Lecture 16: Carbohydrate Metabolism Flashcards by Ryley Tegler

Gluconeogensis

provides gluccose
reciprocal regulation
Cori Cycle

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reciprocal regulation

different directions
Glycolysis regulated by PFK1
Gluconeogenesis regulated by f16BPase

all controlled by allosteric regulator F2-6BP, energy charge, and citrate levles

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Cori Cycle overview

recycle lactate
export lactate to liver
convert it to pyruvate
synth glucose by gluconeogenesis

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What does gluconeogensis accomplish?

liver and kidney cells
make glucose from non carbo sources like glycerol, a.a.s lactate, etc

plants use it to make GAP glucose

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how many ATP needed for glucconeogenesis

4 ATP
2 GTP
2 NADH

SIX ATP

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key enzymes?

pyruvate carboxylase: convert pyruvate to OAA (ALSO IN CITRATE CYCLE)

responsible for just gluconeo
PEPCK: OAA to PEP
FBPase-1 (1,6 BPase) catalyze dephosphylation of fructose to make fructose 6P
Glucose 6PL catalyzes dephosphory of G6P to make glucose

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Glycolysis and gluconeogensis…

OPPOSING PATHWAYS

so substrate concs dictate what direction reactions run

EXCEPT for specific pathways that use specific enzymes

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examples of bypass enzymes in gluconeogenesis that reverse the glycolysis reaction

Fructose 1,6 BPase

G6P

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Net ATP from glycolysis

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What if we ran glycolysis and gluconeogensis at the same time ??

We would use 4 ATP if we ran glycolysis and gluconeogensis at the same time

(you get 2 from glycolysis, but we burn through 6 in gluconeogenesis, meaning we burn through 4 ATP total if run at same time)

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SO why is it important that pathways are regulated?

don’t want to waste ATP!

So don’t want to run glycolysis and gluconeogensis at the same time

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Glycolytic and gluconeogenic pathways are very regulated. How?

Energy charge, acetyl CoA, citrate, alanine are metabolites

F-2, 6 BP is reciprocal regulator

all act on opposing enzymes in pathways

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Glycolysis inhibitors

ATP

citrate

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Glycolysis stimulators

F-2,6 BP

AMP

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Gluconeogenesis inhibitors

F-2,6 BP

AMP

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Gluconeogenesis stimulators

citrate

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pyruvate kinase inhibitors

(regulates glycolysis) (takes pyruvate to OAA)
ATP
Alanine

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pyruvate kinase stimulators

(regulates glycolysis)

F-2,6 BP

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PEPCK inhibitors

ADP (regulates Gluconeogenesis)

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Pyruvate carboxylase inhibitors

(regulates Gluconeogenesis)

ADP

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Pyruvate carboxylase stimulators

(regulates Gluconeogenesis)

Acetyl CoA

Why do we consider the reactions regulated by Pyruvate carboxylase and PEPCK a cost of 4 ATP to convert pyruvate to PEP when we count up the # of ATP needed to generate 1 glucose from 2 pyruvate

We have to run the pair of reactions twice!
if we are making glucose, we need SIX carbons, that means we need TWO pyruvates. Each time, this takes 2 ATP (total of 4)

why do we count GTP as an ATP

because there is no free nrg change to interconvert ATP and GTP

pyruvate carboxylase

pyruvate to OAA, its modified to do this rxn
lysine residue
long swinging arm between the two active sites of the enzyme

where have we seen this enzymatic reaction before? (its activated by acetyl CoA and generates OAA)

citrate cycle!!!! | its activated by acetyl CoA

where is this all taking place???

pyruvate to OAA happens in matrix | all of the rest of glycolysis and gluconeogenesis happens in the cytosol

so how does OAA get to cytosol?

OAA is converted to malate to leave the matrix and go to the cytosol NADH NEEDED malate goes back to OAA once it gets to matrix

glyceraldehyde 3P dehydrogenase

NADH is given to it in glycolysis OPPOSITE OF when there is NAD+ in the cytosol and NADH needs to be regernated during GLYCOLYSIS

Reciprocal regulation definition

levels of metabolites inhibit one enzyme and stimulate another

F-2BP

NOT a metabolite JUST A REGULATOR of PFK1 and PBPase-1 substrate is glucose 6- phoshpate

What is the metabolic logic of reciprocal regulation by citrate?

lots of citrate that we don't need to make more nrg so we start making glucose instead turn on and off 2 pathways with same metabolite=no waste of nrg

Does high F-2,6 BP activate or inhibit flux through the glycolytic pathway

activates

Presence of F-2,6BP and PFK-1

when it is present, it takes a lot less activity to reach half max activity when absent, it takes a lot more substrate to reach half max 25X times higher affinity of PFK1 for its substrate when F-2,6 BP is present

Presence of F-2,6BP and FBPase-1

substrate of FBP-ase 1 is fructose bisphosphate | when F-2,6BP present, it takes more enzume to make half max activity: substate affinity is 15X lower

Does low F-2,6 BP activate or inhibit flux through the gluconeogenic pathway?

ACTIVATES

how is amount of F-2,6BP controlled?

by dual function enzyme PFK-2/FBase-2 | it has TWO active sites

Is PFK-2/FBase-2 one protein with 2 catalytic activities, or two proein subunits that form one quatenary complex

one protein with 2 catalytic actibities its one polypep chain center part connects them the activity of one domain INHIBITS the activity of the other

Glucagon signaling and PFK-2/FBase-2

stimulates phosphorylation of the enzyme (Through protein kinase a--PKA) ACTIVATION of FBP-ase 2 domain

Insulin signaling of PFK-2/FBase-2

stimulates dephosphorylation of enzyme | ACTIVATION of PFK-2 domain

low blood sugar

glucagon signals activate protein kinase a phosphorylates one of PFK-2/FBase-2 domains: inactivates PFK-2 domain FBP-ase 2 activated fructose 6 phospate made from fructose bisposphate more active gluconeogenesis

high blood sugar

``` insulin signals activate protein phosphatase one actviates PFK-2 domain (dephosphorylate the domains) catalyze to make fructose bisphosphate more active glycolysis ```

low blood sugar... whats active/not

glycolysus LESS active | gluconeogenesis MORE active

high blood sugar...whats active/not

glycolysis MORE active | gluconeogenesis LESS active

so what does level of F-2,6 BP do?

recipricoally regulate the enzymes lots of one activates one pathway lost of other activates other pathway inhibits whats not active

phosphorylating glucose with hexokinase does what

traps glucose in the cell

but what about glucose 6P?

it can be imported into the ER and is dephosphorylayed levels lumen goes out of cell for use elsewhere

Cori cycle

``` what happens to lactate made by anerobic muscle ativity lactate goes to liver (gluconeogenesis) liver converts it back to pyruvate NADH produced (can be used by GAP) pyruvate can go back to glucose ```

so whats the point of the cori cycle??

a way we can keep doing glycolysis to get nrg from muscle cells seperate locations for these pathways. happen in different tissues

Cori cycle cost

4 ATP

Explain why the Cori cycle has a net cost of 4 ATP to the organism?

we produce 2 ATP in skeletal muscle | costs 6 ATP in the liver

so why do we do the Cori cycle if it costs 4 ATP?

if muscles need nrg, you have to get it somehow

why do altheletes warm down?

enhances circulation | lactate can be cleared from muscles and used in liver for glucose synth via cori cycle