Glucose Homeostasis and Glycogen Metabolism Flashcards
Purpose of glycogen
We have to maintain blood glucose levels even during fasting times, fats give alot of energy but they are super slow to be converted to glucose, So we store glucose as glycogen which is a branched form of glucose most of the glycogen in our bodies is in the skeletal muscle and in the liver
Glucose metabolism
maintenance of plasma glucose is a critical aspect of homeostasis normal range- 70-100 mg/100 ml, hypoglycemia is under 70 hunger sweating trembling, under 40 leads to death
hyperglycemia: elevated fasting glucose in uncontrolled diabetes. As excess plasma glucose spills into the urine and increases non- enzymatic glycation (amadori reactions)
Plasma glucose is a source of energy especially for RBC brain, and renal medulla (sources of glucose are diet glycogenolysis and gluconeogenisis)
Primary sites of glucose metabolism: liver (blood glucose and G6P), skeletal muscle (ATP), and pancrease islets
Glycogen synthesis
G6P- branch point in Carbohydrate metabolism- its the substrate for glycolysis, glycogen synthesis, and PPP
Pathways of g6p to glycogen are different from the pathways from glycogen back to g6p- this leads to tight regulation and limited futile cycling
Types of regulation: short term (mostly metabolites) and longterm (mostly hormone related- phosphorylation and dephosphorylation)
Insulin stimulates glycogen formation. Epinephrine (from liver and muscle) and glucagon (from liver) stimulate glycogen breakdown
In the muscle G1P formed by glycogen breakdown is used for energy but in the liver its used for maintaining blood glucose levels
Glucose transport
First step in glucose metabolism is glucose transport in the cell, GLUTS are integral membrane proteins that allow facilitated transport of sugars across the membrane
GLUT1-GLUT9 (now GLUT 12) GLUT 1-5 are well charcterized and have tissue specific expression
SGLT1- Na/Glucose co transporter. its used Glucose/galactose uptake and renal glucose absorption
Glut 1 and 3: basal glucose transport, found almost everywhere especially in neuronal cells (3) and RBCs (1)Km is low for glucose so always saturated
Glut 2: has a high km expressed in liver, pancreatic B-cells and the basolateral side of intestines (luminal), the high Km allows for transport of glucose to be proportional to plasma concentration
in the liver: Glut2, glucose is only taken up when blood glucose levels are high ie in the fed state, then in a fasted state liver sends out glucose to maintain normal plasma glucose levels
Glut 4-insulin stimulated glucose transport and transports glucose into fat an skeletal muscle, insulin increases GLUT4 translocase to PM
GLUT5- intestinal fructose uptake for small intestines
Glucose phosphorylation
The GLUT transporters (not SGLT1) are freely reversible, and keep inter and extra cellular glucose concentraions the same
Hexokinases: hav a low km for glucose and use Mg-ATP as the nucleotide substrate Inhibited by G6P (product inhibition)
Glucokinases: expressed in liver and pancreatic B cells (Km for glucose is high, high Vmax and is not inhibited by G6P)
G6P
Begining of branch point for several pathways of metabolism
Fasted state: glycogen to G6P maintains blood glucose, NADPH synthesis and energy production
Fed state: glucose is high so its stored as glycogen
Glycogen synthesis
G6P -> G1P -> UDP- glucose (via phosphoglucomutase and UDP glucose pyrophosphorylase)
the energy of UTP is used to make activated glucose
Glycogen synthase adds UDP glucose to existing chains by alpha 1,4 linkage at the non reducing ends +4 glucoses (prevents free glucose addition)
Reducing end has glycogenin primer for glycogen primer, non reducing ends have sites for glucose removal, branching allows for rapid production of glucose
nucleoside diphosphate kinase converts UDP back to UTP enzyme works on all NDPs and is readily reversible (hight ATP/ADP ratio drives UDP +ATP-> UTP +ADP
Glycogenin is the promer for glycogen it has auto glycosylation activity and adds 8 glucoses to a tyrosin, using UDP-glucose as the donor
Branching enzyme: glucosyl a 4-6 transferase needs 11 glucose, takes 7 glucoses and adds on in 1,6 fashion at least 4 units away from branch point
Glycogen break down (glycogenolysis)
PHOSPHORYLASE
cleavage of 1,4 alpha bond, removes glucose from non reducing ends that are +4 away from branch point, active site pyridoxal phosphate (PLP) residue that acts as a general acid base catalyst
Regulation: G6Pase in liver (not in muscle) G6P can be hydrolyzed to glucose (blood glucose) G6Pase is located on the luminal surface of the ER
Debranching enzyme
you need to debranch because phosphorylase can only be active +4 away from a branch point
Debranching enzyme: bifunctional enzyme with a 4:4 trasnsferase activity (4-a-D glucanotransferase) that removes 3/4 glucose residues at a branch point and moves them to another cahin in an alpha 1,4 linkage
the remaining glucose residue is hydrolyzed to produce glucose so you make a 7 or 8 chain of G1P and you make one glucose, its reversible if you have lots of glucose in the cell
glycogen metabolism regulation
Things that increase breakdown: Epinephrine, glucagon, AMP (muscle), and Calcium
Things that increase build up, Insulin, ATP, G6P, glucose in liver
Glycogen phosphorylase regulation:
Phosphorylase breaks down glycogen and synthase builds it up
Two conformations of phosphorylase T state (inactive) and R state (active) controlled by phosphorylation.
Phosphorylase A: phosphorylated and more active and phosphorylase b is less active and not phosphorylated
Phosphorylase kinase Activated by PKA and CA (phosphorylates phosphorylase (A) leading to breakdown of glycogen)
Protein phosphorylase dephosphorylates phosphorylase (B) and prevents breakdown of glycogen
Phosphoprotein phosphatase dephosphorylates both phosphorylase kinase and glycogen phosphorylase
(de)phosphorylating only switches between the b and a phosphorylase but…
ATP/GTP induces the B phosphorylase to be turned into the T state then phosphorylating the T-B form will convert it into the T-A form and then with low glucose will convert the T-A form into the active R-A form of phosphorylase
AMP will inhibit the R-B- to T-B
Regulation of phosphorylase by Protein phosphatase PP!
insulin causes activation of PP1, then PP1 is able to dephosphorylate glycogen synthase (activating it to make more glycogen), and dephosphorylates phosphorylase kinase (deactivating it, stoping glycogen-lysis), you have lots of glucose so you want to build up and stop breakdown of glycogen (limit futile cycling)
epinephrine- causes phosphorylation through PKA of glycogen synthase, and it causes dissaciation of PP1
