Week 13 - Unit 3 Flashcards
Substrates for Gluconeogenesis (critical for maintaining blood glucose levels during fasting), include ________, _______, and _______ AA.
Glycerol
Lactate
Gluconeogenic AA
Hormonal regulation (ensure GNG and Glycolysis do not occur at the same time): Gluconeogenesis (GNG) mirrors the reverse of glycolysis except at _____ key steps that are regulated. These enzymes are regulated at the level of _____ and _______ modification.
3
Transcription
Covalent
In integration of GNG and fatty Acid oxidation, GNG is reliant on FA oxidation for both _____ and for _______ that acts to stimulate pyruvate carboxylase. Pathways are tied together.
energy
acetylCoA
GNG will be activated under ______ conditions when _______ levels are high.
Fasting
Glucagon
The pathways for Glycolysis vs. GNG diverge at 3 different locations. The first divergence location for GNG is with the conversion of ______ into ________.
Pyruvate
Phosphophenolpyruvate (PEP)
The enzyme in Glycolysis that converts PEP to Pyruvate is ________ ______ and is irreversible. Therefore in GNG to convert Pyruvate to PEP it uses a series of enzymes including ________ then _________.
Pyruvate Kinase
Pyruvate carboxylase
PEP carboxykinase
The second location that the pathways of Glycolysis and GNG diverge is the conversion of _______ backwards to ________.
Fructose 1,6-Phosphate
Fructose 6-Phosphate
What enzyme will regulate the conversion of Fructose 6-P to Fructose 1,6-P in Glycolysis that is irreversible (GNG cant use the same enzyme)?
Phosphofructokinase -1 (irreversible in Glycolysis )
What enzyme will GNG use to convert Fructose 1,6-P back to Fructose 6-P since it can not use Phosphofructokinase-1(irreversible) ?
Fructose 1,6-Bisphosphatase (removal of phosphate group from Fructose 1,6-P)
What is the third and final step that GNG will diverge from Glycolysis in ?
Conversion of Glucose 6-P back to Glucose
What does glycolysis use to make Glucose into Glucose-6P ? is it irreversible?
Glucokinase (in liver)
Hexokinase (most tissues)
What is the main difference between Glucokinase and Hexokinase?
Glucokinase (in liver- only works at higher glucose concentrations)
Hexokinase (most tissues)
What enzyme will GNG use instead of Gluco/hexokinase to make Glucose 6-P back into Glucose ?
Glucose 6-Phosphatase (only in liver and kidneys, same as one used in Glycogenolysis)
-can move out of cell and into the plasma after phosphate is removed
What are the 4 precursors for GNG ? where are we getting the Carbons to synthesize exogenous Glucose?
Glycerol
Alanine
AA that can funnel into TCA cycle or make Pyruvate
Lactate
In GNG, what will convert Pyruvate into Oxaloacetate (OAA) ?
Pyruvate Carboxylase
In GNG, what will convert OAA into Phosphophenolpyruvate ?
Phosphophenolpyruvate carboxykinase
True or False:
The oxidation of Even chain Fatty Acids (majority of type in body) are not a viable substrate for Gluconeogenesis.
True
The oxidation of Even Chain FA results in the production of what?
Then what oxidizes that product / what is its fate?
Why is this important?
Acetyl CoA
Used up in TCA cycle,
- in its oxidation 2 carbons enter TCA and 2 exit as CO2
- no net Carbons available for GNG
What enzyme will get precursor for GNG lactate converted to pyruvate?
lactate dehydrogenase (reversible) will remove (H+) from Lactate to make Pyruvate
What enzyme will convert Alanine to Pyruvate?
Alanine Aminotransferase
Alanine aminotransferase is ________ and will transfer the amine group(NH3+) to ________ (then turns into glutarate) to then make the _______ that is needed.
reversible
Alpha-keto glutarate
Pyruvate (=O) is where the amine group use to be
What enzyme will convert Glycerol to Glycerol 3-Phosphate in GNG?
Is it reversible?
Glycerol Kinase
not reversible
How do you get the Dihydroxyacetone phosphate needed to combine with Glycerol 3-P to make Fructose 1,6-P ?
Comes from Glycerol that was freed during Lipolysis
2 step reaction- Glycerol Kinase (enzyme) and Glycerol 3-P dehydrogenase (enzyme) used
Is the Glycerol 3-Phosphate Dehydrogenase reversible ? (converts Glycerol 3-P to Dihydroxyacetone Phosphate in GNG)
Yes
-involved NAD+ to NADH+ in GNG to make product needed Dihydroxyacetone phosphate
Oxidation of Odd Chain FA is the exception to the FA rule in GNG. Odd chain FA will produce _______ which is then converted into ________ which can enter the TCA cycle as _______. This is the only exception to the rule that oxidation of FA do not contribute substrates to GNG.
Propionyl CoA (from 3 Carbons at omega end of chain)
Methylmalonyl CoA
Succinyl CoA
In first steps of GNG, Pyruvate in the MT is converted to ______ using the enzyme _______ _______ under fasting conditions.
OAA
Pyruvate Carboxylase
Pyruvate Carboxylase requires _______, _______ and ______ to create OAA under fasting conditions in the MT for GNG.
CO2 (added to add a 4th C onto the 3C Pyruvate)
Biotin
ATP
OAA can not be directly shuttled out of MT, it must first be converted to _____ and _______ and then can cross the MT membrane and reconverted to OAA in the cytosol.
Aspartate
Malate
In GNG, once OAA is recombined and out of the MT and in the cytosol , it will be acted on by the enzyme _________ ________ to make Phosphophenolpyruvate.
Phosphophenolpyruvate Carboxykinase
The enzyme Phosphophenolpyruvate carboxykinase will use ________ and release ______ to make PEP from OAA in GNG. (adding Phosphate group)
GTP (takes the P and GDP is released)
CO2
Pyruvate Carboxylase is also activated by ________. This will be important for linking FA oxidation to GNG.
Acetyl CoA
What enzyme converts OAA to Malate in the MT (shuttle system)?
Malate Dehydrogenase ( adding an H+ onto OAA) - it is reversible - if you remove the H+ from Malate by giving it back to NAD+ then you make Oxaloacetate
________ will convert Oxaloacetate to _______ (in MT- not the malate creation , the other one)- will reverse in Cytosol to recreate the OAA
Transaminase
Aspartate
How many carbons does PEP have?
3 Carbons (when it is made from OAA a Carbon is removed as CO2 by PEP Carboxykinase)
___________ _________ will be the enzyme that converts Fructose 1,6-bisphosphate into Fructose 6-P for GNG (bypassing the enzyme __________ from glycolysis that is irreversible)
Fructose 1,6 bisphosphatase
Phosphofructokinase-1
The last diverging step in GNG will be the removal of the phosphate group from Glucose 6-P, in this reaction ________ ______ will remove the Pi and only ______ is generated not ______.
Glucose 6-Phosphatase (in liver and kidneys in ER)- same as used in Glycogenolysis - essential step
Pi
ATP
What are the three critical steps in GNG?
**Each step is regulated and uses different enzymes than in glycolysis
- Conversion of Pyruvate back to PEP
- Conversion of Fructose 1,6-BisP back to Fructose 6-P
- Conversion of Glucose 6-P back to Glucose
The following reaction will generate GNG precursors that can enter directly into GNG, True or False:
Glycerol is converted to Dihydroxyacetone Phosphate in a two step reaction requiring both glycerol kinase and glycerol-3-phosphate dehydrogenase.
True
The following reaction will generate GNG precursors that can enter directly into GNG, True or False:
Fatty Acids are converted to AcetylCoA which is a substrate for GNG.
False
The following reaction will generate GNG precursors that can enter directly into GNG, True or False:
Alanine is converted to pyruvate using alanine aminotranferase.
True - can be directly converted with deamination
The following reaction will generate GNG precursors that can enter directly into GNG, True or False:
Glutamate is converted to alpha-ketoglutarate using glutamate dehydrogenase.
True
-Alpha Ketoglutarate is an intermediate of the TCA cycle , and can be used as substrate for GNG
The following reaction will generate GNG precursors that can enter directly into GNG, True or False:
Propionyl CoA is converted to Succinyl CoA using propionly CoA carboxylase and methylmalonlyl CoA mutase (for use as TCA intermediate)
True - example of odd chain FA usage (even FA not usable)
GNG occurs in Fasted conditions or a ratio of Insulin to Glucagon (I/G) is _________
less than 1 (I/G < 1) - more glucagon than insulin in system
Glucagon increases ________ which one of its roles is to activate ________ ________.
cAMP
Protein Kinase A
Protein Kinase A (activated by glucagon then cAMP) has several purposes including the phosphorylation and INACTIVATION of what 3 things?
- Pyruvate kinase
- Glycogen synthase
- Phosphofructose kinase 2
Protein Kinase A (activated by glucagon then cAMP) has several purposes including the phosphorylation and ACTIVATION of what 2 enzymes required for fasted state ?
- Glycogen Phosphorylase kinase
2. Hormone sensitive lipase (epinephrine)
What 3 proteins are normally active when Insulin is high?
- Pyruvate kinase
- Glycogen synthase
- Phosphofructose kinase 2 (allosteric activator)
Hormone sensitive Lipase can be activated by what 2 things?
- Phosphorylation by Protein kinase A (from glucagon)
2. Epinephrine
In the fasted state, Acetyl CoA is being created by ______ _______ and then the Acetyl CoA will stimulate the activation of _______ enzyme to make more OAA in the MT.
Beta Oxidation (in MT)
Pyruvate Carboxylase
The enzyme Phosphphenolpyruvate carboxykinase is regulated at the level of _______. When will it be made?
Transcription
-transcriptionaly induced under high levels of cAMP
The enzyme Fructose 1,6 Bisphosphatase is similar to PEP carboxykinase in regulation in that both are __________ regulated and induced by high levels of ______.
Transcriptionally
cAMP
Intermediate product Fructose 2,6-P will ______ the enzyme Fructose 1,6-bisphosphatase needed in GNG. Production of Fructose 2,6P is prevented by phosphorylation of _________ enzyme by Protein Kinase A. This will decrease the inhibition that F 2,6-P causes on Fructose 1,6 Bisphosphatase.
inhibit
Phosphofructokinase-2
Glucose 6-phosphatase is also regulated at the ________ level and induced by levels of ______.
transcriptional
cAMP- binds the cAMP Response element binding protein (CREB) that functions as a transcription factor
When will Glycogenolysis and GNG be activated when looking at blood glucose levels?
After about 1.5 to 2 hours past a mean when blood glucose levels have dropped and then plateaued ( Glycogenolysis and GNG will help maintain plateau)
After how many days after not eating will the body be considered “starvation state”?
2 to 8 days
What happens in a “starvation state” (2-8 days not eating) ?
Level of GNG production will decline and the plateau
-because Brain will change to using ketones instead of glucose as fuel source
True or False:
Pyruvate kinase needs to be phosphorylated to be inactive the then allow GNG to proceed.
True - if inactivated (phosphorylated - high levels of cAMP) then PEP will not be converted to Pyruvate in Glycolysis and extra Pyrvate in MT (precursors) can go into GNG to make glucose
PEP Carboxykinase is stimulated by high levels of ?
OAA
Phosphorlyation of PFK-2 will reduce the inhibition of _____ on what ?
F-2,6-bisP
on F-1,6,Phosphatase (allowing then GNG to proceed)
GNG pathway is energy requiring , the energy comes from ________ ________. The coupling of GNG with Beta-oxidation is essential for the maintenance of _______ _____ and cellular ______.
FA Beta-Oxidation
Blood glucose
Energy
Lipolysis, via activation of Hormone Sensitive Lipase, will generate substrate in the form of ________ for required usage in GNG.
Glycerol
Hormone sensitive lipase will also contribute to the release of FFA into the cell to make AcetylCoA which is necessary for GNG in what way? (integration of Beta oxidation with GNG example)
Activation of Pyruvate Carboxylase (converts Pyruvate to OAA)
noteAcetyl CoA is not substrate for GNG***
Hormone sensitive lipase is lastly important for GNG because it will cleave the FFA for Beta oxidation that then generates ________ for energy usage and high levels of _______ will inhibit _________ which inhibits the conversion of Pyruvate to ______.
NADH (can be oxidized to ATP)
NADH
Pyruvate Dehydrogenase Complex (PDC)
Acetyl CoA
ATP generated by the oxidation of NADH (coming from Beta oxidation) in MT is required for _______.
GNG (synthesis of glucose)
When Blood Glucose is low, insulin is low, Glucagon is high:
Glucagon and Epinephrine will facilitate the hydrolysis of _____ in adipose tissue to ____ and ____.
The liver will start Glycogenolysis and shuttle out ____.
Triacylglyerols
- FA
- Glycerol
Glucose
When Blood Glucose is low, insulin is low, Glucagon is high:
The FA coming from the Adipose will enter the liver, be oxidized, to make _______ (stimulator for GNG) and will enter the Skeletal Muscle to make ______ that is used in the TCA cycle for energy generation.
Acetyl CoA
Acetyl CoA
When Blood Glucose is low, insulin is low, Glucagon is high:
In the liver the Acetyl CoA that is made from oxidized FA, can be used as stimulator for _____ and converted into _______ _____.
GNG
Ketone bodies
When Blood Glucose is low, insulin is low, Glucagon is high:
_____ _______ that come from liver from the AcetylCoA can be used first for energy in the muscle, then later in the ______
Ketone bodies
Brain (starvation state)
When Blood Glucose is low, insulin is low, Glucagon is high:
The skeletal muscle will provide AA , mainly in the form of ______ that are used to make glucose through GNG.
Alanine
When Blood Glucose is low, insulin is low, Glucagon is high:
Oxidation of Glucose by the Red Blood cell makes _____ and can be used as substrate for GNG.
Lactate
When Blood Glucose is low, insulin is low, Glucagon is high:
Urea cycle generates Urea as means of disposal of ____ ______ from AA as they are removed to provide substrate for GNG. Urea will travel to kidneys and be excreted in urine.
Amine groups
When Blood Glucose is low, insulin is low, Glucagon is high: (fasted state)
The only tissues that will still be using glucose as the primary fuel source is _____ and _______.
Brain
Red Blood cells
When Blood Glucose is low, insulin is low, Glucagon is high: (fasted state)
What are Muscle, Liver, Adipose oxidizing as primary fuel source? (primary role of lipolysis- helps spare glucose for blood and brain)
Oxidizing Fatty Acids
Glucokinase has a _____ Km for Glucose (in liver) so that major changes in blood glucose are better handled an glucose can be processed withouth reaching kMax too fast.
High
Pyruvate Kinase is inhibited by what 3 things?
- ATP
- Alanine
- Phosphorylation by Protein kinase A (glucagon, epinephrine, leads to high cAMP)
True or False:
Acetate and Acetaldehyde are both non-toxic
False
Only acetate is nontoxic
In ethanol metabolism, it is metabolized in the ______ in both the ____ and _____.
Liver
Cytosol
Mitochondria
The oxidation process in the liver of Ethanol generates _____ that can be reconverted to ______ (used for TCA cycle, FA-synthesis, or ketone synthesis)
Acetate
AcetylCoA
Acute ETOH consumption can lead to ______ and _____. The diversion of GNG substrates coupled with inhibition of beta oxidation creates a metabolic disruption.
hypoglycemia
ketosis
______ a toxic intermediate of ETOH metobolism, will oxidize _______, forms adducts and can damage tissues leading to liver ____ and _____.
Acetaldehyde
proteins
fibrosis
cirrhosis
In the first steps of ETOH metabolism, the liver will metabolism about _____ percent of all ETOH. It is a small molecule that is amphipathic and can be _____ absorbed by the intestine.
90%
directly
Once in the liver, Step one, the ETOH will be metabolized by fairly non-specific _____ ________. This will create more _____ in the ______.
Alcohol Dehydrogenases (ADH- family)
NADH
Cytosol
What is the Second step after Ethanol is acted upon by ADH, what does it create?
Acetaldehyde in the MT
and NADH+ in Cytosol
What is the enzyme that will convert Acetaldehyde to Acetate in the mitochondria? What other product is made in the MT?
Acetaldehyde Dehydrogenase (will add an OH and remove the H) - ALDH
NADH
Acetate can move out of the MT and into the blood stream to then be ?
Taken up by peripheral tissues
- skeletal muscles
Converted back to Acetyl CoA
What enzyme will convert the Acetate from ETOH metabolism into Acetyl CoA (in skeletal muscles) for entrance into TCA cycle
AcetylCoA Synthase (ACS)
The increase in ______ during ETOH metabolism will negatively effect the other pathways needed during _______.
NADH
Fasting
The ______ pathway can be active in heavy drinkers as an alternative way to metabolize ETOH in the cytosol.
MEOS
The MEOS pathway sits in the _______ and primary involves the ______ enzymes. Specifcially the _____ enzyme.
ER
P450 enzymes
CYP2E1
The MEOS mainly contributes to the conversion of ETOH to ______ in the cytosol in heavy chronic drinkers. The CYP2E1 gene transcription is elevated in these conditions.
Acetaldehyde
The MEOS pathway can rapidly clear ETOH using ______ to make the product of ______.
NADPH +H+O2
NADP+ and 2H2O
(NADP will pick up 2 H)
Acetaldehyde levels when elevated are toxic (free radical) and impact protein function, primarily in _____ where it causes cells to be _____ and _______.
RBC membranes
Sticky
Deformed
Due to the effects of Acetaldehyde on RBC membranes, what can this lead to clinically in alcoholics?
Jaundice
Anemia
Ethanol is also an inhibitor of the _______ _______ in the liver. These enzymes are responsible for several drug metabolism mechanisms. This will contribute to ___ ____ as the drug can not be processed effectively.
P450 Monoxygenases
Liver damage
True or False:
MEOS pathway generates less energy through NADPH than the ADH and ALDH portions that create NADH.
True
In GNG, the increased NADH created by ETOH metabolism will negatively effect it due to what effects on Malate/aspartate shuttle and conversion of lactate to pyruvate?
NADH is already elevated so Pyruvate can not be created from Lactate. Instead lactate is made.
Also, as OAA is shuttled out of MT as Malate, it is retained as Malate as high NADH levels keep it that way
In beta oxidation, elevated levels of NADH will ______ the process directly.
inhibit
reduces overall levels of ATP
Because beta oxidation is inhibited by high NADH caused by EOTH metabolism during fasted state, the cell will run low on ATP and have high levels of AMP, AMP is a direct inhibitor of ________. This will inhibit GNG.
fructose 1,6 bisphosphatase
Hypoglycemia will present in acute alcohol consumption as it inhibits ______ and reduces ____ _____ thereby decreasing the maintenance of Glucose in the blood .
GNG
Beta oxidation
Metabolic acidosis in ETOH metabolism will be caused by increased levels of _______ that under high levels of NADH present will convert to ________.
Acetoacetate
D-Beta Hydroxybutarate
-increased levels of this in the blood will contribute to Metabolic Acidosis
The increased levels of NADH from ETOH metabolism will inhibit what three steps in TCA cycle?
- Malate to OAA (reduction of OAA- cant generate citrate)
- Isocitrate to Alpha-KG
- Alpha-KG to Succinyl CoA
Because the Malate can not be converted to OAA (fasting chronic ETOH problem), Citrase will not work so _____ levels will rise in the cell. This will force the Acetyl CoA to move into _____ formation.
Acetyl CoA
Ketone
What are the two pathways that contribute to metabolic acidosis ?
Lactate pathway
Ketone pathway
What is the main ketone produced in EOTH metabolism when AcetylCoA is forced into it due to TCA being shut down?
D-Beta Hydroxybutarate
What two products in high levels after ETOH metabolism will cause metabolic acidosis in the blood?
Lacate (lactic acidosis)
D-Beta Hydroxybutarate
The diversion of ______ for GNG will result in clinical presentation of ______ due to ETOH metabolism.
Precursors
Hypoglycemia
Where does the Lactic acidosis come from due to excessive ETOH?
The high levels of NADH created by ETOH metabolism will prevent the precursor for GNG (Lactate) from being converted to Pyruvate, lactate will build up in body
The fatty liver will occur because the FFA that are released during fasted state (by Hormone sensitive lipase) will travel to liver and _______ _____ can not occur due to ETOH metabolism . The FFA will accumulate in liver.
Beta oxidation
As FFA accumulate in the liver, _______ _______ production is also increased in the liver due to high NADH and ____ are created.
Glycerol 3-P
Triacylglycerides
then get stored in liver, as VLDL particle secretion is impaired
Acetaldehyde can cause damage by binding to _____. This molecule is required for maintaining what in RBC?
Glutathione
Correct oxidation state of Hg in RBC
Acetyladehyde bound to glutathione will ______ it and makes it unable to ______ iron within Hg
oxidize
re-reduce
Acetyladehyde can also bind to _____ (besides glutathione issue) non-specifically and reduce protein function. In general it is a ________ that leads to increased levels of free radicals.
AA
non-specific toxic agent
In Fibrosis of the liver there is an increase in ______ tissue.
Connective
In Fibrosis , the main features include:
Accumulation of both ____ and ____membrane like collagens. Thickening of ______ tissue septae. And increase of laminin and fibronectin.
Fibrillar
Basement
Connective
In Hepatic injury of Sclerosis, there is an _____ of fibrotic tissue. It is the second stage of liver damage after Fibrosis and before Cirrhosis.
aging
In Cirrhosis of the liver, is is the end stage of liver _____ degeneration. The whole liver is heavily distorted by thick bands of _______ surrounding nodules of hepatocytes with regenerative ____.
fibrotic
collagen
foci
