Glycolysis and Gluconeogenesis

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description of gluconeogensis: making NEW glucose (not from glycogen)
-opposite of glycolysis
role of gluconeogensis: replenishes glucose that is consumed by glycolysis
role of gluconeogensis in 1)liver 2)muscle: 1) maintains blood glucose level
2) replenishes glycogen consumed in earlier bursts of muscle activity
can skeletal muscle make glucose?: no, can only go to G6P.. used to replenish/store glycogen
where does glycolysis occur?: cytoplasm
what other sugars can enter glycolysis: 1) fructose directly
2) galactose after conversion to glucose
where does gluconeogensis occur?: 90 % liver
10% kidney
net energy result of glycolysis: 2 ATP
2 NADH (2 electrons each)
rate-determining step in glycolysis: phosphofructokinase
converts Glucose 6 Phosphate to Fructose 6 Phosphate: Phosphoglucoisomerase
Converts Fructose-6-Phosphate to Fructose 1,6 Bisphosphate: Phosphofructokinase
what is a major feedback inhibitor of PFK-1?: ATP
what is the effect of ATP on PFK-1?: alters the Km of PFK-1 for substrate (Fructose-6-Phosphate)
How is Km altered if Low ATP levels: has low Km for F6P
How is Km altered if High ATP levels?: has high Km for F6P
why does it make sense that ATP is negative inhibitor of PFK-1 activity?: ATP is an inhibitor of making more ATP
An intermediate of the TCA cycle that serves as a feedback inhibitor of glycolysis: Citrate
what type of change in pH would inhibit activity of PFK-1 (glycolysis)?: a drop in pH (higher H+)...lactic acid generates H+....has risk of acidifying cell until it dies
Activators of PFK-1 (glycolysis): AMP, ADP and P....all signal that the cell needs more ATP production
catalyzes reaction of ATP + AMP = 2 ADP: Adenylate Kinase
what is the sensitive indicator that ATP is being used?: AMP
Major allosteric regulator of PFK-1....regulatory molecule and not a metabolic intermediate: Fructose-2,6- Bisphosphate
Sets the overall rate of glycolysis: Fructose-2,6- Bisphosphate
(sets rate of glycolysis by setting rate of PFK-1)
what is the concentration of Fructose-2,6-Bisphosphate regulated by?: hormonally regulated by the balance between glucagon and insulin in the liver
how does Fructose-2,6-Bisphosphate work?: modulates the km of PFK-1 for it's substrate, Fructose 1,6- Phosphate and it's inhibition by ATP
what happens to ATP inhibition in the presence of Fructose-2,6- Bisphosphate?: ATP's inhibition is decreased
what forms Fructose-2,6- Bisphosphate?: phosphofructokinae 2 (PFK-2) using Fructose-6-Phosphate as substrate
What breaks down Fructose-2,6-Bisphosphate to Fructose-6-Phosphate and P?: Fructose Bisphosphatase 2
two enzymes contained in a single bifunctional enzyme that regulate Fructose-2,6- Bispohspate: PFK-2 and Fructose Biphosphatase (FBPase-2)
PFK-2 and FBPase-2 contain what three domains?: regulatory domain
kinase domain
phosphatase domain
kinase and phosphatase activites of PFK-s and FPBase are allosterically regulated by what? covalently regulated by what?: Fructose-6-Phosphate
Phosphorylateion of a single serine residue by a protein kinase
In the liver, what occurs on the regulatory domain of PFK-2 and FBPase-2?: serine residue is located right on regulatory domain- covalenly regulates the activity
what is the effect of glycogen on PFK-2 and FBPase 2?: phosphorylates complex and activates FBPase-2...glycolysis slows down and gluconeogenesis is stimulated
Inslulin's effect on F-2,6-Bisphosphate?: increases levels and stimulates liver glycolysis to clear up glucose from the blood.
Fuction of Aldose: Creates a ketone (Dihydroxyacetone Phosphate) and an aldehyde (Glyceraldehyde 3 Phosphate)...later will be used in glycolysis
converts DHAP and GAP: TRIOSE PHOSPHATE ISOMERASE
importance of TRIOSE PHOSPHATE ISOMERASE: without this enzyme, only half of each glucose molecule would proceeed through glycolysis..no net ATP production
First step of generating energy in glycolysis: Glyeraldhyde 3 Phosphate converted to 1, 3 Bisphosphglycerate by GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE
importance of GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE: Generates NADH
what is GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE inactivated by?: heavy metals- Cysteinse SH group
-Arsenate Poisoning- (Arsenate resembles P)
What resembles Phosphate and has potential to poison GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE?: Aresenate
which enzyme harvests the energy of the very high energy anhydride bond?: PHOSPHOGLYCERATE KINASE
what kind of bond is formed when NAD is reduced to NADH?: Very high energy ANHYDRIDE BOND when Glyceraldehyde-3-P is oxidized to a carboxylate.
Enzyme involved in first production of ATP (substrate level phosphorylation): PHOSPHOGLYCERATE KINASE
PHOSPHOGLYCERATE KINASE hydrolyzes which compound to generate ATP?: 1,3- Bisphosphoglycerate
what is product formed when ATP is produced by hydrolization of high energy anhydride bond?: 3-Phosphoglycerate
How is hemoglobin regulation related to glycolysis?: 1,3 Bisphosphoglycerate can be converted to 2,3 Bisphosphoglycerate, which is a regulatory molecule of hemoglobin for Oxygen affinity
How can 2,3 Bisphosphoglycerate re-enter glycolysis?: 2,3 Bisphosphoglycerate Phosphatase converts it back to 3-Phosphoglycerate
What is the role of Phosphoglycerate Muatase: Converts 3 Phosphoglycerate- 2 Phosphoglycerate
what is converted the enzyme that converts 2-Phosphoglycerate to Phosphoenolpyruvate?: ENOLASE
what drives the reaction that uses ENOLASE?: release of water
what is the high energy compound formed that will generate second ATP? (formed from what low energy compound)?: Phosphoenolpyruvate
Role of PYRUVATE KINASE: phosphoenolpyruvate to pyruvate
Seocond IRREVERSIBLE/ KEY step in glycolysis: PYRUVATE KINASE
PYRUVATE KINASE is subject to feedforward activateion by what?: Fructose-1,6-Bisphosphate...allows regulation of the two irreversible stes in glycolysis
PYRUVATE KINASE is subject to feedback inhibition by what molecules: ATP
ALANINE
How does ALANINE inhibit PYRUVATE KINASE?: signals for pprotein degregation and utilization of amino acids by gluconeogenesis.
why is ATP and Alanine regulation important in muscle cells?: only want to be running glycolysis in muscles when they are using energy
why does liver run glycolysis even in an ENERGY RICH state?: to convert to pyruvate- to store fat
Is PYRUVATE KINASE active or inactive when phosphorylated?: INACTIVE
what reactivates PYRUVATE KINASE?: pp1 through dephosphorylation
pp1 wants...: glycogen synthesis
pyruvate
(clears blood glucose)
What covalently regulates LIVER Pyruvate Kinase?: cAMP- dependent Protein Kinase
(Protein Kinase A)- inhibits PYRUVATE KINASE- slows down glycolysis
Two ways that cAMP dependent protein kinase slows down glycolysis: 1) causes decreased levels of F-2,6-Bisphosphate when stimulated by glucagon to phosphorylate bifunctional enzyme
2) inhibits PROTEIN KINASE, which slows down glycolysis
which enzyme helps to regenerate NAD+ in the cell under anaerobic conditions?: Lactate Dehydrogenase
negative side of converting lactate to pyruvate?: make lactate and the H+ that comes with it...makes cell VERY acidic!
How is NAD+ regenerated under anerobic conditions?: Shuttling the reducing equivalents (electrons, but not NADH itself) into the mitochondrion for subsequent oxidative phosphorylation
How does fructose enter glycolysis in tissues other than the liver?: HEXOKINASE converts it to Fructose-6-Phosphate
What other role does Hexokinase play besides phosphorylating glucose?: phosphorylates Fructose- Fructose-6-Phosphate so that it can enter glycolysis
why doesn't glucokinase convert Fructose to Fructose-6-Phosphate?: too much glucose to compete with
enzyme that phosphorylates Fructose in the Liver?: Fructokinase
*** requires ATP
how does fructose usually enter glycolysis if coming from liver?: Glyceraldehyde-3-Phosphate
Fructokinase converts Fructose to what?: Fructose-1-Phosphate
What initially happens to Fructose-1-Phosphate?: Fructose 1-Phosphate Aldolase converts it to GLYCERALDEHYDE and DIHYDROXYACETONE PHOSPHATE
What converts Glyceradledhye (from fructose) to Glyceraldehyde-3-Phosphate?: Triose Kinase (requires ATP)
What converts Dihydroxyacetone Phosphate (from fructose) to Glyceraldehyde 3 Phosphate?: TRIOSE PHOSPHATE ISOMERASE (same as glycolysis)
Four imporant enzymes for fructose: 1) FRUCTOKINASE (phosphorylates)
2)FRUCTOSE 1-P ALDOLASE
3)TRIOSE PHOSPHATE ISOMERASE
4)TRIOSE KINASE
What happens if there is a deficiency in FRUCTOSE-1-PHOSPHATE- ALDOLASE?: Phosphate Depletion Disorder....cell doesn't have unlimited supply of P...all of P would be used up in Fructose-1-P....not enough Ps to make ATP
how does galactose enter glycolysis?: As GDP
what converts UDP Galactose to UDP glucose?: EPIMERASE (switches 1 OH group)
Glycolysis is stimulated by_______ and inhibited by________: INSULIN, GLUCAGON
how do insluin and glucagon regulate glycolysis?: regulating at the level of protein phosphorylation
Where are the 3 IMPORTANT glucagon sites of action?: 1) glucokinase
2) PFK-2
3) pyruvate kinase (LIVER ONLY)....stimulates cAMP dependent protiein kinase to slow down glycolysis
how does glucagon act? via which protein?: cAMP-dependent Protein Kinase
what is the clinical presentation of defects of glycolysis? and why?: hemolytic anemia...rbc's have no other alternative way to make energy
where do most of mutation in glycolysis occur?: pyruvate kinase
what is the one thing you CANNOT make glucose from?: fatty acids
what is the part of triglycerides that can be converted to glucose when in starvation mode?: glycerol
substrates for gluconeogenesis in times of prolonged fasting (4): lactate
pyruvate
glycerol
alpha-ketoacids
glucogenic amino acid: can be degraded to molecules that can be converted to glucose
ketogenic: amino acids that make ketones (lead to Acetyl CoA)....Lysine and Leucine
IRREVERSIBLE STEPS IN GLYCOLYSIS: Glucose- G6P
Fructose- Fructose 1,6-Bisphosphate
Phosphoenolpyruvate-Pyruvate
Four enzymes involved in Gluconeogensis: 1)Pyruvate Carboxylase
2)PEP Carboxylase
3) Fructose 1,6- Bisphosphatase
4)Glucose 6 Phosphatase
Role of Pyruvate Carboxylase: converts pyruvate to oxaloacetate
where does Pyruvate Carboxylase work?: in mitochondrial matrix
what is the coenzyme used by Pyruvate Carboxylase?: Biotin
Frunction of Biotin: coeenzyme that adds CO2
difference between oxaloacetate and pyruvate?: oxaloacetate has extra CO2 (carboxyl group)
oxaloacetate can't get out of mitochondrial matrix, so what is done?: is conerted to MALATE or ASPARTATE
enzyme that converts Oxaloacetate to Malate? What is Produced?: MITOCHONDRIAL MALATE DEHYDROGENASE

-NADH- NAD+
enzyme that converts Oxaloacetate to Apartate?: ASPARTATE AMINOTRANSFERASE
what is the function of malate and aspartate?: used by oxaloacetate to cross the mitochondral membrane in gluconeogensis
malate is oxidized or reduced to oxaloacetate?: oxidized
oxaloacetate is oxidized or reduced to malate?: reduced
enzyme that converts Aspartate back to Oxaloacetate?: Aspartate Aminotransferase (same as other way)
enzyme that converts malate back to oxaloacetate?: Cystolic Malate Dehyrdrogenase
Cystolic Oxaloacetate is converted into what?: PEP
Function of PEP Carboxykinase: converts Oxaloacetate to PEP
what is used to decarboxylate Cystolic Oxaloacetate?: GTP, CO2
what is the expenisve reation in gluconeogensis that generates a very high energy intermediate?: PEP Carboxykinase
why it is believed that ASPARTATE is used instead of MALATE to get out of the mitochondrial matrix?: doesn't use up any NADH in the matrix and didn't make any extra NADH in the cytosol
when going backwards, PEP goes through glycolysis pathway until reaches what step?: PFK-1
what is inactivated during gluconeogenesis to prevent futile cycling?: Liver's PYRUVATE KINASE
when do you generate an NADH in gluconeogensis?: when converting Lactate- Pyruvate
fate of lactate in gluconeogenesis: 1) released by skeletal muscle
2) taken up by liver and converted to pyruvate
3) pyruvate is sent to mitochondral matrix to be converted to PEP
What is the hydrolytic enzyme that overcomes the second irreversible step in gluconeogenesis?: FRUCTOSE-1,6-BISPHOSPHATASE
what stimulates gluconeogenesis?: glucagon-cAMP dependent protein kinase- FBPase2- GLUCONEOGENESIS
during strenuous excersice what keeps energy in muscles when aerobic glycolysis cannot continue?: CORI CYCLE
what is a VERY POTENT inhibitor of gluconeogenesis?: Fructose-2,6-Bisphosphate
What inhibitis Fructose-1,6-Bisphoshatase?: Fructose-2,6-Bisphosphate

AMP (signal for poor energy state)
what activates Fructose-1,6-Bisphoshatase?: ATP (signal for energy-rich state)
what overcomes the last irreversible step in gluconeogenesis?: Glucose-6-Phosphatase
fxn of GLUCOSE-6-PHOSPHATASE?: releases free glucose from G6P
where does GLUCOSE-6-PHOSPHATSE reside?: only in liver, not in muscles!
precursor for gluconeogensis in the liver: PYRUVATE
energy requirement for gluconeogenesis: 6 ATP
high energy bond in gluconeogenesis is found in which compound?: PEP

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