BIOC PART C

1. glucose→ glucose-6-phosphate (hexokinase, or glucokinase in liver) ATP→ADP

3. fructose→ fructose-1,6-bisphosphate (phosphofructokinase-1) ATP→ADP

10. phosphenolpyruvate→ pyruvate (pyruvate kinase) 2ADP→2ATP

3 most exergonic steps glycolysis (and enzymes)

1. pyruvate→phosphenol pyruvate (many enzymes)

8. fructose-1,6- bisphosphate → fructose 6- phosphate (fructose 1,6 bisphosphatase) H2O→Pi

10. glucose-6 phosphate → glucose (glucose 6 phosphatase) H2O→Pi

3 most exergonic steps of gluconeogenesis (and enzymes)

pyruvate enters mitcochondria*

pyruvate→ oxaloactetate (pyruvate caboxylase) +CO2, 2ATP→2ADP

oxaloacetate→ malate (mitochondrial malate dehydrogenase) NADH+H→NAD+

malate exits the mitochondria*

malate→oxaloacetate (cytosolic malate dehydrogenase) NAD+→ NADH+H

oxaloacetate→ phosphenol pyruvate (phosphenol pyruvate carboxylase) -CO2, 2GTP→2GDP

explain all the steps of step one gluconeogenesis (pyruvate to PEP)

IV: fructose-6-phosphate

I: glucose-6-phosphate

what inhibits glucokinase (hexokinase IV)?

what inhibits hexokinase I?

3. F-6-P→F1,6BP (PFK-1)

what is the committed step in glycolysis?

activates: (x100) F26BP, AMP, ADP

inactivates: citrate, ATP

what inhibits step 3 glycolysis?

what activates step 3 glycolysis?

(F-6-P→F1,6BP (PFK-1))

activates: F1,6BP (product of step 3)

inactivates: long chain FA, alanine, ATP, acetyl-COA

what activates step 10 glycolysis?

what inactivates step 10 glycolysis?

(PEP→pyruvate (PK))

pyruvate kinase (PK) is active when glucagon is low in liver (allows glycolysis to proceed)

in liver when glucagon is released it activates PKA which inactivates pyruvate kinase. when is pyruvate kinase active? (step 10 glycolysis)

activates: acetyl COA

inactivates: ADP

what activates step 1 gluconeogenesis?

what inactivates step 1 gluconeogenesis?

(pyruvate→PEP (many enzymes))

activates: ?

inactivates:AMP, F26BP(x10)

what activates step 8 gluconeogenesis?

what inactivates step 8 gluconeogenesis?

(F1,6BP→F6P (F1,6BPase))

glycolysis, gluconeogenesis

in general low energy molecules activate __________ and high energy molecules activate ________

low, high

______ energy molecules favour glycolysis, ______ energy molecules favour gluconeogenesis to occur

low energy molecules include: ADP, AMP, F16BP, F26BP

high energy molecules include: ATP, acetyl-COA, long chain FA, alanine, citrate

low energy molecules include:

high energy molecules include:

sum of chemical transformations (catabolism+anabolism)

metabolism=

degrade carbs, fats, proteins

produce high energy ATP, NADPH, NADH, FADH2

byproducts of CO2,H2O,NH3

describe catabolism (what is used, made and byproducts)

use sugar, amino acids, FA, nitrogenous bases

produce proteins, polysacchardies, nucleic acids

byproducts of ADP, HPO2-, NAD+,FAD, NADP+

describe anabolism (what is used, made and byproducts)

acetylCOA, biomolecules

catabolism coverges to _______, anabolism diverges to _______

F, rate limiting steps are often far from equilibrium. the substrate can be in excess and teh pathway is still slowed down by rate limiting enzyme

rate limiting steps are in equalibrium (T/F)

when products have less energy that substrate and deltaG is negative

gibbs free energy is the ability to do work in a system when is a reaction spontaneous?

increased stability (lower energy products)

increased entropy

energy release to power cell

coupling with nonspontaneous reactions to drive processes forward

why is negative deltaG favoured?

equalibrium

non spontaneous (endergonic)

spontaneous (exergonic)

deltaG=0

deltaG>0

deltaG<0

Ea

enzymes decrease ____ of rxn

deltaG= deltaG ‘ +RT ln product/reactants

deltaG=

ln small/large (small product with large concentration of reactants)

deltaG is negative when

I: max activity in the muscle (only inhibited if G6P concentration high)

IV: normally low glucose affinity, low activity, responds as glucose concentration increases (inhibited by F6P)

hexokinase I is normally at _______ activity

hexokinase IV is normally at ________ activity

glucokinase has a much higher K0.5 than hexokinase

glucokinase K0.5=10

hexokinase K0.5=5

higher k0.5 = lower affinity for glucose

does hexokinase or glucokinase have higher K0.5

in the nucleus. only moves into cytosol to beocme active when glucose concentrations increase

where is hexokinase-IV (glucokinase) found when glucose concentrations are low/ F6P concentrations are high?

synthesis of glucose form non hexose precurors (lactoc acid, glycerol, gluconeogenic AAs)

define gluconeogenesis

gluconeogenesis consumes NADH (glyceraldehyde 3-phosphate dehydrogenase) and the liver mitcochondria degrades FA in gluconeogenesis that produces a lot of NADH.

the way to get the NADH out of the mitcochondria so it can be used in gluconeogenesis is to have it carried out by malate intermediate, then go back to oxaloacetate in the cytoplasm to relase the NADH there (bring it out of mitochondria into cytoplasm)

why does oxaloacetate→malate→oxaloacetate in the first step of gluconeogenesis (whats the point?)

when lactate is feeding gluconeogenesis (not FA breakdown in mitochondria) as lactate dehydrogenase (LDH) produces NADH right in the cytoplasm already (dont need all those steps to get it out of the mitochondria)

when do the multi enzyme steps in step 1 gluconeogenesis not need to take place?

L-malate

is malate in the first step of gluconeogenesis L or D malate?

glycolysis, gluconeogenesis

F26BP is a low energy molecule so it activates ______ and inactivates ______

PFK2 and FBPase2

F26BP production is regulated by a bifunctional enzyme of _______ and _____

not produced (gluconeogenesis occurs)

when FBPase2 is active F26BP is _________

produced (glycolysis occurs)

when PFK2 is active F26BP is _______

phosphoprotein phosphatate (PP), insulin and xylulose

(IN Muscle)inactive PFK2, active FBPase2 → active PFK2, inactive FBPase2

occurs by enzyme _______ which is activated by______

PFK2, glycolysis (inhibit gluconeogenesis)

insulin and xyulose activate phosphoprotein phosphatase enzyme,

from here ______ enzyme is activated, producing F26BP which enourages _________

PKA, glucagon,epinepherine and cAMP

(LIVER)active PFK2, inactive FBPase2 → inactive PFK2, active FBPase2

occurs by enzyme _______ which is activated by______

FBPase2, gluconeogenesis (inhibits glycolysis)

glucagon and cAMP activate PKA enzyme,

from here ______ enzyme is activated, blocking F26BP production which enourages _________

gluconeogenesis

glycolysis

in summary of the last cards regarding F26BP regulation (not rxn just flow chart)

glucagon/cAMP→PKA→FBPase2→decrease F26BP→ activates _______

insulin/xyulose5P→PP→PFK2→increase F26BP→ activates ______

Ser32

in liver isozyme of FBPase2/PFK2, phosphorylation of ________ activates FBPase2

Ser406 and Thr475

In cardiac isozyme of FBPase2/PFK2, phosphorylation of _____ and _____ activates PFK2

glucagon, inhibits (inhibiting PK inhibits glycolysis)

pyruvate kinase (step 10 glycolysis) is allosterically activated by F16BP and inhibited by high energy molecules.

however the liver isozyme of pyruvate kinase is phosphorylated by PKA in response to _________ which __________ the pyruvate kinase to reserve sugar for organs that need it

cytoplasm

parallel to glycolysis

where does the pentose phosphate pathway take place?

does pentose phosphate pathway run parallel to glycolysis or against glycolysis

oxidative: produce 2NADPH (used for reductive biosynthesis) and ribulose-5-phosphate (for nucleotide synthesis)

non-oxidative: replenishes glucose-6-phosphate and glycolytic intermediates, source of xyulose-5-phosphate (activates PFK2 and F26BP production which increases glycolysis)

what are the two main phases of the pentose phosphate pathway and what are the products/ purposes of these phases?

FBPase2 active(-P)

PFK2 active(-OH)

when PFK2/FBPase2 enzyme is phosphorylated the active domain is _________

when PFK2/FBPase2 enzyme is dephosphorylated the active domain is _________

(IN LIVER)

fructose 6 phosphate→ fructose 2,6 bisphosphate by phosphorylation (on 2nd position)

how does PFK2 "“make” F26BP

glucose-6-phosphate → 6-phosphogluconate (NADP+ →NADPH)

• NADPH used in GSSG→ 2GSH reaction by glutathione reductase, and recycled back to NADP+

6-phosphoggluconate →ribulose-5-phosphate (-CO2, NADP+ →NADPH)

• NADPH used in reductive biosynthesis of FA, stearols, etc…

list the steps of the pentose phosphate oxidative pathway from glucose-6-phosphate to ribulose5-phosphate

isomerase and epimerase

In the non oxidative phase, which two types of enzymes inter convert xyulose-5-phosphate and ribulose-5-phosphate?

transketolase (2) and transaldolase (3)

which two enzymes allow of the transfer of 2/3 carbons between sugar phosphates allowing rearrangemnet of 5C molecules to 6C molecules (glycolytic intermediates)?

3-7C

transketolase and transaldolase allow interconversion of sugars between ___C and ____C

(6) 5C sugars→ (5) 6C sugars

the net reaction in PPP is (6) 5C sugars→ ______

3 × 5C=15C

(rearrangements by transketolases and transaldolases)

result: 2 fructose-6-phosphate + 1 glyceraldehyde-3-phosphate

(net 6C+6C+3C=15C conserved)

starting from 1 ribulose-5-phosphate and 2 xyulose 5 phosphate molecules, what are products of PPP

gluconeogenic steps

final glyceraldehyde-3-phosphate can be converted into glucose-6-phosphate by

inhibited by NADPH (neg feedback as NADPH is produced in steps of pathway)

stimulated by NADP+ (pathway needs to make more NADPH)

glucose-6-phsophatase dehydrogenase (glucose-6-phosphate→ 6-phosphogluconolactone rxn in PPP) is inhibited by ______ and stimulated by _____

(regulated by redox stste of the cytosol)

a polymer of glucose stored for quick energy (have about a day supply)

what is glycogen?

regulate blood glucose

glycogen is metabolized in the muscle and liver by glycolysis, the liver also uses glycogen to __________

glucose-6-phosphate→glucose-1-phosphate (phosphoglucomutase)

(note glucose-1,6 phosphate intermediate)

glucose-1-phosphate +UTP→ UDP-glucose +PPi (UDP glucose pyrophosphatase)

the precursor of glycogen synthesis is UDP glucose, how is this produced from glucose-6-P?

activated sugar donor

UDP glucose is the __________ for glycogen synthesis to start

>4

for UDP-glucose to be added to a glycogen chain how long must the glycogen chain be

UDP-glucose + non-reducting end of glycogen chain→ UDP + longer glycogen chain

how does UDP glucose become part of glycogen?

the breakdown of glycogen

glycogen phsphorylase a + Pi cleaves off non reducing end and removes a glucose-1-phosphate from the glycogen

(reverse of glycogen synthesis)

what is glyconeogenesis? what enzyme is used?

reduce cellular osmotic pressure in cell to take in more glucose

why store glucose as glycogen?

to be the phosphate on glucose-1-phosphate and save energy (no ATP needed)

why is Pi used to cleave glucose-1-phosphate off from glycogen?

phsophorylation (makes glycogen synthase b- inactive)

gkycogen synthase kinase 3 (GSK3) is inactivated by _______

phsophorylation done by glycogen phosphorylase kinase b

glycogen phosphorylase is activated by ______ done by _______________ enzyme

dephosphorylation done by glycogen phosporylase a phosphatatse

glycogen phosphorylase is inactivated by ________ done by ____________ enzyme

PKA

glycogen phosphorylase kinase b is mediated by ______

phosphorylase a phosphatase

glycogen phsophorylase is a glucose sensor, glucose binding has an allosteric effcet on glycogen phsophorylase a and favours its dephosphorylation to glycogen phosphorylase b by enzyme _________ to produce glycogen phoshorylase b

enzyme that breaks down glycogen into glucose-1-phosphate

want it active when glucose is LOW, and inactive when glucose is already HIGH

what is glycogen phosphorylase? what it do and when u want it active>

inhibits catalytic activity and it exposes the phosphate groups on the serine residues, making them accessible. these accessible phosphate groups can the be better removed by protein phsophorylase 1 (making it dephsophorylated) now it becomes glycogen phosphorylase b.

how does glucose binding start shifting glycogen phsophorylase a to glycogen phsophroylase b?

inactivates (a→b)

high glucose ______ glycogen phosporylase

glycogen synthase a →glycogen synthase b ( by GSK3)

glycogen synthase b→ glycogen synthase a (by PP1)

glycogen synthase a →glycogen synthase b ( by ____________)

glycogen synthase b→ glycogen synthase a (by ____________)

glycogen phosphorylase a →glycogen phosphorylase b ( by PP1 )

glycogen phosphorylase b→ glycogen phosphorylase a (by phsophorylase kinase )

glycogen phosphorylase a →glycogen phosphorylase b ( by _________)

glycogen phosphorylase b→ glycogen phosphorylase a (by _________ )

glycogen phosphorylase active when: the cell needs energy (low glucose) and functions to break down glycogen

glycogen synthase active when: energy levels are high (high glucose) and functions to add glucose to store as glycogen

glycogen phosporylase is active when _____________ and functions to __________

glycogen sythase is active when _____________ and functions to __________

increase glycogen breakdown

decrrease glycolysis and glycogen synthesis

PKA regulation ensures that when blood sugar is low, the liver increases __________ and decreases ___________ and ____________ so that sugar can go to tissues that need it more

muscle: increased glycogenolysis and glycolysis (glycogen→pyruvate)

liver: increased glycogenolysis and gluconeogenesis, decreased glycolysis

what does epinephrine signal to occur in muscle?

what do epinephrine and gluacgon signal to occur in liver?

Myocytes lack glucagon receptors
Muscle pyruvate kinase is not phosphorylated by PKA
Muscle lacks gluconeogenic enzymes
Muscle lacks a key enzyme for glucose export
→ Muscle uses stored glycogen and glucose for itself

why does muscle not do gluconeogenesis? why are muscle and liver metabolisms different?

muscle: decreased glycogenolysis and increased glycolysis (pyruvate→glycogen)

liver: decreased glycogenolysis and gluconeogenesis, increased glycolysis

What does insulin signal to occur in muscle?

What do insulin (and low glucagon) signal to occur in liver?

In muscle:

• Epinephrine says "use your glycogen for energy NOW" → glycogenolysis + glycolysis ↑

• Insulin says "you have plenty of glucose, store it" → glycogen synthesis ↑, glycolysis ↓

In liver:

• Epinephrine/glucagon say "make and release glucose into the blood" → glycogenolysis + gluconeogenesis ↑, glycolysis ↓

• Insulin says "blood glucose is high, stop making more" → glycogenolysis + gluconeogenesis ↓, glycolysis ↑

The core logic:

• Epinephrine = fight-or-flight → muscles need fuel fast, liver dumps glucose into blood

• Glucagon = low blood sugar → liver makes glucose to raise blood levels back up

• Insulin = high blood sugar → everyone take up glucose, store it, stop making it

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