BIO 361 (Biochem) > Gluconeogenesis > Flashcards

Gluconeogenesis Flashcards

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1
Q

How much glucose does the brain typically need in a day?

(What porportion of our total glucose stores is this?)

A

~120 g of glucose

–> This is greater than 1/2 of the total glucose stored in our liver and muscles as glycogen

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2
Q

What conditions deplete glycogen?

A

Starvation

Long Fasts

Rigorous Exercise

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3
Q

What do RBCs rely on for energy?

A

SOLELY GLYCOLYSIS

–> Because they lack mitochondria

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4
Q

When glycogen is depleted, we need a way to….

A

Create glucose from NON-CARBOHYDRATE sources!

(turn other biomolecules into glucose)

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5
Q

Define gluconeogenesis

A

The generation of “new” glucose molecules from NON-CARBOHYDRATE sources/precursors

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6
Q

Gluconeogenesis is a pathway that converts ________ and other related __________ carbon compounds into _______

A

Gluconeogenesis is a pathway that converts PYRUVATE and other related 3 + 4 carbon compounds into GLUCOSE

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7
Q

In what tissues does gluconeogenesis occur?

A

Mainly in the liver, and to a smaller extent in the kidneys

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8
Q

In ANIMALS, what are the main precursors of gluconeogenesis?

A

1) Lactate

2) Pyruvate

3) Glycerol

4) Glucogenic AAs (alanine, aspartate, etc.)

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9
Q

What do lactate, pyruvate, and glycerol all have in common?

A

They’re all 3 carbon molecules that can act as precursors in gluconeogenesis

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10
Q

Glucogenic Molecules

A

Molecules that can be converted to pyruvate or oxaloacetate AND can therefore serve as starting material for gluconeogenesis

–> Molecules capable of converting into glucose!

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11
Q

What is a precursor to gluconeogenesis that plants use but animals do not?

A

3-phosphoglycerate (3PG) –> Made from CO2 fixation

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12
Q

Explain the difference between animal precursors to gluconeogenesis in how they enter the pathway:

A

1) Lactate –> Gets converted to pyruvate, enters part of KREB cycle to convert to PEP before continuing on

2) Pyruvate + Glucogenic AAs –> Enter part of KREB cycle to convert to PEP before continuing on

3) Glycerol –> Enters AFTER PEP production (does not get converted to PEP)

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13
Q

Gluconeogenesis is NOT the ___________________

Why?

A

Gluconeogenesis is NOT the REVERSE OF GLYCOLYSIS

–> Although the pathways share SEVEN steps, there are 3 irreversible steps in each that differ

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14
Q

How are the seven reversible reactions of glycolysis reversed for gluconeogenesis?

A

By altering the ratio of the concentration of reactants to products!

–> Can push the reaction in the glucose direction rather than the pyruvate direction

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15
Q

What are the 3 irreversible rxns of GLYCOLYSIS?

A

Step 1) Glucose —–> Glucose-6-Phosphate (via hexokinase + ATP)

Step 3) Fructose-6-Phosphate ——–> Fructose-1,6-bisphosphate (via PFK-1 + ATP)

Step 10) Phosphoenol pyruvate (PEP) ———> Pyruvate (via Pyruvate Kinase + ADP)

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16
Q

Why are the 3 irreversible rxns of glycolysis irreversible?

Why is this a problem for gluconeogenesis?

A

–> Because they have a ΔG that is HIGH and NEGATIVE

–> Problem for gluconeogenesis b/c in glucogenic conditions, these rxns STILL have a ΔG that is HIGH and NEGATIVE (still irreversible in glucogenic conditions)

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17
Q

Bypass Reactions

A

Irreversible rxns of gluconeogenesis that are used to bypass/work around the irreversible rxns of glycolysis

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18
Q

Where do gluconeogenesis and glycolysis occur?

A

They both occur in the cytoplasm!

== we need a way to reciprocally regulate them! (when one is active, one is inactive)

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19
Q

Explain the steps of gluconeogensis broadly:

A

1) Pyruvate ——> PEP (via multistep bypass mechanism)

2) PEP ——> 2-phosphoglycerate (ENOLASE)

3) 2-phosphoglycerate ——–> 3-phosphoglycerate (Phosphoglycerate mutase)

4) 3-phosphoglycerate ———> 1,3-biphosphoglycerate (Phosphoglycerate kinase)

5) 1,3-biphosphoglycerate —–> Glyceraldehyde-3-phosphate(G3P) (G3P Dehydrogenase)

6) (Some) G3P ——–> Dihydroxyacetonephosphate (DHAP) (triphosphate isomerase)

7) G3P + DHAP ——-> Fructose-1,6-bisphosphate (Aldolase)

8) Fructose-1,6-bisphosphate ——> Fructose-6-phosphate (BYPASS via Fructose-1,6,-bisphosphatase-1 = FBPase-1)

9) Fructose-6-phosphate ———> Glucose-6-phosphate (G6P) (Phosphohexose isomerase)

10) Glucose-6-phosphate ——–> GLUCOSE (BYPASS via Glucose-6-phosphatase)

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20
Q

What is the overall goal of the first bypass rxn?

A

To convert pyruvate to phosphoenolpyruvate

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21
Q

What are the overall steps of the first bypass rxn? (pyruvate precursor)

A

1) Pyruvate enters the mitochondrion

2) Pyruvate is converted into oxaloacetate (OAA)

3) Oxaloacetate is converted into malate (using one NADH)

4) Malate is transported out of the mitochondrion

5) Cytosolic malate is converted into OAA (creating one NADH)

6) Cytosolic OAA is converted into PEP

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22
Q

What enzymes are used in the first bypass rxn? (pyruvate precursor)

A

1) Pyruvate Carboxylase = Carboxylates PEP to form OAA (PEP + CO2 = OAA)

2) Malate Dehydrogenase (mito) = Reduces OAA to malate in the mitochondrion (while oxidizing NADH to NAD+)

3) Malate Dehydrogenase (cyto) = Oxidizes malate to OAA in the cytosol (while reducing NAD+ to NADH)

4) PEP Carboxykinase = Simultaneously decarboxylates and phosphorylates OAA to form PEP

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23
Q

What are the phases of the first bypass rxn?

A

Phase 1 = PEP —-> OAA

Phase 2 = OAA —-> —–> —–> PEP

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24
Q

What is the overall rxn equation for Phase 1 of the first bypass rxn?

A
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25
What is the setup of the pyruvate carboxylase enzyme?
Pyruvate carboxylase enzyme has a conserved lysine residue at which a BIOTIN coenzyme attaches to via the Lys amino grp and the biotin COO- grp == Forming an amide linkage --> This biotin-lys arm lies in the middle between two enzymatic sites Site 1 = Where biotin "picks up" CO2 from HCO3- Site 2 = Where biotin "donates" CO2 to pyruvate to carboxylate it into OAA
26
Explain the steps of catalysis for pyruvate carboxylase:
1) At site 1 of the enzyme, ATP is used to phosphorylate HCO3- (= releases ADP) 2) Biotin then covalently bonds (via its nitrogen atom) to CO2 by substituting in for the phosphate grp (= releases Pi grp) 3) Once CO2 bound, the biotinyl-lys arm "swings" over to site 2 of the enzyme 4) At site 2, pyruvate is waiting; once the biotinyl-lys arm has swung over to site 2, CO2 is brought close to pyruvate and undergoes a carboxylation rxn (= the terminal double bond of pyruvate enolate form attacks CO2, creating oxaloacetate)
27
Explain the chemical structures in the process of pyruvate carboxylation (via pyruvate carboxylase)
28
How is OAA transported OUT of the mitochondrion?
MALATE SHUTTLE! --> OAA gets converted to malate in the mitochondrion which is then transported out of the mitochondrion --> Once in the cytosol, malate is converted back into OAA
29
What two rxn expressions represent the malate shuttle process?
30
Why is the malate shuttle needed? (explain its importance)
**2 Main Reasons:** #1) There is no transporter for OAA to go OUT of the mitochondrion = malate shuttle allows for OAA to get into the cytoplasm to then convert to PEP #2) The malate shuttle also allows for the "transport" of NADH from the mitochondrion to the cytosol! == Important because NADH is needed in a later step of gluconeogenesis! (1,3-biphosphoglycerate ----> glyceraldehyde-3-phosphate) --> NADH concentration in the cytosol is kept LOW, so without the malate shuttle, there wouldn't be enough NADH to allow gluconeogenesis to continue!
31
What is the difference in NADH concentration between the mitochondrion and the cytosol?
Mitochondria = 7x greater concentration of NADH compared to the cytosol!
32
What happens to OAA after its been moved into the cytosol via the malate shuttle?
OAA gets converted to PEP using PEP carboxykinase enzyme --> This enzyme utilizes GTP to phosphorylate OAA --> This phosphorylation event triggers a simultaneous decarboxylation in which CO2 is released! == PEP!
33
What is the rxn expression for the conversion of OAA into PEP?
34
Is the conversion of OAA to PEP reversible or irreversible?
Technically, the rxn is REVERSIBLE... BUT because PEP (the product of this rxn) is used immediately upon its formation, the concentration of PEP (product) is kept very low == pushes the rxn forward and makes it IRREVERSIBLE!
35
What is phosphoenol pyruvate carboxykinase?
A GTP-dependent enzyme that catalyzes the simultaneous phosphorylation and carboxylation of OAA to PEP! --> Used in the first bypass rxn of gluconeogenesis!
36
Explain the overall process of Phase 2 of the first bypass rxn:
1) OAA is reduced to Malate in the mitochondrion via mitochondrial malate dehydrogenase 1.1) Simultaneously, NADH is oxidized to NAD+ in the mitochondrion 2) Malate is transported OUT of the mitochondrion via a transporter in the mitochondrial membrane 3) Malate in the cytosol is then oxidized back to OAA via cytosolic malate dehydrogenase 3.1) Simultaneously, NAD+ is reduced to NADH in the cytosol! 4) OAA in the cytosol is then simultaneously decarboxylated and phosphorylated via PEP carboxykinase to produce PEP! (utilizes one GTP to do so)
37
What is the difference between OAA and malate?
OAA = keto grp. on the 2nd carbon Malate = OH grp. on the 2nd carbon
38
What is the overall rxn expression for the 1st bypass rxn?
39
In the first bypass reaction, the same CO2 is gained AND lost... As such this carboxylation-decarboxylation sequence serves to______________
This carboxylation-decarboxylation sequence of the first bypass reaction **serves to ACTIVATE PYRUVATE to allow for its conversion to PEP!**
40
How does the first bypass rxn change if lactate is used as a precursor?
If lactate is the precursor: 1) No malate shuttle used 2) NADH is produced in the cytosol during conversion of lactate to pyruvate 3) OAA is converted directly to PEP INSIDE of the mitochondrion 4) PEP is then shuttled out of the mitochondrion into the cytosol
41
Explain the first bypass rxn process if lactate is used as the precursor:
1) Lactate is oxidized to pyruvate in the cytosol using *lactate dehydrogenase* --> This process reduces NAD+ to NADH in the cytosol! 2) Pyruvate is transported into the mitochondrion 3) In the mitochondrion, pyruvate is carboxylated to OAA via *pyruvate carboxylase* which utilizes one ATP molecule and HCO3- --> releases ADP + Pi 4) OAA in the mitochondrion is then simultaneously decarboxylated and phosphorylated via a *MITOCHONDRIAL PEP carboxykinase* using one molecule of GTP == Forms PEP + releases CO2 + GDP 5) Mitochondrial PEP is then transported into the cytosol
42
How come no malate shuttle is needed in gluconeogenesis if lactate is used as the precursor?
Because NADH is already made in the cytosol when lactate is oxidized to pyruvate! == So the malate shuttle isn't needed to transport NADH out of the mitochondrion and into the cytosol!
43
What is the difference between mitochondrial and cytosolic forms of PEP carboxykinase?
They carry out the same function BUT they are encoded by separate nuclear genes!
44
Explain the second bypass rxn of gluconeogenesis?
Fructose-1,6-Bisphosphate is dephosphorylated at C1 via a hydrolysis rxn carried out by **FBPase-1** to form Fructose-6-phosphate
45
In the second bypass rxn, what is getting hydrolyzed?
The bond between C1 and the phosphate grp attached is getting hydrolyzed = C1 is going from a phosphate grp carbon to an OH grp carbon!
46
What is the overall rxn expression for the second bypass rxn?
47
What is the enzyme used in the second bypass rxn?
Fructose-1,6-bisphosphatase AKA. "FBPase-1" (NOT the same as FBPase-2!!!)
48
Explain the third bypass rxn of gluconeogenesis?
Glucose-6-phosphate is dephosphorylated at C6 via a hydrolysis rxn carried out by **G6Pase** to form glucose!
49
What is the overall rxn expression for the third bypass rxn?
50
What is similar between the second and third bypass rxns?
They are BOTH hydrolysis rxns in which a phosphate grp is being removed and replaced with an OH grp! == Both are catalyzed by phosphatase enzymes!
51
Where is glucose-6-phosphatase located?
In the ER membrane, with its active site facing INTO the lumen of the ER == Allowing for spatial separation of glycolysis and gluconeogenesis
52
What is the enzyme used in the third bypass rxn?
Glucose-6-phosphatase AKA. G6Pase
53
What is the OVERALL rxn expression for the entirety of gluconeogenesis?
54
How many high energy phosphate grps are needed to form ONE glucose molecule?
**SIX!!** 4 from ATP and 2 from GTP == 2 ATP + 1 GTP for each pyruvate molecule!
55
In what steps are ATP and GTP used during gluconeogenesis?
**Phase 1 of 1st Bypass Rxn = Uses 1 ATP** --> Pyruvate carboxylase uses ATP to carboxylate pyruvate into OAA **Phase 2 of 1st Bypass Rxn = Uses 1 GTP** --> PEP carboxykinase uses GTP to decarboxylate/phosphorylate OAA to form PEP! **3-phosphoglycerate ----> 1,3-biphosphoglycerate** --> Phosphoglycerate kinase utilizes ATP to phosphorylatee 3-phosphoglycerate!
56
What are the 4 justifications of the energy expenditure in gluconeogenesis?
1) Energy expenditure ensures the synthesis of glucose is irreversible! (ensures the pathway proceeds in ONE direction!) 2) Eventual oxidative breakdown of synthesized glucose will release 30-32 ATP = will eventually pay off! 3) Prevents the excretion of unutilized pyruvate = if pyruvate is not needed it simply gets excreted, wasting all of its potential energy 4) Many different molecules feed into gluconeogenesis
57
Glycolysis and gluconeogenesis typically _____________ occur at the same time because_________
Glycolysis and gluconeogenesis typically **DO NOT** occur at the same time because... **It's wasteful!** (lose energy)
58
The simultaneous running of glycolysis and gluconeogenesis wastes energy where in the pathway? Provide Example:
At each of the corresponding 3 irreversible rxns of both pathways, if glycolysis and gluconeogenesis are run at the same time, these steps will consume energy without completing any chemical or biological work! Ex: If the 2nd bypass rxn and the 3rd glycolytic rxn occur at the same time, ATP is consumed and energy is released as HEAT!
59
What is the difference between energy usage and production in glycolysis and gluconeogenesis?
Glycolysis = Net generation of 2ATP + 1NADH Gluconeogenesis = Consumption of 4ATP + 2GTP +2NADH
60
How do cells prevent the waste of simultaneously running glycolysis and gluconeogenesis?
RECIPROCAL REGULATION! = When one pathway is active, the other is inactive Methods: 1) Reciprocal allosteric regulation of PFK-1 and FBPase-1 by F26BP 2) Spatial separation of glycolysis and gluconeogenesis
61
What ultimately regulates the allosteric regulator F26BP?
**HORMONES** **Glucagon** = When blood sugar is low, stimulates gluconeogenesis and inhibits glycolysis by DECREASING [F26BP] **Insulin** = When blood sugar is high, inhibits gluconeogenesis and stimulates glycolysis by INCREASING [F26BP]
62
What is F26BP?
F26BP = Fructose-2,6,-Bisphosphate --> An allosteric regulator of PFK-1 and FBPase-1
63
Effect of F26BP on PFK-1
When F26BP binds PFK-1: --> **Increases affinity of PFK-1 to its substrate fructose-6-phosphate (↓KM) = promotes glycolysis!** When F26BP is not present, PFK-1 is virtually inactive! = Needs A LOT of substrate (F6P) to activate the enzyme = glycolysis inhibited
64
Effect of F26BP on FBPase-1
When F26BP binds FBPase-1: -->**Decreases affinity of FBPase-1 to its substrate fructose-1,6-BP (↑KM) = inhibits gluconeogenesis!** When F26BP is not present, FBPase-1 is NOT inhibited = promotes gluconeogenesis!
65
What determines the cellular concentration of allosteric regulator F26BP?
The rate of its synthesis and degradation!
66
What enzymes control the synthesis and degradation of F26BP?
**F26BP synthesis = Controlled by PFK-2** (phosphofructokinase-2) **F26BP Degradation = Controlled by FBPase-2** (fructose-2,6-bisphosphatase)
67
PFK-2 and FBPase-2 have ______________enzymatic activities BUT they are __________
PFK-2 and FBPase-2 have **separate** enzymatic activities BUT they are **components of ONE bifunctional protein!**
68
How do FBPase-2 and PFK-1 create/degrade F26BP?
**PFK-2** = Phosphorylates fructose-6P to form F26BP **FBPase-2** = Hydrolyzes/dephosphorylates F26BP to form fructose-6P
69
Explain the process by which**glucagon** impacts PFK-2/FBPase-2 activity and how this contributes to reciprocal regulation
1) Glucagon is released + activates adenylyl cyclase 2) Adenylyl cyclase produces cAMP 3) A cAMP-dependent protein kinase becomes activated due to ↑[cAMP] == Phosphorylates the PFK-2/FBPase-2 protein 4) Phosphorylated state of the protein = FBPase-2 function is ACTIVATED! (and PFK-2 is inactive) 5) FBPase-2 dephosphorylates F26BP = decreases F26BP concentration == **promotes gluconeogenesis and slows glycolysis**
70
Explain the process by which**insulin** impacts PFK-2/FBPase-2 activity and how this contributes to reciprocal regulation
1) Insulin is released = directly activates a phosphoprotein phosphatase 2) Activated phosphoprotein phosphatase dephosphorylates the PFK-2/FBPase-2 protein 3) Dephosphorylated state of the protein = PFK-2 function is ACTIVATED! (and FBPase-2 is inactive) 4) PFK-2 phosphorylated fructose-6P to form more F26BP = increases F26BP concentration == **inhibits gluconeogenesis and promotes glycolysis**
71
In the phosphorylated/dephosphorylated states of PFK-2/FBPase-2 protein, which functions are active/inactive?
Phosphorylated = FBPase-2 ACTIVE + PFK-2 inactive Dephosphorylated = FBPase-2 inactive + PFK-2 ACTIVE
72
In hepatocytes, how are glycolysis and gluconeogenesis physically separated?
By localizing the enzyme glucose-6-phosphatase IN the ER membrane with its active site IN the lumen = G6P is converted to glucose in the gluconeogenesis pathway IN the lumen, away from glycolytic enzymes == Prevents glucose that has been newly generated from just entering glycolysis right away!
73
Explain the process of the 3rd bypass rxn in terms of spatial separation:
1) Glucose-6P is made in the cytosol and then trafficked through a G6P transporter in the ER membrane (T1) == G6P enters the ER lumen 2) In the ER lumen G6P has access to the ACTIVE SITE of glucose-6-phosphatase == G6P is hydrolyzed by this enzyme to form GLUCOSE in the lumen! 3) Glucose in the lumen is then transported OUT fo the ER and into the cytosol via a glucose transporter (T2) 4) As the ER membrane and PM are so close together, glucose that enters the cytosol from the ER immediately gets transported OUT of the cell via a GLUT2 transporter in the PM! == Glucose newly produced does NOT get the chance to undergo glycolysis in the hepatocyte! 5) Glucose enters the bloodstream via a capillary and gets transported to tissues in need!
BIO 361 (Biochem)
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