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What is gluconeogenesis?
A metabolic process that creates glucose from non-carbohydrate sources, such as amino acids, glycerol, and lactate during starvation and vigorous exercise
Why does gluconeogenesis occur?
Tissues require a continuous supply of glucose as a metabolic fuel therefore cells must be able to synthesize it when needed
What organs are gluconeogenesis production exclusive to?
Liver and a little bit of kidneys
What parts of the body only generate ATP from glucose?
Brain, nervous system, and red blood cells
Is gluconeogenesis anabolic or catabolic?
Anabolic because it uses ATP for energy (not phosphorylation)
Where does gluconeogenesis occur in the cell?
Cytosol and mitochondria
Why is gluconeogenesis similar to but not the reverse of glycolysis?
Only 7/11 steps are shared
What are the two precursors of gluconeogenesis in this course?
Glycerol and lactate
In glycerol-dependent gluconeogenesis what part of the molecule is used?
Glycerol backbone (fatty acid tails used for beta-oxidation)
What is glycerol converted to in gluconeogenesis?
Glycerol → glycerol phosphate → DHAP
What happens after glycerol is converted to DHAP in gluconeogenesis?
Essentially glycolysis occurs in reverse
What is the Cori cycle/lactate-dependent gluconeogenesis briefly?
Lactate is released into the blood by exercising skeletal muscle and RBCs into the liver and is converted to glucose which is released back into the blood
Which 3 irreversible steps from glycolysis differ and must be “bypassed” in gluconeogenesis?
Hexokinase, PFK1, PK (2 reactions occur causing gluconeogenesis to be 11 steps)
What is the first goal of lactate-dependent gluconeogenesis?
Make PEP
What is the pathway of lactate-dependent gluconeogenesis (Option L) if an organism does make lactate?
Lactate, cytosol → pyruvate, mitochondria → OAA, matrix → PEP (lactate dehydrogenase, pyruvate carboxylase, mitochondrial PEP carboxykinase)
Why is GTP needed in option L from OAA to PEP?
For phosphorylation because ATP can only be used for energy
In option L what cofactor is needed from pyruvate to OAA?
Biotin with ATP
What is the pathway of lactate-independent gluconeogenesis?
Pyruvate → OAA → malate, cytosol → OAA → PEP (pyruvate carboxylase, mitochondrial malate dehydrogenase, cytosolic malate dehydrogenase, cytosolic PEP carboxykinase)
What does PK do in glycolysis and what enzyme reverses this in gluconeogenesis?
PEP → pyruvate (two reactions therefore two enzymes reverse this: pyruvate carboxylase (pyruvate→OAA) and mitochondrial PEP carboxykinase (OAA→PEP)
What does PFK1 do in glycolysis and what enzyme reverses this in gluconeogenesis?
F6P → F1,6P (FBPase-1 in the cytosol)
What is FBPase-2?
Similar to PFK2 of PK1 it is a regulatory enzyme that converts F2,6 to F6 (opposite of PFK2)
What are 2 allosteric inhibitors of FBPase-1?
AMP (need ATP therefore glycolysis will occur), >F2,6 (PFK2 rxn pdt that pushes rxn forward)
In terms of regulation of FBPase-1, how does it differ from glycolysis and gluconeogenesis?
An effect on one will have the opposite effect on the other
What does Hexokinase do in glycolysis and what enzyme reverses this in gluconeogenesis?
Glucose → G6P (G6P translocase, transports into lumen of ER and G6P, catalyzes formation of glucose)
Where does the dephosphorylation of G6P occur?
ER
What releases excess P from the dephosphorylation of G6P?
T2 embedded protein removes excess P to the cytosol
What releases glucose from the ER after the dephosphorylation of G6P?
T3-embedded protein transports it out of the liver and to the blood
What regulates gluconeogenesis?
Glucagon is a hormone that is released during the fasting state
In terms of glucose, what do glucagon and insulin do?
Glucagon increases blood glucose levels, insulin decreases blood glucose levels
What is glucagon stimulated by and what is insulin stimulated by?
Low blood sugar, high blood sugar
What is glucagon inhibited by and what is insulin inhibited by?
High blood glucose, low blood glucose
What does glucagon get released and when does insulin get released?
Fasting state, fed state
What is beta-oxidation?
Catabolism of fatty acids (not dietary fats but adipocytes)
What does beta-oxidation produce?
Acetyl-CoA and reducing agents (NADH, FADH2)
Where does beta oxidation take place?
Mitochondria
Why are beta-oxidation and ketones coupled?
Beta-oxidation is required for ketogenesis
What part of the glycerol is used in beta-oxidation?
FA tail of glycerol backbone, each FA is released one at a time
Where does glycerol in beta-oxidation come from?
Triacylglycerols (TAGs) which are energy-rich fuels
How is the degradation also the first stage of beta-oxidation initiated?
Epinephrine and glucagon whichs stimulate lipolysis by initiating cAMP signal which activities PKA and initiates a cascade of enzymes needed to breakdown TAGs (1st messenger=glucagon, 2nd messenger=cyclic AMP)
What are the respective fates of TAGs and its components?
Glycerol→liver (gluconeogenesis), Fatty acids→albumin→muscle→mitochondria (beta-oxidation)
How are FAs activated in the cytoplasm of the cell?
Using enzyme FA thiokinase which adds CoA creating Fatty acyl CoA
How is Fatty acyl CoA transported from the cytoplasm to the mitochondria?
CPT1 (embedded transport molecule) that removes CoA and attaches carnitine creating acylcarnitine
How is acylcarnitine transported into the mitochondrial matrix?
Carnitine-acylcarnitine translocase
How is Fatty Acyl CoA regenerated in the matrix? How is carnitine-acylcarnitine translocase used again here?
CPT2 removes carnitine from acylcarnitine and adds CoA, to remove carnitine out of matrix
What are the 4 steps of beta-oxidation?
Oxidation, +FADH2 (ETC), 2) Hydration, 3) 2nd Oxidation, +NADH (ETC), 4) Thiolysis, +Acetyl-CoA (TCA)
How is a fatty acid tail broken down in beta-oxidation?
2 C at a time (even with odd-numbered tails)
How much ATP is produced from beta-oxidation resulting in 8 acetyl-CoA, 7 NADH, 7 FADH2?
131 ATP (net=129 ATP)
Will the body prioritize beta-oxidation to obtain energy?
No, glucose is always broken down first
When does ketogenesis occur?
When the body lacks sufficient carbohydrates to burn for energy and uses the Acetyl-CoA from beta-oxidation to make ketones
Where is ketogenesis restricted to?
Liver, unlike beta-oxidation which can occur in any cell
What are the 3 ketone bodies produced?
acetoacetate, 3-hydroxybutyrate (beta-hydroxybutyrate), and acetone (exhaled product)
Where are ketone bodies used?
muscle and brain primarily
How does ketogenesis begin?
Combining 2 acetyl-CoA molecules
What determines if 3-hydroxybutyrate (beta-hydroxybutyrate) is produced instead of acetoacetate?
Whether NADH is reduced or not
Where are the ketone bodies used?
Muscle, anywhere not the liver
How is 3-hydroxybutyrate used by tissues?
Oxidized to yield acetoacetate and NADH
How is acetoacetate used by tissues?
Converted to acetoacetyl CoA (from Succinyl CoA) and cleaved to produce 2 Acetyl CoA
What cycle uses the products of both ketogenesis and gluconeogenesis to create energy?
TCA
What is glycogen and where is it stored?
Branched polymer of glucose, largest stores of glycogen are in liver and skeletal muscles
What are the two types of bonds that connect glycogen?
Straight bonds held by alpha 1,4 branch bonds held by alpha 1,6
What are the 3 steps of glycogen synthesis?
glycogenin creates the glycogenic core 2) glycogen synthase extends the core using alpha 1,4 bonds into a straight line 3) glycogen branching enzyme creates branches using alpha 1,6 bonds
What form of glucose must be used in glycogen?
Activated form of glucose called UDP-glucose formed by the reaction of UTP and glucose 1-phosphate
What is UDP-glucose’s role in glycogen production?
Glucose donor
Why is glycogen an efficient storage form for glucose?
It only takes 1 ATP to make and release 31 ATP when broken down
What are the 3 steps of glycogen breakdown?
1) release of glucose 1-phosphate from glycogen [glycogen phosphorylase] 2) remodeling of glycogen to allow continued degradation [transferase+debranching enzyme/alpha 1-6 glucosidase] 3) conversion of glucose 1-6 phosphate into glucose 6-phosphate [phosphoglucomutase]
How is glucose 6-phosphate utilized?
glycolysis 2) gluconeogenesis 3) pentose phosphate pathway
What enzyme converts glucose 1-phosphate to glucose 6-phosphate?
phosphoglucomutase
Why does glycogen phosphorylase leave one glycosidic bond?
It leaves the alpha 1,6 linkage because it can only break alpha 1,4 bonds
What enzyme removes the lonely glucose molecule left behind by the glycogen phosphorylase?
alpha 1,6 glucosidase
Glycine
nonpolar
Alanine
nonpolar
Valine
nonpolar
Leucine
nonpolar
Isoleucine
nonpolar
Phenylalanine
nonpolar
Tryptophan
nonpolar
Methionine
nonpolar
Proline
nonpolar
Serine
polar
Threonine
polar
Tyrosine
polar
Asparagine
polar
Glutamine
polar
Cysteine
polar
Histidine
basic
Lysine
basic
Arginine
basic
Aspartic acid
acidic
Glutamic acid
acidic
Acidic side chains…
Donate protons
Basic side chains…
Accept protons
Acidic side chains…
Donate protons
Basic side chains…
Accept protons
What is physiologic pH?
7.4
What is the pH of an amino group?
About 9.6
What is the pH of a carboxy group?
About 2
At physiologic pH how does an amino acid look?
carboxyl deprotonated (COO-), amino protonated (-NH3+)
At what pH are both amino and carboxyl groups ionized?
7.4, physiologic
What is physiologic pH?
7.4
What is the pH of an amino group?
About 9.6
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