metabolismo de la glucose part 2 Flashcards
diffusion Vs. facilitated diffusion Vs. coupled active transport
GLUT Vs. SGLT ?
GLUT> allow glucose to go across the membrane, down a concentration gradient and they function IN REVERSE; they allow glucose to enter the cell or to leave the cell
SGLT> these transporters take glucose from a domain that has high sodium and drives it to where there’s low sodium. they bring in two sodiums for each glucose. main places where these transporters are used are in the gut (glucose absorption) and the kidneys to retrieve any glucose that has spilled into the urine
regulation of enzyme activity Vs. regulation of gene transcription.
regulation of enzyme activity is ‘acute’ and much faster than regulation of hormone activity, which is much slower, and more ‘adaptive’
how does enzyme regulation occur under insulin/glucagon ?
signal transduction/ kinase cascades
insulin Vs. glucagon mode of action
insulin signals through tyrosine kinases “kinase cascade” - doesn’t involve cyclic AMP
while counter-regulatory hormones (that counter the activity of insulin) e.g.epinepherine) they signal through G-protein coupled receptos and elevations in cyclic AMP
GPCR
Activate enzymes, control transcription, stimulate secretion
glucose metabolism generic cell
liver: fed-fasted transition
overall glycolysis rxn
glycolysis first 2 irreversible steps
glycolysis last 2 irreversible steps
Position of ATP on the bioenergetic scale of phosphate compounds
where are SGLT’s found ?
SGLT’s found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron; where they contribute to renal absorption of glucose
the GLUTs ?
facilitative GLUT transporters allow glucose to go down a concentration gradient
most glucose enters cells through the GLUT transporters
glucose becomes trapped or committed to glycolysis once its phosphorylated into glucose 6-phosphate inside the cell; since these transporters wont transport glucose 6-phosphate —> concentration gradient of high glucose out and low glucose inside is maintained: very little free glucose inside the cell.
5 most important GLUT types ?
why is Km important ?
the four known hexokinases ?
HK’s 1,2, and 3 Vs. HK-4
HK 1,2,3 –> are inhibited by G-6-P while Pi releases the inhibition and all of them have a high affinity to G-6-P
HK-1 has a house keeping activity (energy production): a catabolic activity
HK-2 in muscle and adipose has an anabolic function; G-6-P it produces goes into glycogen synthesis in both.
Hexokinases I,II,III are saturated at normal blood glucose concentration (5mM), whereas Hexokinase IV is not.
• The amount of glucose6-P formed by HK-IV is sensitive to a rise in blood glucose.
Glucokinase is not inhibited by glucose6-P.
HK-4 affinity Vs. other HK’s ?
what exactly is the main gauge of the amount of glucose in the blood ?
The amount of glucose6-P formed by HKIV is sensitive to a rise in blood glucose.
glucose-insulin correlation graph
explain the orderly process of hormone-independent, glucose-dependent insulin secretion into the blood
glucose gets into the cytosol via GLUT 2 of the beta cells (GLUT-1 in humans) where HK-IV converts it to G-6-P –> high G-6-P is an indicator of high blood glycose –> glycolysis –> high ATP
beta cells make insulin and they transport it from the TGN (Trans Golgi Network) to special vesicles in which insulin gets stored #it will be independent from the transport of other proteins from the TGN (a very specialized system). these insulin storage vesicles are pre-docked at the plasma membrane.
what translates into an increase in ATP levels that close the ATP-dependent K+ channel ?
the low affinity of HK-IV makes it more saturated as glucose levels go up –> more G-6-P would be generated , which would enter glycolysis –> more ATP –> K+ channel closes
jsnxmnbdsbndjdentire glucose-depdendent insulin release diagram
is HK-4 the only glucose sensot that leads to insulin release into the blood ?
No ! +vely charged amino acids play a roles as well ! –> depolarize the membrane and open the voltage gated Ca+ channels
how does the Km of both GLUT-2 and HK-IV of the liver contribute to glucose metabolism ?
transport of glucose increases
production of G-6-P increases
how is HK-IV distributed in the nucleus and cytosol accroding to the body’s needs?
now that glucokinase is segregated inside the nucleus away from the cytosol, when glucose levels are low, most of glucokinase will be bound by the protein and stuck in the nucleus; which means the liver will not be metabolizing a lot of glucose because it doesnt have glucokinase in the cytosol; this is a dynamic process; the bound BP is trafficking back and forth but it prefers to spend most of the time inside the nucleus. as blood glucose levels rise, glucose binds to the BP; so the BP will be released from glucokinase so the unbound glucokinase now stays in the cytosol. as this dynamic equilibrium goes on, and as more bound glucokinase trafficks back and forth, it will eventually be unbound in the cytosol (will be redistributed in the cytosol) —> drives glucose metabolism
#low glucose levels—\> BP-bound HK-IV —\> stuck in nucleus #high glucose levels—\> BP-bound GLUCOSE —\> HK-IV trafficked back into cytosol and unbound —\> drives glucose metabolism
fine-tuning of the hexikinase activity ?
Fr6-P increases binding -> tones down glycolysis (when available G-6-P overwhelms glycolytic capacity it makes less HK-IV available) (more like fine-tuning)
Fr1-P decreases binding –> makes more HK-IV available; since fructolysis feeds into glycolysis ; fructose is more like an upstream substrate for glycolysis –> Fr1-P promotes glycolysis
allosteric regulators of PFK-1 ?
activators: AMP
Inhibitors: H+, citrate, ATP
Citrate inhibits PFK-1
its most important regulation would be in the liver in the fasted state where the liver is principally using fatty acids as an energy source and you’ll end up having a lot of citrate cause you’ll be metabolizing alot and then that citrate will feedback and inhibit the forward step in glycolysis
fructose2,6-bisphosphatase on PFK-1 ?
STIMULATOR !
insulin increases liver F2,6-P2
glucagon decreases liver F2,6-P2
sum up allosteric activators and inhibitors of PFK-1 ?
remember that having the fructose 2,6-BF side rxn controlled by different hormones that act on different isoforms presents a very elegant solution for convenient regulation that essentially uses the same glycolysis enzymes and only differs in the isoforms that run the side rxn
allosteric regulation of pyruvate kinase ?
activated by F1,6-P2
inhibited by ATP
three REGULATORY steps in GLYCOLYSIS
summary of their allosteric regulators and inhibitors ?
hexokinase F-6-P (-)
F-1-P (+)
AMP (+)
ATP (-)
Citrate (-)
H (-)
Pyruvate kinase F1,6 -P2 (+)
ATP (-)
what’s special about fructose metabolism ?
the PFK-1 regulatory step is bypassed
galactose metabolism ? how it feeds into glycolysis ?
galactose –> galactose 1 p –> glucose 1 P –> glucose 6 p——> pyruvate
