Week 2 Flashcards
Which parts of the body produce lactate even when oxygen is present?
Erythrocytes, retina and the brain, responsible for 10% of overall glucose breakdown.
What is the cycle that uses lactate to synthesise glucose in the liver?
Cori Cycle
What are the two components needed to make everything that a cell needs?
glutamine and glucose
Is allosteric regulation of glycolysis long or short term?
It is short term (mins/hours)
Is hormonal regulation of glycolysis longer lasting?
hours to days
Which cells in the pancreas trigger insulin?
Beta cells of the pancreas
Which cells in the pancreas trigger glucagon?
Alpha cells of the pancreas.
Which enzyme is the hexokinase of the liver?
Glucokinase
A deficiency in GK causes what?
A rare from of young Type 2 diabetes
What directly inhibits GK?
G6P, indirectly and directly activated by glucose
What happens when GK is inactive?
GK is brought to the nucleus and bound to GKRP, F6P tightens the complex binding
What happens when GK is active?
GK is released and converted to glucose by competitive glucose binding
What causes hemolytic anaemia?
Pyruvate kinase deficiency leads to cells becoming fragile and lysing.
What transcription factor is caused by high glucose levels within liver cells? FED State
ChREBP
What does ChREBP facilitate?
the conversion of excess glucose to pyruvate which is metabolized to acetyl-CoA, the main precursor for synthesis of fatty acids,, for long term energy storage as adipose tissue
What is a hormone which aids in glucose homeostasis?
Leptin, peptide hormone regulation, signals from white adipose tissue to the brain
What does leptin do therapeutically?
Decreases insulin levels, decreases blood glucose. It is a satiety hormone to stop food intake.
How is acetyl CoA formed?
It is a direct end product of carbohydrate catabolism (glycolysis), fatty acid catabolism (beta oxidation) and of much of protein (amino acid catabolism)
Entry point into the TCA cycle for all these catabolic pathways
What is the end product of glucose catabolism?
Pyrvuate
Where does pyruvate move from to?
First pyruvate is transported into the matric of the mitochondria by a transporter.
What is pyruvate converted to before the citric acid cycle uses enzyme dehydrogenase (PDH) in a complex?
must be converted to Acetyl CoA
What happens to pyruvate in the pyruvate dehydrogenase reaction?
It is oxidized and decarboxylated to acetyl co A by PDH complex, occurs in the mitochondria.
What are the two forms of regulation that PDH activity abides by ?
Allosteric and covalent phosphorylation regulation
Mutations in PDH or in thiamine can lead to?
Pyruvate build up, energy dysfunction, loss of brain function
Where does glycolysis occur?
In the cell cytoplasm
Where do catabolic pathways occur?
mitochondria
What glucogenic amino acids make up glutamate?
Arginine
glutamine
histidine
proline
What glucogenic amino acids make up succinyl CoA?
Isoleucine, methionine, threonine, valine
What glucogenic amino acids make up oxaloacetate?
Asparagine and aspartate
What glucogenic amino acids make up pyruvate?
Alanine, cysteine, glycine, serine, threonine, tryptophan
What ketogenic amino acids makeup acetyl co A?
Isoleucine, leucine, threonine, tryptophan
What ketogenic amino acids make up acetoacetyl Co A?
Leucine, Lysine, Phenylalanine, Tryptophan, Tyrosine.
What does the TCA cycle produce?
2C acetyl CoA
Succinate to Fumarate involves ?
Succinate dehydrogenase or complex II
What does the TCA cycle produce overall?
3NADH, 1 FADH, 1GTP and 2 CO2
How much ATP/Acetyl Co A is produced from TCA cycle?
12 ATP/Acetyl CoA
What enzyme is the strong key determinant in whether the TCA cycle is turned on/off?
Pyruvate Dehydrogenase
What are the three exergonic enzymes which regulate the TCA cycle?
- citrate synthase
- isocitrate synthase
- alpha ketoglutarate dehydrogenase
The regulation, exergonic enzymes allosterically regulate by …
- energy indicators
- product accumulation
- substrate availability
Which high energy indicators turn off the TCA cycle?
Citrate, NADH, ATP
When in the fasted state and there is low energy, the TCA is turned off due to low levels of..
ADP
Where is isocitrate dehydrogenase found?
In the mitochondria and in the cytosol.
During the fed state, the demand for ATP is diminished while the level of …. increases?
Carbohydrate-derived intermediates
When in the fed state, insulin levels are increased to stimulate ….. and the accumulation of ATP and NADH inhibits isocitrate dehydrogenase, causing a mitochondrial accumulation of citrate.
pyruvate dehydrogenase
When citrate is exported to the cytosol it is done so because?
The synthesis of fatty acids, which are exported from the liver for storage in adipose tissue as triglycerides
What are the three regulatory subunits of alpha-ketoglutarate dehydrogenase?
E1, E2, E3
How much ATP does each NADH generate?
2.5 ATP
How much ATP does each FADH generate?
1.5ATP
Citrate pushes glycolysis to storage by inhibiting what?
phosphofructo-kinase
What is way in which ketoglutarate is produced?
transamination of glutamate
What is succinyl Co A produced from?
Propionyl CoA
How is fumarate produced?
from the urea cycle, catabolism amino acid: phenylalanine and tyrosine, purine synthesis.
How is oxaloacetate produced?
The transamination of aspartic acid which can be used to make pyruvate and citrate.
In glial tumours, the NADPH dependent isocitrate dehydrogenase (IDH) has an unusual genetic defect
IDH1 and IDH2 loses normal function and gains a new activity converting alpha ketoglutarate to 2-hyroyxglutarate (2-HG) which accumulates in mM amounts in tumors. New drugs aim to target at IDH deficiencies.
What is a way of impacting gene expression which can be detected through techniques such as RNA sequencing?
microRNAs - central to the altering of glycolysis in tumor cells
What is an example of a tumour suppressor protein?
p53
What is an oncogenic event?
The inactivation mutation of mitochondrion specific proteins such as succinate dehydrogenase and fumarate dehydrogenase, resulting in the accumulation of succinate and fumarate in the cytosol.
The accumulation of fumarate and succinate in the cytosol promotes the transcription factor?
HiF… reprogramming of metabolism towards anaerobic glycolysis
What are the 4 fates of glucose?
structure
storage
nucleic acid synthesis
energy and metabolic intermediates
What is another way of producing oxaloacetate?
Biotin mediated oxaloacetate production
How is G6P converted to glucose in ER of liver epithelial cells (hepatocytes)
G6P is converted into glucose by glucose 6 phosphatase
Where is glucose 6 phosphatase located to keep it separate from the glycolytic pathway?
The the ER as it is the same enzyme in the last step of glycogenolysis in the liver
Why is G6P sent into the blood from the muscle tissue?
Due to the lack of the enzyme G6P, thus G6P enters the glycolytic pathway.
What type of receptor is glucagon and insulin?
GPCR
What is the bulk storage form in the body?
Triacylglycerol’s in adipose tissue
What is a type of drug that is used to treat obesity and type II diabetes?
Metformin, its overall effect is to reduce the circulating glucose. Gluconeogenesis is inhibited. Glucose is excreted rather than taken to the blood.
What is the process of needing glucose to getting glucose in the fasted state?
Glycogenesis, glycogenolysis, gluconeogenesis
What are the 3 primary sources of glucose?
diet
degradation of glycogen
gluconeogenesis
Does muscle have its own store of glycogen that can be degraded during exercise?
Yes
What is the level to which if blood glucose falls below they are suffering from hypoglycemia?
2.5mmol/L
How long can liver glycogen last?
10-18 hours
what type of chain is glycogen?
A branched chain of glucose, the branching allows for faster storage/release.
What is each glycogen chain anchored to?
Glycogenin enzyme
When glucokinase is activated due to high levels of G6P what does it force?
It forces the glucose into other pathways as G6P. Energy production - glycolysis, PPP, fatty acid and glycerol synthesis for TAG
Where does glycogenesis occur?
cytosol
How many residues are on each chain of glycogen?
12-14
What is the rate-limiting enzyme in the glycogenesis pathway?
glycogen synthase
UDP glucose can be used to make?
glycoproteins, glycolipids, proteoglycans
In glycogenolysis, glucose is released by ?
G6P in the ER
What enzyme is used in the conversion of glycogen to free glucose?
PLP
What does the muscle have none of?
G6 phosphatase
What enzyme is involved in the conversion of glucose 1-P to glucose 6-P?
Phosphoglucomutase
What promotes the breakdown of glycogen to glucose 1-P?
calcium and AMP for muscle only
What are the 3 hormonal regulators for glycogenesis and glycogenolysis?
Glucagon, epinephrine and insulin
These act through membrane-bound receptors
The hormonal regulation of glycogenesis and glycogenolysis alters the activity of?
glycogen phosphorylase
glycogen synthase
What are the key proteins involved in glycogenesis and glycogenolysis?
- Adenyl Cyclase
- cAMP dependent protein kinase A
- Glycogen phosphorylase kinase
- Protein phosphatase 1
Glycogenolysis can also be activated in response to both acute and chronic stress, including:
physiologic
pathologic
psychologic
Where does gluconeogenesis primarily occur?
In the liver and in the kidneys
