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MSK Week 4 > 2.4.4. Fructose and Galactose Metabolism AND Pentose Pathway > Flashcards

2.4.4. Fructose and Galactose Metabolism AND Pentose Pathway Flashcards

1
Q

What is the helpful mnemonic FABGUT mean?

A

Fructose is to Aldolase B as Galactose is to UridylTransferase (FAB GUT)

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2
Q

Where in the body do we find Aldolase B? What about Aldolase A?

A

Aldolase B is in the liver, renal cortex, and intestinal cells. Aldolase A is in the muscle

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3
Q

What is the first step we take in converting fructose to glycolysis intermediates?

A

phosphorylation by fructokinase

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4
Q

Describe the second step of turning fructose into glycolysis intermediates which starts with Fructose-1-P

A

Second step (rate-limiting) = glyceraldehyde + DHAP (like glycolysis) are made by using Aldolase B on Fructose-1-P

DHAP can enter glycolysis immediately after this step

Glyceraldehyde must be converted to G-3-P by triose kinase before it can enter glycolysis

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5
Q

What are UDP activated sugars?

A

The term “UDP-activated sugars” refers to sugars that have an attached UDP (uridine diphosphate, a nucleoside diphosphate). Think of this like ATP, but with a different nucleic base, and one less phosphate…

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6
Q

What are the three steps that turn Galactose to Glucose-6-phosphate?

A
  1. Galactose → Galactose-1-Phosphate (via galactokinase)- uses ATP
  2. Galactose-1-Phosphate → glucose-1-phosphate (via galactose-1-phosphate uridylyltransferase)
  3. Glucose-1-phosphate → glucose-6-phosphate (via phosphoglucomutase).

NET REACTION: Galactose + ATP → Glucose-6-phosphate + ADP

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7
Q

What does the enzyme epimerase do?

A

UDP-glucose and UDP-galactose can be interconverted by the enzyme “epimerase”

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8
Q

Disorders of which pathway, fructose or galactose, tend to be worse?

A

Disorders of fructose metabolism are clinically more mild than synonymous galactose disorders

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9
Q

What is the hereditary pattern for Essential Fructosemia and what is the associated defect?

A

Autosomal Recessive

hepatic fructokinase can’t convert Fructose to Fructose-1-phosphate

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10
Q

What symptoms do we see with Essential Fructosemia?

A

symptoms: fructosemia (relatively mild), fructosuria after fructose injection. It is mostly a benign condition because fructose is slowly phosphorylated by hexokinase in OTHER tissues and still metabolized via glycolysis.

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11
Q

Hereditary pattern and defect associated with Hereditary Fructose Intolerance?

A

Autosomal Recessive

Defect: aldolase B is defective (liver) and can’t create glyceraldehyde and dihydroxyacetone phosphate (DHAP) from F1P. Ultimately, F1P accumulates and inhibits glucose production, causing severe hypoglycemia if any more fructose is ingested

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12
Q

Effect of Hereditary Fructose Intolerence on Glycolysis as compared to fructose metabolism?

A

Aldolase B can function just fine in GLYCOLYSIS (on F-1,6-BP), BUT NOT in fructose metabolism, since this enzyme is the sole metabolizer of Fructose-1-phosphate

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13
Q

Symptoms of Hereditary Fructose Intolerance? How do we treat it?

A

Vomiting after ingesting fructose

Cirrhosis

Fasting Hypoglycemia

Hepatomegaly

Failure to Thrive

Treatment: Eliminate Fructose from Diet

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14
Q

How does Hereditary Fructose Intolerance cause fasting hypoglycemia?

A

F1P is a competitive inhibitor of glycogen phosphorylase (allows glycogen to be catabolized into glucose) and if F1P accumulates, ATP and Pi are depleted

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15
Q

Where does the defect for galactosemia typically present itself? Where else can it present itself in a less common way?

A

Classic - Defect in the enzyme Galactose-1-phosphate uridylyltransferase that turns Galactose 1-phosphate into glucose1-phosphate. It can also present itself in the first, irreversible, step of this process just before the classic route with a bad galactokinase enzyme that turns Galactose into Galactose 1-Phosphate

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16
Q

Describe Galactose metabolism and indicate where galactosemia typically presents itself.

A
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17
Q

What hereditary pattern and specific defect do we see with classic galactosemia?

A

Autosomal Recessive

Defect: galactose-1-phosphate uridylyltransferase can’t convert galactose-1-phosphate and UDP-glucose into glucose-1-phosphate

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18
Q

What is the main metabolic problem with classic glactosemia and what symptos are associated with it?

A

metabolic effect: Gal-1-P accumulates in the liver, and galactose accumulates in the blood and all tissues

Symptoms and Signs:

  1. Aversion to Milk
  2. Failure to Thrive
  3. Cataracts in babies
  4. Intellectual disability
  5. Hepatomegaly due to high Gal-1-P in the liver causing damage
  6. E.Coli sepsis in neonates
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19
Q

Why is classic galactosemia the most dangerous form?

A

Elevation of Gal-1-P→ inhibits phosphoglucomutase, interfering with glycogen synthesis and degradation

Hypoglycemia can occur after ingestion of galactose (milk and milk products, also “artificial sweeteners” and medication “fillers”)

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20
Q

Treatment for classic galactosemia?

A

treatment: eliminate dietary lactose and galactose

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21
Q

How do we get galactose if we choose not to ingest any?

A
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22
Q

Describe the hereditary pattern and defect associated with non classical galactosemia

A

Autosomal recessive

Defect: galactokinase can’t convert galactose and ATP into galactose-1-phosphate. This naturally-irreversible step is defective

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23
Q

Symptoms of nonclassical galactosemia

A

galactose appears in blood and urine

infantile cataracts

May initially present as failure to track objects or to develop a social smile

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24
Q

Effect of eating a meal and fasting on the conversion of galactose to UDP-glucose and glucose-1-phosphate

A

Fasting: in liver converted to blood glucose

After a meal: in liver converted to glycogen

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25
Q

Function of the enzyme galactosyl transferase

A

the enzyme that adds galactose units to the growing polysaccharide chains is galactosyl transferase

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26
Q

How do mammary glands produce lactose?

A

UDP-galactose reacts with glucose in the lactating mammary gland to produce the milk sugar lactose. Alpha-lactobumin (a modifier protein) binds to galactosyl transferase, lowering its Km for glucose so that glucose adds to galactose, forming lactose

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27
Q

How does Glycerol enter the glycolytic/gluconeogenic pathway?

A

1) glycerol is first converted to glycerol-3-phosphate by glycerol kinase
2) glycerol-phosphate is converted to DHAP by glycerol-3-phosphate dehydrogenase

DHAP can now enter glycolysis as a natural metabolic intermediate

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28
Q

Typical function of the polyol pathway?

A

normally, the polyol pathway converts glucose to fructose

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29
Q

Describe the polyol pathway of converting glucose to fructose

A

1) Aldolase reductase reduces glucose to sorbitol (a sugar-alcohol)

This step OXIDIZES NADPH –> NADP+

2) Sorbitol dehydrogenase oxidizes sorbitol to fructose

NAD+ is reduced to NADH (net energy is conserved b/w these two rxns)

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30
Q

So the Polyol pathway can turn glucose to fructose. Can it do the same for galactose?

A

Not really.

It follows the same first step by turning galactose to galactitol, similar to glucose to sorbitol, but the keto sugar for galactose never gets produced because sorbitol dehydrogenase can’t oxidize galactitol and there is no separate enzyme.

31
Q

Discuss the pros and cons of administering intravenous fructose to diabetics

A

pro: better organoleptic properties

most is converted to glucose (~50%) and liver glycogen (~17%) - this could also be a con, depending on the patient’s diet…

con: can rapidly produce lactate and/or fatty acids because it enters glycolysis after the control point (PFK-1)

32
Q

Describe the molecule latose

A

lactose is a disaccharide, made with one galactose and one glucose molecule bound via a beta-1,4 glycosidic linkage

33
Q

What does lactase do? How is it linked to lactose intolerance?

A

lactase, the enzyme, is found in many tissues - this enzyme breaks the beta-1,4- glycosidic bond

low levels of this enzyme (lactase) cause lactose intolerance

34
Q

Symptoms of lactose intolerance

A

physical discomfort, diarrhea, dehydration, or related symptoms

lactose isn’t absorbed (because it isn’t metabolized by lactase), so it’s converted to lactic acid, methane, and hydrogen gas by GI bacteria

35
Q

Treatment for lactose intolerance

A

treatments: eliminate dietary galactose, take supplemental lactase pills

36
Q

Other names for the Pentose Phosphate Pathway

A

HMP Shunt = Hexose Monophosphate pathway shunt

Also called the Phosphogluconate Pathway

37
Q

How much ATP is produced and used during the Pentose Phosphate pathway?

A

No ATP is used or produced

38
Q

Summary of products from the Pentose Phosphate pathway:

A

Provides NADPH from abundantly available glucose-6-P. NADPH plays a role in both creation and neutralization of ROS (immune response→ rapid release of of ROS).

Also yields ribose for nucleotide synthesis and glycolytic intermediates

39
Q

Where in the cell do the two phases of the Pentose Phosphate pathway occur?

A

Both phases occur in the cytoplasm

40
Q

Where in the body does the Pentose Phosphate Pathway occur?

A

lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs

41
Q

Why is it important to maintain a pool of reduced glutathione?

A

Having a pool of reduced glutathione (requires NADPH) is essential for protection against free radical species - reduced glutathione effectively neutralizes the radical species threat, but forms disulfide bridges with other glutathione molecules in the process, so it needs to be replenished…

42
Q

Effect of decreased NADPH in RBCs?

A

decreased NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (Recall that we need NADPH for the glutathionine pathway which neutralizes ROS)

We can also get hemolytic anemia due to infection (ROS generated by inflammatory response can diffuse into RBCs and cause oxidative damage).

43
Q

Most common enzymopathy? What parts of the world do we see it and why is it so common there?

A

G6PDH-ase deficiency is the most common enzymopathy (X-linked trait). It affects ~11% of males of African and Mediterranean origin (where malaria was/is endemic).

Reason for high prevalence: heterozygous females are protected against malaria and affected males typically have ~10% of normal enzyme activity which is sufficient to handle normal oxidative stress

44
Q

How do RBCs deal with oxidative damage if they can’t go through the pentose phosphate pathway (like when the enzyme Glucose-6-Phosphate doesn’t work, which is needed for the first step to create NADPH)

A

RBCs can’t repair oxidative damage by replacing lipids, proteins, etc… :’(

this can lead to the formation of Heinz bodies, which are small, round inclusions of denatured hemoglobin within the RBC

RBCs can lyse, potentially resulting in hemolytic anemia

45
Q

Describe the basic mechanism that causes the creation of Heinz bodies

A
46
Q

What are bite cells and how do they relate to Heinz Bodies?

A

Heinz Bodies- oxidized Hemoglobin precipitated within RBCs; Bite Cells result from the phagocytic removal of Heinz bodies by splenic macrophages.

“Bite into some Heinz ketchup”

47
Q

Compare the structures of NADPH and NADH

A

NADH

NADPH

48
Q

Compare the use of NADPH to NADH and explain its effectiveness at reduction reactions. How much NADPH do our cells hold?

A

NADPH is NOT oxidized by Complex 1 of the mitochondrial ETC, and it isn’t recognized at all by enzymes that utilize NAD+/NADH, thus, the cell can maintain a very high ratio of NADPH : NADP+ = ~70, compared to the intracellular ratio of NADH : NAD+ = 0.00083.

This makes NADPH way more effective for reduction reactions!

49
Q

2 most important pathways that use NADPH

A

NADPH used to reduced glutathione and fatty acid synthesis

50
Q

Describe the two phases of the Pentose Phosphate pathway

A

In the OXIDATIVE PHASE, one carbon from G-6-P is released as CO2, 2 NADPH are generated, and ribulose-5-phosphate is synthesized

In the NON-OXIDATIVE PHASE, pentose phosphates made from the oxidative steps are converted to fructose-6-phosphate and glyceraldehyde-3-phosphate

51
Q

One of the products of the oxidative phase of the Pentose Phosphate Pathway is Ribulose-5-Phosphate. What is the fate of this product?

A

ribulose-5-phosphate can be converted to ribose-5-phosphate for nucleotide synthesis, or it can generate pentose phosphates to be used in the non-oxidative portion of the pathway.

52
Q

In the NON-OXIDATIVE PHASE, pentose phosphates made from the oxidative steps are converted to fructose-6-phosphate and glyceraldehyde-3-phosphate. How can we generate nucleotides from this step?

A

because this phase’s reactions are reversible, they can be used to generate ribose-5-phosphate for nucleotide synthesis from glycolytic intermediates!

53
Q

Net reaction of the oxidative phase of the PPP:

A
54
Q

When NADPH levels are low, what does the oxidative pathway do?

A

When NADPH levels are LOW, the oxidative pathway can be used to generate ribose-5-phosphate for nucleotide synthesis

55
Q

Describe reactive oxygen species (ROS)

A

molecular oxygen (O2) is a biradical in the ground state, and it reacts slowly with organic material

ultimately, O2 forms ROS that react RAPIDLY w/organic material (includes superoxide, hydrogen peroxide, hydroxyl radical)

56
Q

Transition metals in the cell and their relationship to ROS

A

transition metals like Fe2+ or Cu+ also catalyze hydroxyl radical formation. Fortunately, these metals are highly sequestered in the cell, but unfortunately, crushing injuries can release previously-sequestered Fe, causing an increase in ROS injury

57
Q

Describe the Haber-Weiss Reaction

A
58
Q

Describe Ionizing radiations mechanism for producing ROS

A
59
Q

Describe the Fenton Reaction

A
60
Q

What is Glutathionine’s effect on ROS and what is the enzyme needed to cause this

A

Glutathione is one of the main cellular defenses against ROS damage. glutathione = a gamma-glutamylcysteinylglycine tripeptide w/ a free sulfhydryl group. It reduces H2O2 and lipid peroxides by formation of disulfide bridges.

These reactions are catalyzed by glutathione peroxidases, which are selenium enzymes

61
Q

How do we reverse the glutathione reaction?

A

glutathione reductase regenerates reduced glutathione. This enzyme contains a FAD group, allowing electron transfer from NADPH to glutathione

62
Q

What are the functions of transaldolases and transketolases?

A

Shuffling 2-carbon and 3-carbon fragments between sugars is catalyzed by:

transketolase = transfers 2-C units

transaldolase = transfers 3-C units

63
Q

What is the mechanism for the transketolase activity and what cofactor, if any, do we need to do it?

A
64
Q

What is the mechanism for transaldolase activity and what cofactor, if any, do we need to do it?

A

No cofactor

65
Q

There are 3 reactions catalyzed by transketolases and transaldolases. Which reactions use which enzymes and cofactors?

A
  1. Uses transketolase and Thiamine PP to transfer 2C units
  2. Uses transaldolase with no cofactor to transfer 3C units
  3. Uses transketolase and Thiamine PP to transfer 2C units
66
Q

What is the first Transketolase Reaction?

A
67
Q

What is the first Transaldolase reaction (second reaction of the three reaction set)?

A
68
Q

What is the final transketolase reaction which wraps up the three step reaction using transketolases and transaldolases?

A
69
Q

What is the effect of high NADPH levels on the non-oxidative pathway of PPP?

A

When NADPH levels are HIGH, the non-oxidative pathway can be used to generate ribose-5-phosphate for nucleotide synthesis from fructose-6-phosphate and glyceraldehyde-3-phosphate

70
Q

What enzymes are important for converting between pentose phosphate sugars? What do they do specifically?

A

Conversion among pentoses is catalyzed by:

epimerase: recall, “epimer” refers to a pair of stereoisomers
isomerase: “isomers” have the same chemical formula but different structure

71
Q

How does the PPP change when there is a greater need for Ribose-5-phosphate than NADPH? What is the net reaction under this mode?

A
  1. the oxidative phase is “off,” thus G6P dehydrogenase, Gluconolactonase, and 6-phosphogluconate dehydrogenase are all inactive
  2. Glycolysis and the non-oxidative phase reactions are active

Net reaction: 5 G6P + ATP → 6 R5P + ADP + 2H+

72
Q

How does the PPP change when there is an equal need for NADPH and Ribose-5-Phosphate? What is the net reaction in this mode?

A
  1. only the oxidative phase is necessary. isomerase converts ribulose-5-phosphate → ribose-5-phosphate (one carbon is liberated as CO2)

NET REACTION: G6P + 2 NADP+ + H2O → R5P + 2 NADPH + 2H+ + CO2

73
Q

How does the PPP change when there is a need for NADPH over Ribose-5-Phosphate? What is the net reaction in this mode?

A

BOTH oxidative and nonoxidative phases are necessary. R5P is converted back to G6P by non-oxidative and glycolysis-related reactions (six carbons are liberated as CO2 (an entire molecule of G6P is used!))

NET REACTION

G6P + 12 NADP+ + 7 H2O → 6 CO2 + 12 NADPH + 12 H+ + Pi

74
Q

Describe the net reaction when we need Pyruvate and NADPH

A

MSK Week 4 (11 decks)

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