Flashcards in CHO Metabolism Deck (43)
Can glucose diffuse across the hydrophobic phospholipid bilayer of the cell membrane?
Why or why not?
No, because it is polar
How does glucose enter cells from the bloodstream?
binds to transport proteins – proteins that bind glucose on one side of the membrane and release it on the opposite side.
What are the two types of transport proteins in intestinal epithelial cells?
1) Na+ dependent glucose transporter
2) Facilitative glucose transporter
Where do Na+ Dependent Glucose Transporter reside?
on the lumenal side of absorptive epithelial cells
takes glucose up into cells from the GI lumen
How does Na+ Dependent Glucose Transporter work?
When Na+/K+ ATPase transports sodium out the cell, it leaves a deficiency of sodium inside the cell. Sodium then flows down its concentration gradient into the cell, bringing glucose with it into the cell from the lumen (up its concentration gradient- i.e. low in the lumen to high in the cell)
It is considered a secondary active transport- symport
T or F. Sodium dependent transporters reside on the lumenal side of absorptive epithelial cells
T. they bring glucose into the cell from the lumen
dependent on ATPase on basal side of intestinal epithelial cells that are keeping intracellular Na+ levels low
How is glucose then moved out of epithelial GI cells into the bloodstream?
using GLUT 1-5 protein family (have 12 transmembrane spanning segments)- located on basal side of cells
these move glucose DOWN its conc. gradient (i.e. high to low)
GLUT 1 and 3 are found where?
all mammalian tissue (both are particularly important in neuronal cells and BBB)
These have the LOWEST Km!- i.e. easiest/fastest binding of glucose
What do GLUT 1 and 3 do?
basal glucose uptake
GLUT 2 is found where?
liver and pancreatic B cells
high Km!!! (15-20mM)- only kicks in after a carb rich meal and glucose levels are elevated
What does GLUT 2 do in both areas where it works?
****in pancreas- stimulates glucose uptake in pancreatic b-cells. Glucose is metabolized via glycolysis generating ATP resulting in an elevated ATP/ADP ratio in the cells. This results (eventually) in an increase in cytosolic Ca2+ which triggers the fusion of insulin-containing vesicles with the plasma membrane RELEASING INSULIN into the bloodstream. (km=~15mM- aka after meal)***. So the GLUT 2 are only taking up glucose when BG is high, and insulin is needed
How it works- high ATP causes closure of ATP dependent K+ channels on the membranes, which causes opening of membrane Ca2+ channels, allowing Ca2+ to enter the cell and cause insulin filled vesicles to diffuse out of the cell (uses SNARES for fusion). Insulin will u-regulate the number of GLUT 2 receptors on the cell (feedback)
in liver- removes excess glucose from the blood (high kM ~15). Excess uptake of glucose will be stored as glycogen as a spare energy source
GLUT 4 is found where? What stimulates it?
muscle and fat cells
Insulin (stimulated to release in oacreatic b cells by GLUT 2) stimulates the recruitment/fusion of GLUT 4 to the membrane therefore increasing glucose transport (while the rate of re-uptake of the GLUT 4 transporters from the membrane remains the same)
GLUT 5 is found where?
What does GLUT 5 do?
What are the basic 3 steps of Facilitative Glucose Transport?
1) glucose binds on outside of cell through its hydroxyl groups
2) Transport protein undergoes conformational change and glucose is transported without rotating
3) Transport protein closes as glucose is released
NOTE: this assumes extracellular conc of glc is high and intracellular conc is low. If it was reversed, you'd see passive movement of glc into the bloodstream through GLUT
What happens first when glucose enters a cell?
it is phosphorylated (or alternatively exported back out).
What is glucose phosphorylated by when it enters a cell?
hexokinase (HK) isozymes (ATP dependent process)
What is glucose phosphorylated into when it enters a cell?
Phosphorylation of glucose into glucose-6-phosphate allows glucose to enter which metabolic pathways?
Glycolysis – source of ATP (energy) for cells
Pentose Phosphate pathway – source of NADPH
Glycogen Synthesis – storage polymer of glucose
What are the main functions of Glc Phosphorylation? (there are 4)
Controls the amount of glc taken up by cells.
“Activates” glc for further metabolism.
Keeps glc within cell since Glc-6-P cannot be transported across plasma membrane.
Determine the direction of glc metabolism.
What enzyme can convert Glucose-6-phosphate back to glucose?
glucose-6-phosphatase (only found in liver and kidney)
HK IV is called what?
GLUCOKINASE (GK). GK and HK differ in many of their properties and tissue distribution. (has a high Km- won't kick in until BG is high)
NOTE: HKs (hexokinases) I-III are very similar
Does phosphorylation of glucose by hexokinsase require ATP?
What kinds of tissues can HK I-III be found in?
What kinds of tissues can GK be found in?
ONLY liver, b-cells of pancreas
What is the Km (for glucose) of HK I-III?
0.1 (i.e. wants to bind glucose)
What is the Km (for glucose) of GK?
10-20mM (high!!)- under normal circumstances
What happens to the Km of GK during fasting situations?
it lowers to facilitate increased uptake/processing of glucose (~5mM)
What are HK I-III inhibited by?
glu-6-P. Thus if you make glu-6-p and it doesn't enter into a metabolic pathway, it inhibits further production of glu-6-p by HK I-III
What is GK stimulated by?
insulin. Bringing glucose in and phosphorylating it using GK makes glc-6-p which then goes through glycolysis. Increased ATP as a result of glycolysis results in increased insulin production (similar to how GLUT 2 works). Increased insulin production then causes more uptake of glucose, and the cycle continues until BG returns to normal and GK runs out of glucose to act on (i.e. it is never down regulated)
NOTE: This only occurs when BG is elevated (15-20mM)
Where is glucose-6-Phosphatase found?
liver and kidney only. NOT muscle
What is another way glu-6-p can be made?
breakdown of glu-1-p from glycogen
Why are RBCs completely dependent on glucose for energy?
They don't have mitochondria- thus, can't oxidize fatty acids for energy and need glucose. This is why RBCs have tons of GLUT 1 transporters on their cell surface and their Km =1-7 (i.e. very low- will take up lots of glucose given the chance even if BG is low)
Why is the brain highly dependent on glucose?
fatty acids cannot get over the BBB to release energy
Why does diffusion of glucose across the BBB require GLUTs?
The basal membrane of BBB cells is continuous (effective tight junctions) so no passive diffusion can occur just based on concentration gradients (only other parts of the body-non-neuronal- where gap junctions are spaced further and allow for non-specific passive diffusion- needs GLUT 1
What is GLUT 1 used for in the BBB?
diffusion of glucose into the cell
What is GLUT 3 used for in the BBB?
utilization of glucose by neuronal cells
Does muscle ever break down glycogen for extracellular diffusion to other tissues? Why?
No. Muscle only breaks down glycogen to glucose-6-p for internal use. Glu-6-p can't be moved outside the organ because muscle does not have glucose-6-phosphatase
Where is glu-6-phosphatase found in the cell?
spanning the membrane of the ER
How many transmembrane spanning proteins does glu-6-phosphatse have? What are they?
T1, T2, and T3
What does the T1 protein of glu-6-phosphatase do?
brings glu-6-p into the lumen of the ER where the catalytic portion of the enzyme makes glucose and inorganic phosphate
What does the T2 protein of glu-6-phosphatase do?
transports the inorganic phosphate out of the lumen of the ER to the cytosol after breakdown of glu-6-p