Exam 3 Lecture 1: Gluconeogenesis Flashcards
What happens after you consume carbs?
After consumption of carbohydrates:
- Insulin-dependent glucose transport into adipose tissue and heart and skeletal muscle
- Insulin-independent glucose transport into liver and other tissues
- Active glycolytic pathway
- PDH active in tissues with mitochondria (creating acetyl coA)
- AcCoA metabolized/oxidized in the TCA Cycle
In the liver, insulin promotes the expression of which glycolytic enzymes?
Insulin promotes the following enzyme’s expression in the liver:
- Glucokinase
- PFK-1
- Pyruvate Kinase
What is the overall effect of glucagon and epi on glycolysis?
FASTED STATE: what enzymes get inhibited and which enzymes are transcribed less
Glucagon and Epi:
- inhibit PFK-2: inhibits PFK-1 and therefore inhibits glycolysis
- Inhibits pyruvate kinase
- ALSO decreases the gene transcription of the following enzmes: Glucokinase, PFK-1, Pyruvate Kinase
The fasted states promotes/activates which pathways?
Glucagon and Epi:
- promote glucose synthesis (via gluconeogenesis)
- Increase gene transcription of gluconeogenic enzymes
- Promote mobilization of glucose via glycogen degradation
What are the preferred energy sources of the following tissues:
Liver
Adipose
Skeletal Muscle
Heart Muscle
Brain Tissue
Liver: fatty, glucose, AA’s
Adipose Tissue: Fatty Acids
Skeletal Muscle: Fatty Acids (rest), glucose (exertion)
Heart Muscle: fatty acids
Brain: GLUCOSE (fed state), ketone bodies and glucose (starved state)
Glucose homeostatis requires two pathways…..?
They both take place in the ______
Glucose homeostatis requires two pathways:
Gluconeogenesis
Glycogen Degradation
Both take place in the liver
Explain how glycogen and pyruvate get turned into glucose
Gluconeogenesis:
Is the synthesis of glucose from noncarb sources such as:______, _______, ______, and ______
Gluconeogenesis is the synthesis of glucose from non-carb sources such as pyruvate, lactate, glycerol, and glucogenic AA’s
Gluconeogenesis:
Is stimulated by what?
Where does gluconeogenesis take place?
How many ATP’s does it require?
Gluconeogenesis:
- Low blood glucose stimulates gluconeogenesis
- Takes place mainly in the liver, and to some extent the kidney
- It is an ATP (6 ATPs) dependent process.
Pyruvate is converted to PEP in a two step process via oxaloacetate, which can be viewed as….?
_____ and ____ are involved in this activation, which requires the expenditure of ATP
Pyruvate is converted into PEP in a two step process via oxaloacetate, which can be viewed as the “activated” form of pyruvate
Bicarbonate and the cofactor biotin are involved in this activation, which requires the expenditure of ATP
What do the following gluconeogenic precursors come from?
Lactate
Gluconeogenic AA’s like ALANINE
Glycerol
Major Gluconeogenic Precursors:
Lactate: general metabolism, RBC metabolism and muscle metabolism
Gluconeogenic AA’s (Alanine): overnight degradation of muscle AA’s
Glycerol: degradation of adipose tissue triacylglycerols
Draw the diagram showing where the various gluconeogenic precursors enter the pathway (lactate, aspartate, glycerol, alanine)
Neonate’s brain is very dependent on glucose for glycogen degradation and gluconeogenesis.
It takes a few hours to induce the enzyme _______ which is needed to make glucose from lactate or alanine.
Thus there is a risk of ____ during the first few hours after birth.
Neonates:
Takes a few hours to induce the enzyme PEP Carboxykinase, which is important in turning lactate and alanine into glucose.
Thus, there is a risk of hypoglycemia during the first few hours after birth.
Gluconeogenesis takes place in _______
Glycolysis is active in _______
Gluconeogenesis takes place in liver and kidney
Glycolysis is active in nearly every living cell.
Explain the Cori Cycle/Glucose Lactase Cycle
How many ATPs are required?
Cori Cycle/Glucose Lactose Cycle:
Lactate is made in RBCs and skeletal muscles from glycolysis (from pyruvate)
Lactate then enters the blood stream where it goes to the liver
Lactate can then undergo gluconeogenesis in the liver to form glucose (this requires 6 ATPs)
Explain the Alanine Cycle/ the glucose alanine cycle
How many ATPs does it require?
Pyruvate gets deaminated to form alanine in muscle cells
Then alanine enters the bloodstream and goes into the liver.
Alanine is deaminated to pyruvate (which can then enter gluconeogenesis and get turned into glucose)
That reaction creates toxic NH2, which undergoes ureagenesis in the liver to create urea, which goes to the kidneys
Note: this cycle uses 10 ATPs total
Why does the glucose alanine cycle require additional ATP input?
Alanine cycle requires additional ATP input because ureagenesis is needed to remove NH2 and that process is ATP intensive.
Gluconeogenesis from all precursors requires ___
Gluconeogenesis from AA’s requires additional ___ which is used for _____
During an overnight fast _______ is used as the major source of ATPs for gluconeogenesis, not from ___
Gluconeogenesis from all precursors requires ATP
Gluconeogenesis from AA’s requires additional ATPs which is used for ureagenesis
During an overnight fast, oxidation of fatty acids serves as the major source of ATP for gluconeogenesis, not from the source of lactate or alanine-mediated gluconeogenesis.
Once acetyl coA is made it can/cannot be used to make glucose; it is commited to either ____ or _______.
Once acetyl coA is made it CANNOT be used to make glucose
Acetyl coA is comitted to either fatty acid synthesis or the Krebs cycle
Glycerol is a precursor for synthesis of ________ in the liver and adipose tissue.
Glycerol is a precursor for the synthesis of triaglycerols and of phospholipids in the liver and adipose tissue
What happens to glycerol and fatty acids when the body uses stored fat as a source of energy?
When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the blood stream.
Glycerol will be converted into its intermediate _____ before entering the pathway of glycolysis or gluconeogenesis (depending on physiological conditions)
Glycerol is converted into glyceraldehyde 3-P before entering glycolysis or gluconeogenesis
This rxn is done by the enzyme glycerol kinase
Top Hat Question:
The major source of ATP for gluconeogenesis is from what source?
Major source of ATP for gluconeogenesis comes from fatty acid oxidation
Propionyl CoA is a good/bad precursor for gluconeogenesis.
How is propionyl coA formed?
Propionyl CoA is a GOOD precursor for gluconeogenesis (it’s made up of 3 carbons)
Propionyl CoA is formed as a product of beta oxidation of odd chain fatty acids, isoleucine, valine, and alpha-ketobutyric acid.
What are the four enzymes that are required to reverse the three irreversible steps of glycolysis?
Mitochondrial: Pyruvate Carboxylase
Cytoplasmic: PEP Carboxykinase
Cytoplasmic: Fructose 1,6-Bisphophatase
Cytoplasmic: Glucose 6-Phosphatase
Explain the reaction of Pyruvate Carbosylase
Where does it occur?
What does it need to proceed
To get out of the mitochondria, pyruvate needs to add CO2 to create oxaloacetate
(this rxn is preformed by pyruvate carboxylase)
This reaction needs CO2, ATP, and biotin (a cofactor) to proceed
What activates the pyruvate carboxylase reaction?
Pyruvate Carboxylase is activated by acetyl coA
remember pyruvate carboxylase takes pyruvate, adds CO2 to create oxaloacetate
(this rxn needs ATP, and biotin which is a cofactor)
Explain the Pyruvate Carboxylase Genetic Deficiency:
- Symptoms?
- What accumulates in the blood stream?
Pyruvate Carboxylase Genetic Deficiency:
- Symptoms: failure to thrive, developmental delays, recurrent seizures, metabolic acidosis
- Lack of PC enzyme creates accumulation of pyruvate in the plasma, which gets converted into lactate by LDH, causing elevated lactic acid levels in the plasma also
- Also, high alanine levels are found in serum because pyruvate can also be deaminated into alanine
Draw the diagram of the ER and explain the transporter and the glucose-6-phosphatase enzyme
Glucose 6-phosphatase requires _____ and ___
Glucose 6 phosphatase requires the enzyme activity and transport of glucose 6-phosphate into the ER.
A genetic defect in either the ____ or the ____ interferes with gluconeogenesis, and results in accumulation of glycogen in the liver.
A genetic defect in either the transporter or the phosphatase interferes with gluconeogenesis and results in the accumulation of glycogen in the liver.
Glucose 6-Phosphatase Deficiency:
Explain what it is.
What is another name for it
Glucose 6-Phosphatase Defiency aka Von Gierke Disease:
- Group of inherited metabolic diseases
- It is characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver (enlarged), elevated serum uric acid, and elevated serum lactate.
Compare the regulation of glucokinase with glucose 6-phosphatase
Compare the regulation of PFK-1 and fructose 1,6, bisphosphatase
Explain the difference in regulation of pyruvate kinase vs PEPCK and pyruvate carboxylase
Explain the overall regulation of the synthesis of key hepatic glycolytic and gluconeogenic enzymes
Glycolysis: insulin increases the synthesis of key glycolytic enzymes… list them
Gluconeogenesis: glucagon and epinephrine increases the synthesis of key gluconeogenic enzymes… list them
Glycolysis:
Insulin increases the synthesis of these enzymes: Glucokinase, PFK-1, and Pyruvate Kinase
Gluconeogenesis:
Glucagon and Epi increase the synthesis of these enzymes: Pyruvate Carboxylase, PEPCK, Fructose 1,6-Bisphosphatase, and Glucose 6-Phosphatase
Ehtanol metabolism can cause _________; the high ____ opposes gluconeogenesis
Ethanol metabolism (Ethanol Dehydrogenase) increases the ratio of _______
Increased ____ promotes the conversion of two gluconeogenic precursors (_____ & ______) into the conversion to _____ and ______
Why does this cause hypothermia?
Ehtanol metabolism can cause hypothermia: the high NADH level opposes gluconeogenesis.
Ethanol metabolism (Ethanol Dehydrogenase) increases the ratio of NADH/NAD+.
Increased NADH promotes the conversion of two gluconeogenic precursors (pyruvate and oxaloacetate) to lactate and malate.
Thus removing pyruvate and oxaloacetate from the pool of glucose precursors (hypoglycemia)
The increased NADH from ethanol metabolism oxidizes/reduces the gluconeogenic precursors pyruvate and OAA to lactate and malate.
Pyruvate and OAA are REDUCED to lactate and malate
Increased NADH leads to ______ formation
Decreased NADH leads to _______ formation
Increased NADH leads to increased lactate formation
Decreased NADH leads to decreased lactate formation
Pyruvate Carboxylase uses ___ as its energy source and is located in the _______
PEPCK uses ___ as its energy source and is located in the ______
Pyruvate Carboxylase: uses ATP, located in mitochondria
PEPCK: uses GTP, located in cytoplasm
