Lecture 10 Overview of CHO Metabolism I Flashcards
What is the integration of the pathways for macronutrient metabolism into oxidative phosphorylation?
- CHO: glucose is broken down to pyruvate via glycolysis then converted to acetyl CoA which enters the krebs cycle producing conezymes to enter the ETC.
- Protein: protein is broken down into amino acids which can be 1. converted to pyruvate (then acetyl CoA → CAC →ETC) 2. can enter directly into the CAC (select amino acids), or 3. converted to acetyl CoA (enter CAC → ETC)
- triacylglycerides: broken down to glycerol + fatty acids. Glycerol can enter glycolysis and proceed from there. Fatty acids can be converted to acetyl CoA or to coenzymes.
What pathways take place only in the liver?
- gluconeogenesis: pyruvate →glucose
- glycerol entering into glycolysis
- Cori cycle: lactate →pyruvate
- amino acids conversion to urea
- amino acids entering CAC
- amino acid conversion to pyruvate
- amino acid CAC into glyolysis
Pathway integration of macronutrient metabolism
Overview of glucose metabolism
- G6P is produced by the phosphorylation of free glucose, glycogen degradation, and by gluconeogenesis
- G6P is a precursor for glycogen synthesis and the PPP
- G6P can be hydrolyzed to glucose in the liver
- Pyruvate from glycolysis can be further broken down to acetyl-CoA for oxidation in the CAC.
- Lactate and amino acids can be reversibly converted to pyruvate and are precursors for glucoeneogenesis
What is the average intake of CHO?
CHO makes up about ~30-70% of energy from food (north america)
Efficiency of CHO digestion/ absorption
Efficient and rapid
* ~30-90 min
* around 60 min should see peak
General fate of circulating blood glucose
glucose is absorbed into the portal vein
* liver is the first pass and removes ~1/3 of glucose + most fructose & galactose
* Remaining glucose circulates throughout the body to provide energy to cells and stimulate insulin release
Sources of glucose?
- exogenous (from diet)
- glycogen storage degradation
- endogenous synthesis from gluconeogenic precursors
Use depends on homestatic needs
Fate of glucose metabolism BESIDES energy
Building block for other critical molecules:
* Precursor for synthesis of other CHO (i.e mammary lactose, ribose for NA)
* Precursor for sugar residues in other compounds (glycoproteins, glycolipids, proteoglycans)
NOT JUST ENERGY
Role of CHO as an energy source
The body requires a constant need for glucose for energy as it is our main fuel source
* blood glucose is tightly regulated predominantly by the liver via balance between oxidation, biosynthesis & storage.
Liver is constantly sensing the glucose concentrations
What cells are VERY dependant on glucose?
- RBCs
- Nerves
- Intestinal mucosa
- Brain
All cells needs glucose of course
What is are expected values for normal fasting blood glucose concentrations?
between 70 mg/dL (3.9 mmol/L) and 100 mg/dL (5.6 mmol/L)
* ~90 mg/dL (5 mmol/L) is the mean
What is the sequence of responses to falling arterial plasma glucose concentrations?
major issues seen when concentration is below 3 mmol/L
ATP production of glycolysis vs. complete oxidation
- glycolysis: produces some ATP (net = 2) → only substrate level phosphorylation
- complete oxidation: produces lots of ATP (net = 34) →mostly via oxidative phosphorylation
location and energy system of glycolysis vs. complete oxidation
- glycolysis: occurs in the cytoplasm of all cells and is anaerobic
- complete oxidation: occurs in the inner membrane of the mitochondria of select cells and is aerobic
What cells do not have complete oxidation?
Lack mitochondria:
* RBCs
* retina
* white muscle fibres
* leukocytes
* nerve cells
Glucose metabolism in skeletal muscle cells
- glycolysis
- complete oxidation
- glycogen storage
- excess pyruvate exported during exercise as alanine
Glucose metabolism in cardiac muscle cells
- Glycolysis
- Complete oxidation with high density of mitochondria
What is the primary fuel source for cardiac muscle?
FAs are the primary fuel source here due to its β-oxidation equipment
Glucose metabolism in hepatocytes
The liver can do everything!
* complete glucose oxidation
* store glucose as glycogen
* produce glucose from glycogen
* Use Cs from glucose for AA or FA synthesis
* Synthesize glucose from lactate, pyruvate or alanine
* Produce ribose-5-phosphate via PPP
What is the primary gatekeeper for peripheral metabolism of glucose?
the liver!
Glucose metabolism in RBCs
No mitochondria so glucose is metabolised to lactate & released into circulation.
Others: retina, white muscle fibres, leukocytes, nerve cells
Glucose metabolism in the brain
- Complete oxidation of glucose and is very dependant on blood concentrations as it has little/ no storage of glycogen
- Can also oxidize ketones when neccessary
Why does the brain not have glycogen storage?
The brain does not have space to store glycogen which takes up a lot room since it has a alrge water holding capacity.
Glucose metabolism in β-cells in pancreas
Completely oxidize glucose with a high density of mitochondria with most pyruvate entering the mitochondria; therefore more equitable balance of pyruvate production and use
Why do the β-cells of the pancreas have a high mitochondrial density?
It is a glucose sensor which releases insulin as a homeostatic response and is tightly regulated
Glucose metabolism in adipocytes
- Synthesis of glycerol for fat synthesis or complete oxidation
- Excess Glc is metabolized to Acetyl-CoA then stored as fat (released as needed)
What are the RLS of glycolysis?
Enzyme activity that are irreversible and require energy to move forward
1. HK - hexokinase (glycolysis)/ glucokinase (gluconeogenesis)
2. PFK - phosphpfructokinase
3. PK - pyruvate kinase
Describe the HK RLS of glycolysis
Reaction 1
* phosphorylates Glc to G6P (making it negative) trapping the molecule within the cell
* Different isoforms in cells so a rate of limitation
* energy requirement is 1 ATP (coupled to ATP hydrolysis)
* allosteric regulation via direct (allosteric inhibition by G6P build up) and indirect (low PFK activity, and G6P build up)
Describe the PFK RLS of glycolysis
Reaction 3
* phosphorylates F6P to FBP
* It is the committed step of glycolysis and is thus unique to glycolysis (high delta value)
* Consumes 1 ATP (ATP hydrolysis)
* tightly regulated allosterically by multiple substrate (See BIOCH 310 Lecture 3)
* Controls glycolytic flux
Desrcribe the PK RLS of glycolysis
- End of the pay off step
- 4 ATP molecules (substrate level phosphorylation) and 2 pyruvate are produced from glycolysis by the end of this step.
- Important site of hormonal and nutritional regulation
How does fructose enter glycolysis?
- Liver: Comes in as GAP
- Muscle: Comes in as F6P
Implications of fructose uptake in the liver
Fructose is phosporylated to F1P by fructokinase and F1P is then cleaved and enters as 2 molecules of GAP
* Liver has ↑GK, ↑FK & ↓HK
* Once fructose enters the cycle in the liver it cannot go back and bypasses the PFK reaction. Therefore excessive fructose intake can lead to unregulated production of lactic acid and fat synthesis since PFK regulate glucose catabolism.
Implications of fructose uptake in the muscle
fructose enters glycolysis in muscle via hexokinase and enters as F6P
* fructose intake can be regulated in the muscle by PFK therefore
* Muscle has ↑HK but ↓FK (no GK)
What is gluconeogenesis?
Reversal of glycolysis to make glucose from pyruvate bypassing the irreversible steps of glycolysis
* primarily liver (90%) & kidney (10%-45% depending on needs)
* Other tissues do not produce glucose because they lack the enzyme glucose-6-phosphatase
What is the ultimate purpose of gluconeogenesis?
Necessary to maintain blood glucose concentration
What does gluconeogenesis use to make glucose?
- Pyruvate from glycolysis
- Lactate from the Cori cycle (lactate producation from muscle then converted back to pyruvate in the liver)
- Alanine + other aa (except lysine and leucine) from muscle protein catabolism
- glycerol from lypolysis
What substrate nets the most ATP in gluconeogenesis?
Lactate as a substrate
What is the najot substrate for gluconeogenesis in the kidney?
Glutamine
What is an important regulatory step of gluconeogenesis?
PEPCK (phosphoenolpyruvate carbocykinase)
* coupled to GTP for reaction to occur
Clinical relevance of PEPCK in infants
Levels low until neonatal period therefore activtiy increases a few hours after birth and need dietary source.
* premature infants are particularly prone to hypoglycemia because they do not fully express this enzyme yet affecting gluconeogenesis, ketogensis and glycogenolysis
What enzymes in gluconeogenesis replace the RLS of glycolysis?
- PK is replaced with the enzymes pyruvate carboxylase and PEPCK which consume ATP + CO2 and GTP respectively
- PFK is replaced by fructose bis-phosphatase
- HK is replaced by glucose-6-phosphatase
How do glycolysis and gluconeogenesis work together?
glycolysis and gluconeogenesis occur at the same time however one side will be amplified depending on short or long term regulation.
How is glycolysis and gluconeogensis balance regulated?
- Balance of pathways is regulated for allosteric/ covalent modifications (enzyme activity) or changes in enzymes concentration (gene expression) at key steps
