

What is the pathogenesis of hemolytic anemia in G6PD deficiency?

A
  • The deficiency leads to low NADPH
  • Low NADPH means oxidized glutathione cannot be reduced, leading to accumulation of ROS
  • Glutathione also functions in keeping the thiol (—SH) groups of proteins in the reduced state, e.g. in hemoglobin, so loss of glutathione activity causes denaturation
  • The RBC becomes more rigid
78
Q

What are the variants of G6PD deficiency?

A
  • B is the wild type
  • Mediterranean variant B– (class II) is due to a point mutation at bp 563 (C→T) with severe, episodic hemolytic anemia
  • African variant A– (class III) is due to 2 point mutations with moderate disease
  • African variant A (class IV) causes normal activity
  • Class I has very severe, chronic hemolytic anemia

Metabolism (6 decks)

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