Kerry Loomes05 Flashcards
What is the structure of AMP-Activated protein Kinase?
Consists of three protein sub units, catalytic alpha, and the beta and gamma regulatory subunits
The gamma subunit detects changes in the ATP:AMP ratio by having two binding sites for AMP which when bound expose the proteins catalytic domain on the alpha unit
THe alpha unit can be activated via phosphorylation at threonine 172
The beta and alpha units have 2 isoforms and the gamma unit has 3 isoforms
What is the function of AMP-Activated protein kinase?
Maintains the intracellular energy balance, an increase in AMP levels (low energy level) results in activation of AMPK via phosphorylation which will result in AMPK driving energy producing pathways like glycolysis as well as phosphorylating energy demanding processes and having long term effects through gene regulation
What are the energy consuming pathways which AMPK turns off when activated?
Inhibition of gluconeogenesis and fatty acid production
What are the features of cancer cells energetically?
They are greedy for energy and use a disproportionate share of the energy in the environment
Even if oxygen is entering the cell then lactate is produced as cancer cells avoid oxidative phosphorylation using mainly glycolysis and lactate fermentation (Known as the Warburg effect)
What is the usual function and regulation of HIF (Hypoxia inducible factor)?
HIF is a heterodimer of an unstable alpha and stable beta subunit, when oxygen levels are low HIF moves to the nucleus and turns on genes to respond to hypoxia
If oxygen levels are normal then HIF-Alpha is hydroxylated on one or two propyl residues so it can be marked by a ubiquitin ligase enzyme to be degraded by the proteasome ending signalling
What is the Pasteur effect?
When oxygen levels are low then HIF is stabilized and upregulates genes involved in glycolysis, if oxygen levels are low then HIF is degraded and glucose is metabolized through oxidative phosphorylation in the mitochondria
What is the role of HIF in cancer cells?
Cancer cells are unable to suppress HIF activity, so there is continued increase of glycolysis making them energetically wasteful
What is the advantage of cancer cells being energetically wasteful?
If they were efficient then too much ATP would be produced shutting off glycolysis
It ensures there are large amounts of ADP for biosynthesis and NADPH and acetyl coA which are the raw building blocks for cellular synthesis
Being greedy for energy means that neighbouring normal cells are starved
Secretion of products such as lactate, ammonia and alanine
Why is glutamine essential for cancer cells>?
This compound which is highly abundant in the blood is essential for cell growth as it provides a supply of nitrogen which is needed for the synthesis of nucleotides and non-essential amino acids
Glutamine also helps increase the uptake of essential amino acids, maintain the TCA cycle through providing carbon bio skeletons
support NADPH production for lipid and nucleotide biosynthesis
How can the metabolism of cancer cells be used as a drug target?
If oxidative phosphorylation could be turned back on then glycolysis and tumour growth may be inhibited
Why could pyruvate dehydrogenase be a target of cancer therapies?
Pyruvate dehydrogenase can be converted to the inactive state through addition of phosphate groups, this is catalyzed by pyruvate dehydrogenase kinase, if PDHK is inhibited then this would increase pyruvate dehydrogenase activity
Increased pyruvate dehydrogenase activity would result in more conversion of pyruvate to acetyl coA driving oxidative phosphorylation reducing the ability of the cell to be wasteful
What is an example of a molecule that inhibits pyruvate dehydrogenase kinase?
Dicloroacetate inhibits pyruvate dehydrogenase kinase and has been shown to decrease lactate levels to reduce cellular proliferaton and has had anticancer effects reported for prostate and endometrial cancer cells
What are the energy consuming pathways which AMPK turns off when activated?
Inhibition of gluconeogenesis and fatty acid production
What are the features of cancer cells energetically?
They are greedy for energy and use a disproportionate share of the energy in the environment
Even if oxygen is entering the cell then lactate is produced as cancer cells avoid oxidative phosphorylation using mainly glycolysis and lactate fermentation (Known as the Warburg effect)
What is the usual function and regulation of HIF (Hypoxia inducible factor)?
HIF is a heterodimer of an unstable alpha and stable beta subunit, when oxygen levels are low HIF moves to the nucleus and turns on genes to respond to hypoxia
If oxygen levels are normal then HIF-Alpha is hydroxylated on one or two propyl residues so it can be marked by a ubiquitin ligase enzyme to be degraded by the proteasome ending signalling
