Meds design Flashcards
Describe the process of glycolysis.
Glucose phosphorylated to glucose-6-phosphate using hexakinase.
Glucose-6-phosphate then isomerizes into fructose-6-phosphate.
Fructose-6-phosphate is then phosphorylated using phosphofructokinase 1 (PFK1) —–> Fructose-1,6-bisphosphate.
Several steps laster, phosphoenolpyruvate is produced.
Pyruvate kinase and ATP is then used to produce pyruvate.
Pyruvate can then be used to produce Acetyl-CoA with a pyruvate dehydrogenase complex, or proceed to the TCA cycle.
What is PFK1
Phosphofructokinase-1
Primary control enzyme of glycolysis. Phosphorylates fructose-6-phosphate to form fructose-1,6-bisphosphate for glycolysis to continue.
Allosteric enzyme – binding of a substrate results in increased or reduced subsequent binding of substrates.
At low [ATP], there is high activity and shows michaelis menten kinetics. (Requires glycolysis to increase ATP conc)
At high [ATP], there is low activity, and shows sigmoidal activity. (No need for glycolysis)
Inhibited ATP, Citrate and H+
– negative feedback control by products of the pathway
Stimulated by AMP
What is PFK2
Counteracts inhibiting effects of ATP on PFK1 to allow glycolysis to proceed.
Converts some of the F6P into F-2,6-P. This activates PFK1. F-2,6-P is also an allosteric activator of pyruvate kinase to also allow glycolysis to occur at a faster rate.
Describe the Cori cycle.
Recycles R-lactate into glucose.
Lactate is transported from muscles to the liver via the blood.
Lactate dehydrogenase converts R-lactate to pyruvate using a molecule of NAD+.
Pyruvate is converted into glucose via gluconeogenesis.
Requires a total of 6x ATP per glucose molecule
(Glucose -> pyruvate produces 2x ATP)
Describe the process of gluconeogenesis via pyruvate.
Pyruvate is converted into oxaloacetate via pyruvate carboxylase.
Oxaloacetate is converted into phosphoenolpyruvate via phosphoenolpyruvate carboxykinase.
Several steps then occur to convert phosphoenolpyruvate into Fructose-1,6-bisphosphate.
Fructose-1,6-bisphosphatase is then used to dephosphorylate it into Fructose-6-phosphate
Fructose-6-phosphate can then be converted into glucose.
How is glycolysis and gluconeogenesis regulated?
Cell energy levels
- Citrate
- AMP
- ADP
- ATP
Hormonal control
-Glucagon
What is glucagon? How does it work.
Glucagon is a hormone secreted in response to low glucose levels. – Down regulates glycolysis, upregulates gluconeogenesis.
Glucagon binds to the receptor and stimulates cAMP mediated signalling.
Protein kinase A is activated
PFK2 is phosphorylated by PKA
- > causes F-6-P kinase to be less active
- > increases activity of F-2,6-BP phosphatase
Overall results in a reduction in F-2,6-BP levels.
Pyruvate kinase activity is also reduced.
Reduces glycolysis stimulation via F26BP levels.
What is insulin and how does it work.
Insulin is a hormone secreted in response to high glucose levels. – Upregulates glycolysis and downregulates gluconeogenesis.
In the fed state, it increases the concentration of GLUT4, allowing uptake of glucose into adipose cells and muscles.
Inhibitory effects of glucagon are countered – PFK2 phosphorylation is reduced,
PFK2 activity is increased, F26BP phosphatase activity is reduced
- -> Overall increase in the rate of glycolysis due to increased F26BP levels stimulating PFK1
- -> Pyruvate kinase activity also increased due to reduced phosphorylation
What is the effect of adrenaline on the metabolism of glucose.
Effects are similar to glucagon.
Glycogenolysi is stimulated (breakdown of glycogen)
Glycogeneosis is inhibited (production of glycogen)
Via modulation of the activities of PFK1, hexokinase, and pyruvate kinase by phosphorylation?
Anaerobic respiration usually occurs due to the “panic” nature of the situation
Describe the TCA cycle.
Pyruvate is converted into Acetyl-CoA via the pyruvate dehydrogenase complex.
Oxaloacetate and acetyl-CoA condense to form citrate.
Cis-aconitase rearranges citrate into isocitrate
Isocitrate is oxidised and decarboxylated to form 2-oxoglutarate using isocitrate dehydrogenase.
2-oxoglutarate is decarboxylated via 2-OG dehydrogenase complex forming succinyl-CoA
Succinyl-CoA is converted into succinate
Succinate is then desaturated, and FADH2 is formed.
The complex is then hydrated and oxidised to form NADH and oxaloacetate.
How is the TCA cycle regulated.
High levels of ATP, NADH and other products from the TCA cycle are inhibitors of the cycle.
Succinyl-CoA inhibits 2-OG dehydrogenase via negative feedback
ADP stimulates the increase in activity of isocitrate dehydrogenase.
What is the anaplerotic reaction?
TCA cycle produces material for biosynthesis. Oxaloacetate concentration will therefore decrease. The reaction occurs to replenish oxaloacetate levels.
Acetyl-CoA will accumulate to high concentrations and decrease the activity of the pyruvate dehydrogenase complex to reduce the amount of acetyl-CoA produced from pyruvate.
This will also stimulate greater activity from pyruvate carboxylase to produce oxaloacetate from pyruvate.
Overall, this results in the levels of oxaloacetate and acetyl-CoA rebalanced.
How is glycogen produced from glucose?
Glucose-6-phosphate is rearranged into glucose-1-phosphate with an isomerase (different phosphate group is used)
UTP reacts with glucose-1-phosphate to produce UDP-glucose.
Glycogen synthase then creates a chain of glucose. Glycogen phosphorylase will produce glucose-1-phosphate
A branching enzyme produces the characteristic 1,6 branching in glycogen
Why are ketone bodies formed in diabetics?
Glucose is scarce.
Fatty acids are degraded to produce acetyl-CoA.
Acetyl-CoA is converted into acetoacetate and 3-hydroxybutyrate. This circulates the blood and is used as fuel instead of glucose.
Acetone is produced from acetoacetate – resulting in the solvent smell on diabetics breath when hyperglycaemic.
What is a glycation reaction?
A non enzymatic reaction of a sugar molecule with a nucleophile.
Eg. HbA1c is haemoglobin glycated.
This can only happen in reducing sugars – aldehyde or ketone (or ketal/acetal)
Ketoses are also reducing because they tautomerise to aldehydes in basic solution.
They reduce Cu2+ and Ag+ in basic solutions
