Gluconeogenesis
synthesis of new glucose from NON-CARBOHYDRATE source (making new glucose in fasting state)
TRUE/FALSE: Gluconeogenesis is a synthesis pathway because making new glucose.
FALSE --> new glucose is being made, BUT it happens in a catabolic state (fasting/starving), so it is a catabolic pathway
Why does gluconeogenesis occur?
b/c availability of glucose for the brain & nervous system is very important (in fasting state body needs way to provide)
Is gluconeogenesis the reverse of glycolysis?
Not quite, b/c glycolysis->pyruvate had out of 10 glycolytic enzymes, 3 enzymes that were non-reversible; therefore, these 3 enzymes (hexokinase, PFK-1, pyruvate kinase) create an activation barrier; to pass activation barrier new enzymes are needed
Precursors for Gluconeogenesis:
- alpha-keto Amino Acids (all 18 except Leucine and Lysine)
- Glycerol portion of Fatty Acids
- Lactate (reversal of glycolysis)
TRUE/FALSE: Gluconeogenesis is a series of enzymatic reactions that produce Glucose from carbohydrates.
FALSE --> Gluconeogenesis sources are non-carbohydrate (lactate, glycerol, TCA cycle intermediates, alpha-keto acids/amino acids)
Enzymes reactions specific to gluconeogenesis for bypassing the irreversible steps of glycolysis:
Pyruvate carboxylase; PEPCK
Fru-1,6-Bisphosphatase-1 (FBP1)
Glu-6-Phosphatase
Gluconeogenesis occurs primarily in the ____ and to a lesser extent in the _____.
liver (90%)
kidney (10%)
Gluconeogenesis requires...
energy
(pos. delta-G; endothermic)
In absence of dietary carbohydrates, liver glycogen is depleted ___.
~ 18 hours
(so after 16-17 hrs fasting, pretty much exhausted all body's glucose stores & body goes to catabolic state)
____ is released into the blood by cells lacking mitochondria, such as occurs in RBCs or during anaerobic conditions like exercising skeletal muscle.
Lactate
Lactate from muscle circulates to liver where converted to Glucose and released back to blood...
Cori Cycle
(concerns only muscle and liver tissue; lactate recyclation)
RBCs only get energy from ____.
glucose
(no mitochondria present; cannot brk dwn fats w/o mitochondria)
___ is released during hydrolysis of triaglycerols in adipose tissue and delivered to blood by liver.
Glycerol
___ are derived from the metabolism of glucogenic amino acids
alpha-keto acids
Metabolism of Glucneogenic Precursors...
A.) Conversion of lactate to pyruvate
B.) Conversion of Alanine to pyruvate (NH3 transferred to alpha-ketoglutarate to produce glutamate)
C.) Conversion of glyceral to DHAP
Lactate + NAD+ -[______]->
[lactate dehydrogenase]-> pyruvate + NADH,H+
Alanine -[_______]->
[alanine transferase]-> pyruvate
Glycerol + ATP -[_____]-> Gly-3-P (+ADP)
glycerol kinase
Gly-3-P + NAD+ -[________]->
[Glycerol 3-phosphate dehydrogenase]-> dihydroxacetone phosphate + NADH,H+
1st step to bypass irreversible glycolytic reaction is conversion of ____ to ____ (involves 2 enzymes).
pyruvate, phosphoenolpyruvate (PEP)
2 enzymes required to bypass irreversible glycolytic reaction: pyruvate->PEP
1.) pyruvate carboxylase (pyruvate->oxaloacetate)
2.) PEPCK: phosphoenolpyruvate carboxykinase (oxaloacetate->PEP)
If needed (lactate precursor), pyruvate transferred from cytosol to mitochondrial compartment where it is a substrate for _____ _____ (requires ATP).
pyruvate carboxlase
In _____, pyruvate is carboxylated to produce oxaloacetate (OOA).
mitochondria
Oxaloacetate is reduce to malate via ____ ____ then crosses mitochondrial membrane and reoxidized to oxaloacetate by cytosolic ______ _____.
malate dehydrogenase,
malate dehydrogenase
____ then converts oxaloacetate to PEP through decarboylation of oxaloacetate (requires GTP).
PEPCK: phosphoenolpyruvate carboxykinase
____ is activated and transferred to pyruvate by pyruvate carboxylase producing oxaloacetate.
CO2
Oxaloacetate cannot cross the mitochondrial membrane, so it is reduce to _____ that can.
malate
In the cytosol, ____ is reoxidized to ____, which is converted to phosphoenolpyruvate by PEPCK.
malate,
oxaloacetate
2nd bypass reaction unique to gluconeogenis is catalyzed by ____ ____.
fructose 1,6-bisphosphate-1
(*Important regulatory site of gluconeogenesis)
3rd, final catalytic step is conversion of ____ ____ to glucose providing free glucose for transport from the liver.
Glucose 6-Phosphate
(catalyzed by GLU-6-PHOSPHATASE)
TRUE/FALSE: Glu-6-Phosphatase is unique to gluconeogenesis.
FALSE --> Glu-6-Phosphatase is unique to both GNG and glycogenolysis
TRUE/FALSE: We cannot reverse pyruvate to Acetyle CoA.
TRUE
(reason pyruvate is not involved in gluconeogenesis)
Gluconeogenesis requires energy (calories) because...
- an energy investment process
- endothermic reaction
Need ___ ATP and ___ mol NADH,H+ to make 1 mol glucose (from 2 mol pyruvate).
6 ATP,
2 NADH
Main function of liver is to provide _____/______.
gluconeogenesis/glycogen
Liver provides glucose from glycogen ___.
1st
After liver provides glucose from glycogen...
then muscle break down happens.
after liver provides glu from glycogen 1st and then from muscle break down...
liver makes AAs available for gluconeogenesis in liver.
Where does gluconeogenesis link with TCA cycle?
oxaloacetate (all Krebs cycle intermediates are GNG precursors)
Regulation of gluconeogenesis:
pyruvate caroxylase/PEPCK [pyruvate<->PEP]
Fru bisphophatase-1 [Fru-1,6-bis-P<->Fru-6-P
Glu-6-P [Glu-6-P<-> Glu]
Regulation of Glycolysis:
Pyruvate [pyruvate <-> PEP]
Phosphofructo-kinase-1 [Fru-1,6,bis-P<->Fru-6-P]
Glucokinase [Glu6-P<->Glu]
Glucagon
catabolic hormone
Low Fru 2,6-bis-phosphate levels...
- activates Fru-6-bisphosphate-1
-inhibits phosphofructokinase 1
Glucagon via cAMP activation of protein kinase, converts ____ ____ to inactive (phosphorylated) form.
pyruvate kinase
Glucagon induces PEPCK gene to ____ PEP carboxy kinase levels.
increase
Increased substrate levels -> ____ rate hepatic gluconeogenesis.
Increased
Increased Free Amino Acids released from muscle due to ____ insulin levls.
low
Increased Acetyl CoA during fasted state beta-oxidation of fatty acids results in increased acetyle CoA-> activate _____ ______
pyruvate carboxylase
High ____ causes elevated cAMP and increased levels of active protein kinase A.
glucagon
Increased protein kinase activity favors the ___ __ form of PFK2/FBP.
phosphorylated
Phosphorylated PFK-2 is ___, whereas FBP2 is ____; this impedes the formation of Fru-2,6-bisphosphate.
inactive
Decreased level of Fru-2,6-bisphosphate decreases the inhibition of ____, which leads to an increase rate of gluconegenesis.
FBP-1
("upregulation")