Flashcards in Carbohydrate Metabolism Pt. 2 Deck (146):
How many grams of glucose does our body need in one day?
How many grams of glucose does our brain need in one day?
How much glucose is present in our body fluids?
How much glucose is readily present in our glycogen?
Can our glycogen reserves provide glucose for long periods of time?
No. Our glycogen reserves only can give us about 190 g of glucose. Our body as a whole needs about 160g. Thus, we glycogen only gives us enough for about a day.
When is gluconeogenesis useful?
During longer periods of fasting, gluconeogenesis is v important.
What is gluconeogenesis
gluconeogenesis is the creation of glucose from carbs and non-carb precursors
When does gluconeogenesis occur?
Gluconeogenesis will occur when our glucose and glycogen stores have been depleted. That is, when we are starving, on a low carb diet (ketogenic diet) or during exercise.
Where does gluconeogenesis occur?
1. liver* (main site)
2. small intestine
Overall summary of gluconeogenesis?
Converts pyruvate--> glucose
What are the major precursors of gluconeogenesis?
Gluconeogenesis must bypass the irreversible steps of glycolysis. What enzymes do this?
1. Pyruvate carboxylase
2. PEP carboxykinase
When is gluconeogenesis favored?
Glucose and glycogen are low
Tissue location of gluconeogenesis
1. liver- mostly
Where does gluconeogenesis occur?
Gluconeogenesis occurs in two areas:
Positive regulators of gluconeogenesis
3. acetyl co-A
Negative regulators of gluconeogenesis
What is the net yield of gluconeogenesis? 0
Uses: 4 ATP and 2 GTP
Makes: 6 ATP equilvalents
so 0 net yield
What is the net yield of gluconeogenesis? 0
Uses: 4 ATP and 2 GTP
Makes: 6 ATP equilvalents
so 0 net yield
Pyruvate carboxylase in the gluconeogenesis
In gluconeogenesis, pyruvate carboxylase is the ONLY gluconeogenesis enzyme found in the MT. Here, it will convert [pyruvate-->OAA] though carboxylation.
Pyruvate carboxylase has a BIOTIN COFACTOR and is activated by [acetyl-coA] and [cortisol]
What type of co-factor does pyruvate carboxylase have?
What activates the biotin co-factor on pyruvate carboxylase?
1. acetyl co-A
How can we prevent gluconeogenesis from occuring all of the time?
As we have mentioned, pyruvate carboxylase converts [pyruvate--> OAA] in the MT. OAA cannot pass the MT membrane to go outside into the cytosol.
SOOO. OAA must be converted into [malate] by [malate dehydrogenase]. Malate can readily cross the MT membrane into the cytosol. It is then [REOXIDIZED] into OAA.
Pyruvate carboxylase is an enzyme located in the ______, that converts ______ to ______
Can OAA readily pass the MT membrane--> cytosol?
No. It must be converted to malate via malate DH in the MT and re-converted to OAA once outside.
This ensures that specificity of gluconeogenesis.
PEP Carboxykinase in gluconeogenesis
[OAA]--> [PEP] through phosphorylation & decarboxylation. A GTP is used.
Activators of PEP carboxykinase
What two processes are occur when PEP carboxykinase [OAA--> PEP]?
Fructose-1,6-Bisphosphotase in gluconeogenesis
Fructose-1,6-bisphosphotase converts [F16P-->F6P].
IT IS THE RATE LIMITING STEP
[those two are both activators for glycolysis]
What is the rate limiting step in gluconeogenesis?
Glucose-6-Phosphotase in Gluconeogenesis
[G6P--> glucose] via [G6Pase] via a dephosphorylation.
What activates G6Pase?
What substance is a activator for all regulatory enzymes in gluconeogenesis?
CORTISOL. It is a activator of the biotin cofactor on Pyruvate kinase.
Where is G6Pase found?
SI, liver, kidneys and pancreas
G6P--> glucose via _____________, which is located in ______________
lumen of the ER
G6Pase has what kind of transporter?
Transportation of G6P and Glucose
1. G6P is transported into the lumen of the ER using a G6P transporter.
2. Here, G6Pase will convert G6P to glucose
3. Glucose is then moved to the cytoplasm using GLUT7 transporter
What is the relevance of the Cori Cycle?
As we have previously said, anaerobic glycolysis occurs in 1. exercising muscle and 2. RBC. It converts pyruvate--> [lactate]. However, we do not want a buildup of lactate in these cells. So, the Cori Cycle prevents this by moving lactate out of these cells, into the blood, into the liver where the lactate can undergo gluconeogenesis. Glucose is made and then sent back to [exercising muscle] and [RBC].
What are the two disorders that can occur in gluconeogenesis?
1. F-1,6-BP deficiency
2. Von Gierke Dz
What are the order of things broken down for gluconeogenesis?
What happens where there is a F-1,6-BP deficiency in gluconeogenesis?
A F-1,6-BP deficiency in gluconeogenesis is similar to Tarui disease in glycolysis.
We are unable to make glucose from our sources.
Von Gierke Disease
Von Gierke disease occurs when there is a problem with glucose-6-phosphotase (G6Pase).
In this disease, glucose is essentially stuck inside of the cell and cannot be transported into the blood from the liver in [gluconeogenesis and glycogenolysis].
What cycles can Von Gierke Dz appear in?
_________ can be cleaved by sucrase to make
__________ & _________.
Sucrose can be cleaved by sucrase to make
fructose & glucose
_________ can be cleaved by lactase to make
_________ & _______
Lactose can be cleaved by lactase to make
galactose & glucose
How does the cell take up fructose?
How does the cell take up [galactose] and [glucose], made from sucrose and lactose?
GLUT5 Transporters do what?
Move fructose into the cell
SGLT-1 Transporters do what?
Move galactose and glucose into the cell.
GLUT2 Transporters do what?
GLUT2 transporters move cells from [fructose, galactose and glucose] from the [CELL--> BLOOD].
So these work once these items are already inside the cell.
Fanconi Bickel Syndrome occurs when the GLUT2 receptors are fucked up. Fructose, glucose and galactose inside of the cell cannot be taken out into the bloodstream.
What are the genetics of Fanconi Bickel Syndrome?
What transporter is affected in Fanconi Bickel Syndrome?
GLUT2- which moves fructose, galactose and glucose out of the cell into the bloodstream.
Polyol Pathway (basic)
Polyol pathway is the conversion of [glucose] into [fructose]
Why would we want to convert glucose to fructose in the polyol pathway?
We want to do this because fructose metabolism is FASTER. We can bypass the rate limiting step.
Describe the polyol pathway
[Glucose--> sorbitol] via aldose reductase
[Sorbital--> fructose] via sorbital DH
Pt Matthew lacks sorbital DH. What can happen?
Sorbital DH converts sorbital--> fructose.
If a patient lacks sorbital DH, they will have a build up of sorbital, which can cause cataracts.
How is fructose metabolized?
Fructose can be metabolized two ways:
1. Hexokinase can phosphorylate [fructose--> F6P], where it can then enter glycolysis.
Metabolism is faster if it bypasses the rate-limiting step and is converted into [glyceraldehyde-3-phosphate G3P].
Is High Fructose Corn Syrup linked to obesity?
It is thought that HFCS is linked to diabetes because since it passes the rate limiting step of PFK-1, it is easier turned to fat. However, only 55% of HFCS is fructose. the rest is sucrose. so, it is though that an overall increase in calories and sugar is linked to obesity.
Galactose can be metabolized and enter glycolysis as G6P
Galactose can be metabolized and enter glycolysis as
Enzymes in Galactose metabolism
Pathway for galactose metabolism
galactose--> galactose-1-phosphate via [galactokinase]
galactose-1-phosphate--> glucose-1-phosphate via [GALT]
It will then eventually be turned into G6P and can enter glycolysis
What happens if there is a defect in ______ and ______ enzymes for galactose metabolism?
galactokinase and GALT
Galactosemia-->a build up of galactitol
Galactosemia is a build up of galactose because GALT or galactokinase are defective.
Can cause cataracts
PPP is a oxidative/reductive pathway?
In the PPP, what is the primary substrate we begin with?
It takes G6P to make ribose and NADPH.
Does the PPP make energy?
No, it does not make ATP or GTP.
Where does the PPP occur?
Cytosol, like glycolysis.
What happens to G6P in PPP?
G6P is oxidized to ribulose-5-phosphate and NAD+ is reduced to NADPH.
2 main steps in PPP
1. oxidative that is irreversible (catabolic)
2. non-oxidative that is reversible (anabolic)
thus, PPP is AMPHIBOLIC!!!!!
Oxidative steps of PPP makes
2 NADPH and 1 CO2
There are ___ oxidatative steps in PPP.
1st oxidative step of PPP
G6P is oxidized by [G6P DH]
& NADP+ is reduced to NADPH.
This is the rate limiting step!
What were to happen if someone were deficient in G6P DH?
They would not be able to make NADPH. This occurs in a high proportion of African-Americans, making them more susceptible to hemolytic anemia.
Why is NADPH important though?
NADPH is super important because it helps to make glutathione, a anti-oxidant that helps us to detoxify H2O2.
2nd oxidative step in PPP
Phosphoglucanate DH will create ribulose-5-phosphate through decarboxylation.
CO2 is released and NADPH is made.
Non-oxidative steps in PPP
The second part of the PPP is non-oxidative. It turns ribulose 5-phosphate--> ribose-5-phosphate, the precursor to many nucleotides.
ribose 5 phosphate can then made [G3P or [F6P] and enter glycolysis or gluconeogenesis.
Non-oxidative part of PPP turns ________ into _______.
ribulose 5 phosphate
Product of non-oxidative PPP (_______) can then do what?
is the precursor to nucleotides.
ribose-5-phosphate can then be converted into G3P or F6P and then enter glycolysis.
A cell is dividing rapidly. Which phase of the PPP will it favor?
The rapidly dividing cell will favor the oxidative phase because it needs to make DNA.
This can also be obtained by reversing the non-oxidative phase.
Cells that have a high demand for NADPH will favor what phase of the PPP? Why?
A cell that has a high demand for NADPH will favor the non-oxidative phase. Why?
The non-oxidative phase creates metabolites that can enter glycolysis (G3P) and (F6P) and glucneogenesis. If these products are made, they can enter GLUCONEOGENESIS and re-enter the PPP.
What enzyme catalyzes the rate limiting step in PPP?
Glucose-6-Phosphate DH (G6P DH)
Glycogen is a polymer of _____
Glucoses in glycogen are held together by _______
Polymers at the branch points of glycogen are held together by
________ is the polymer for the production of glycogen
The first glucose will attach itself to ______. This is called the ______ end.
The first glucose will attach itself to glycogenin. This is called the reducing end (not free.
The free end of glycogen is called the _______.
How can we spot the non-reducing end in glycogen?
OH group at the carbon 4.
How can we spot the reducing end of glycogen?
Reducing end is attached to glycogenin.
Glycogen is stored in granules in two places: the liver and muscle.
The granules has all of the enzymes needed to metabolize glycogen.
Are the roles for glycogen in the muscle and glycogen in the liver the same?
What does glycogen in the liver do?
Glycogen in the liver helps to regulate our blood sugar.
What does glycogen in the muscles do?
Used as a reservoir for when we are working out!
What are the three key steps in glycogenosis
1. Trap and activate glucose
2. Elongate the chain
3. NOW WE GOTTA BRANCH
Trap and activate glucose
1. hexokinase/glucokinase will bring glucose into the cell and trap it! --> G6P
2. G6P--> G1P [via PGM phosphoglucomutase]
3. G1P will then be tagged with UDP to create [UDP-Glucose]
Elongate the chain!
UDP-Glucose is added to the primer (glycogenin) via glycogen synthase
Rate limiting step!
This will continue
BRANCH THAT SHIT
Glucosyl (4:6) transferase will break the elongating chain and attach it elsewhere using a alpha-1,6-linkage
What enzyme is responsible for elongating the chain?
Adds UPD-Glucose to glycogenin
What enzyme is responsible for branching?
glucosyl (4:6) transferase
breaks elongating chain and adds it somewhere else
What enzyme is the rate limiting step in glycogenosis?
Glycogenolysis has ___ key steps
1. Chain shortening
2. Branch transfer to the long chain
Chain shortening in glycogenolysis
1. Glycogen phosphorylase will phosphorylate and remove glucose resides as [glucose-1-phosphates].
RATE LIMITING ENZYME
This will continue until you are 4 away from the branch point!
Branch Transfer to long chain in glycogenolysis
1. Debranching enzyme will remove 3/4 remaining glucoses and transfer them to chain and attach to the non-reducing end
We now have 1 glucose left. [Alpha-1,6-glucosidase] will now remove the last glucose and release it as a FREE glucose!
Glu-1-P and free glucose are released in a ratio of
What is the rate limiting step in glycogenolysis?
______ will remove the last glucose from the alpha-1,6-linkage and release it as a free glucose
What happens to Glu-1-P in the muscle?
Glu-1-P in the muscle is converted to G6P and enters glycolysis in the muscle to provide ATP.
G6P will never leave the cell because it does not have a G6Pase. Thus, as we said, the "glucose" in the muscle only fends for itself.
What happens to Glu-1-P in the liver?
converted to Glucose to help regulate our blood sugar.
Does glycogenolysis (glycogen breakdown) occur in the lysosome?
alpha-1,6-glycosidase is also called
Pompe disease occurs in lysosomal breakdown of glycogen when there is a problem with alpha-1,6-glycosidase. we have a hard time breaking down glycogen.
Why is regulation of glycogen metabolism important?
1. helps to maintain blood sugar
2. provides energy for our muscles.
For glycogen synthase to work, do you want it to be dephos or phosphorylated?
Glycogen synthase is active when it is DEphosphorylated
Glycogen phosphorylase is active when it is _______
For glycogen phosphorylase to be active, do you want it dephos or phosphorylated?
Glycogenolysis is favored in the FASTING state. Why?
Blood glucose is low.
glucagon is high.
If Ca2+ and AMP is high in our muscles, what is this telling us?
[Q:] Does glucagon act on muscle?
NO. Muscle is not affected by insulin and glucagon because the glycogen in it is only used for the muscle.
Insulin binds to what kind of receptors?
How does insulin regulate glycogen metabolism in terms of glycogen synthase and glycogen phosphorylase?
Insulin enters the body
Glycogen synthase will be dephosphorylated= making it active!
Glycogen phosphorylase will be dephosphorylated= inactive
How does glucagon regulate glycogen metabolism in terms of glycogen synthase and glycogen phosphorylase?
Glucagon is released in our body.
Glycogen synthase is phosphorylated= inactive
Glycogen phosphorylase is phosphorylated= active.
glucagon does/does not act on muscle
What protein kinase does glucagon activate?
Protein kinase A
Insulin and glycogen metabolism pathway
Increase insulin= increase glucose= glycogenosis
Glycogenosis occurs via glycogen synthase, which is active when DEPHOSPHORYLATED.
Insulin comes in and binds to tyrosine kinase. 2 things happen:
1. triggers glut4 receptors to membrane to let Glu in.
2. activates protein kinase B.
3. Protein kinase B will phosphorylate PP1 (protein phosphotase 1)
3. PP1 will dephosphorylate glycogen synthase and dephosphorylate glycogen phosphorylase.
insulin binds to
glucagon binds to
Epinephrine and glycogen metabolism
Epinephrine is released when we are working out in our muscles. it tells us to break down glycogen (glycogenolysis). Has the same mechanism as glucagon because it binds to the same receptors
Epi binds to GCPR
G protein will activate AC to convert ATP--> cAMP
cAMP activates protein kinase A
Protein kinase A will then phosphorylate glycogen synthase and glycogen phosphorylase.
All glycogen storing diseases are
Glycogen disorders that affect breakdown will do what?
Glycogen disorders that affect synthesis will
cause patient to depend on FREE glucose
We cannot make glycogen because it is responsible for elongating the chain
Acid maltase (alpha-1,6- glucosidase)
Problem with lysosomal glycogenolysis.
We cannot release the last Glu to be released as a free glucose.
Debranching enzyme (alpha-1,6-glucosidase)
Consequence: long linear glucose with short branches
Von Gierkes Disease
cannot release glucose
Glycogen phosphorylase in the muscle
We cannot provide NRG to our working muscle
Glycogen phosphorylase in the liver
Cannot break glycogen down to provide glucose to regulate our blood sugar. thus, we will depend on only our free glucose
How can we treat glycogen storing disease?
Diet. A lot of them are inborn disease. Research is now pushing for enzyme replacement therapy
Liver glycogen phosphorylase and muscle glycogen phosohrylase are _______
Mutation in liver glycogen phosphorylase leads to
Mutation in muscle glycogen P leads to
What is the enzyme in glycogenesis that introduces the branch?
glucosyl 4:6 transferase
at 11 residues, will cut off and introduce at an alpha1:6linkage