Carbohydrates And Metabolism Flashcards
One glucose is converted to glucose -6-P it can enter several pathways. What are they?
-Glycolysis
-Pentose phosphate shunt
-Glycogenesis
Glycolysis: Which enzyme is needed to commit glucose-6-P to glycolysis?
Hexokinase; key step in glycolytic pathway
The enzymes of three irreversible reactions are also the main regulated enzymes of glycolysis.
What are they?
Hexokinase (glucokinase in the liver): phosphorylates glucose to form glucose-6-phosphate, trapping glucose within the cell & committing it to glycolysis
Phosphofructokinase-1 (PFK-1): Catalyzes the conversion of fructose-6-phosphate to fructose-1,6-biphosphate (key step), and subject to allosteric regulation.
Pyruvate kinase: Converts phosphoenolpyruvate (PEP) to pyruvate, producing ATP
What does hexokinase catalyze?
Phosphorylation of glucose to produce G6P. Traps glucose within the cell and prepares it for further metabolic pathways.
Hexokinase in muscle:
reversibly regulated by G6P ( example of product inhibition)
When cellular concentrations of G6P rise above normal, Hexokinase is temporarily inhibited to bring the rate of Glucose-6-Phosphate into balance with its rate of utilization.
What reaction does PFK-1 catalyze?
fructose-6-phosphate (F6P) => fructose-1,6-biphosphate (F-1,6-B)
PFK-1 is under complex allosteric regulation:
1: ATP inhibits PFK-1 by binding to an allosteric site;
-Lowers the affinity of the enzyme for F6P
-AMP and ADP relieve the inhibition of PFK-1
Why this makes sense logically: allows the cell to fine-tune its glycolytic activity based on its current energy status, ensuring efficient utilization of glucose and ATP production in response to the cell’s energy needs.
2: Citrate
-Key intermediate in CAC
-High citrate levels inhibit PFK-1; high citrate serves a signal that the cell is meeting its current needs for energy
3: Fructose 2,6- phosphate:
-most significant allosteric regulator
-Activates PFK-1; Fructose -2,6- bisphosphate enhances the affinity of PFK-1 for F6P/ Stimulates glycolysis
-Inhibits FBP-1, slowing gluconeogenesis
Fructose- 2,6- bisphosphate continued:
Fructose- 2,6- bisphosphate is formed by phosphorylating F6P, catalyzed by phosphofructokinase-2 (PFK-2)
What reaction does pyruvate kinase catalyze?
Converts phosphoenolpyruvate (PEP) to pyruvate, producing ATP
Pyruvate kinase is allosterically regulated: Inhibition-explain each logically:
1) ATP
2) Acetyl-CoA
3) Fatty-acids
1) ATP: when ATP is high => signals that the cell has sufficient energy reserves.
-ATP binds to allosteric site of pyruvate kinase, and switches the enzyme to it’s less active form.
-negative feedback mechanism; reducing pyruvate kinases activity when energy levels are high.
2: Acetyl-CoA: Intermediate in CAC cycle can allosterically inhibit pyruvate kinase;
-When the cell has abundant Acetl-CoA, indicates that the citric acid cycle is processing metabolites efficiently and there is a surplus of energy.
-Acetyl-CoA binds to allosteric site ; promoting the enzymes less active form, slowing down glycolysis and conversion of pyruvate to Acetyl-CoA. Regulating production of more energy.
-Negative feedback mechanism, reduces the glycolytic pathway when energy sources are ample.
3: Fatty acids: Inhibits pyruvate kinase indirectly;
-High levels of fatty acids in the cell typically signal that there is a need to prioritize the utilization of fatty acids for energy production instead of glucose.
-Enter the cell, undergo beta-oxidation, generating Acetyl-CoA.
-This then can activate pyruvate kinase, but fatty acids are more inhibitory due to diverting the cells focus away from glucose metabolism towards lipid metabolism for more energy production.
Pyruvate kinase is allosterically regulated:
Activation:
Fructose 1, 6 bisphosphate
Glycolysis is regulated hormonally by _________ and ___________.
insulin; glucagon
Insulin: promotes the transcription of _____________, ______________, & _____________
Hexokinase, phosphofructokinase-1, and pyruvate kinase
(also promotes the activation of PFK-1 & inhibition of FBP-2)
Glucagon reduces the expression of _______, _____, and ___________.
hexokinase, PFK-1 & pyruvate kinase
(promotes the activation of FBP-2 & inhibition of PFK-2)
Hexokinase is activate by:
Glucose; when glucose is high, hexokinase facilitates the phosphorylation of G6P.
Hexokinase is inhibited by:
Glucose-6-phosphate; high levels of G6P signal the glycolytic pathway is already processing glucose, and further phosphorylation is not needed.
PFK-1 is activated by:
AMP; when cell’s energy levels are low and there is an accumulation of AMP, PFK-1 becomes more active.
AMP (product of ATP degradation)
PFK-1 is inhibited by:
ATP; there is enough energy in the cell
Citrate: High levels of citrate indicate the cell has ample energy reserves
Pyruvate kinase is activated by:
F-1,6-B: when these levels are high, signifies glycolysis is in full swing, and there is a demand for pyruvate production.
Pyruvate kinase is inhibited by:
ATP: when high, signals energy levels are sufficient
Alanine: Amino acid, high levels can signal that amino acid metabolism is prevailing over glycolysis.
Metabolism of other important sugars:
___________, _________, and ________ are converted into glycolytic intermediates.
Fructose, mannose, & galactose
Where does fructose metabolism predominantly occur?
Liver
Fructose metabiolism:
Which monosaccharide is metabolized faster, glucose or fructose, why?
Glucose:
1) cellular reuptake: transporters;GLUT1 & GLUT4 allow ofor efficient and rapid uptake of glucose.
2) Regulatory enzymes: Glycolytic pathway through phosphorylation by hexokinase G6P
3) Regulatory factors: Insulin; promotes glucose uptake and utilization
Excessive consumption of fructose , especially in the form of high-fructose corn syrup is associated with various metabolic issues such as: fatty liver disease & insulin resistance
The first two bypass reactions are the main regulated reactions of gluconeogenesis:
Why were these bypass reactions?
Because pyruvate kinase cannot be converted back into phosphoenolpyruvate, so the by pass is converting pyruvate into oxaloacetate to then “reverse” the irreversible reaction in gluconeogenesis.
In order to bypass the hexokinase reaction that only goes in one direction, a series of other reactions need to be made to convert G6P back to glucose in the ER.
This allows glucose to be synthesised in fasting states.
Pyruvate can be converted either to:
A) Acetyl-CoA => enter CAC
B) Oxaloacetate => enter GNG
C) Lactate (Cori cycle)
What enzyme catalyzes conversion of pyruvate to oxaloacetate?
Pyruvate carboxylase
Acetyl-CoA is a allosteric ____________ of pyruvate carboxylase.
activator
What reaction does FBP-1 catalyze?
-Allosterically inhibited by AMP
-Allosterically inhibited by F-1,6-B
DHAP & GA3P
Gluconeogenesis is regulated hormonally by _____________ & _____________.
Insulin & glucagon
Glucagon:
-Promotes activation of FBP-2, lowering levels of F-2,6-B
-Can also induce the transcription of PEP carboxykinase
Pyruvate carboxylase is activated by:
Acetyl CoA: Signal that the cell has abundant energy reserves which then promotes the pyruvate => oxaloacetate conversion.
Ensures oxaloacetate is present for gluconeogenesis when there is excess energy substrates.
Pyruvate carboxylase is inhibited by:
ADP: When cellular energies are low, there is higher ADP to ATP (energy deficit) pyruvate carboxykinase activity is reduced.
Inhibition helps conserve oxaloacetate for energy production through glycolysis & CAC.
Insulin: Indirectly inhibits pyruvate carboxykinase. Promotes uptake of pyruvate into mitochondria, where it’s converted to Acetyl-CoA.
This redirection limits its availability for pyruvate carboxylase, decreasing oxaloacetate synthesis.
PEP carboxykinase is activated by:
Glucagon: when blood glucose levels are low glucagon is released by pancreas.
High fat diets (indirect activation)
PEP carboxykinase is inhibited by:
Insulin: blood glucose levels are high, insulin is released by the pancreas to lower it.
FBP-1 is activated by:
Citrate: CAC, when cellular energies are high, there is excess citrate, indicates CAC is active and energy reserves are sufficient.
Promotes the gluconeogenesis to produce glucose when energy is abundant.
FBP-1 is inhibited by:
F-2,6-B: When this is high, glycolysis is favored of gluconeogenesis
AMP: reflects low cellular energy levels, to help prevent glucose synthesis when glycolysis should be favored.
Pentose Phosphate Shunt:
Alternative metabolic pathway for glucose that “shunts” molecules into and out of glycolysis
Purpose: Generates two main products:
-NADPH
-Ribose-5-phosphate (pentose phosphate)
Also generates:
-Fructose-6-phosphate
-Glyceraldehyde-3-phosphate
Both can feed back into glycolysis
Why is the pentose phosphate shunt called a “shunt?”
Because it shunts G6P and provides an alternative route for glucose metabolism.
Where does the pentose phosphate shunt occur?
This happens in the cytoplasm of the eukaryotic cell.
What are the two phases of the pentose phosphate shunt?
Oxidative:
-Irreversible reactions
Non-oxidative:
-Reversible reactions
Oxidative Phase:
Glucose-6-phosphate => Ribulose-5-phosphate:
Generates: 2 NADPH
Functions:
-Fatty acid synthesis
-Reduces glutathione
Glutathione is an ___________
Antioxidant:
-3 amino acid peptide: glycine, cystine, glutamine
-Neutralizes (reduces) hydrogen peroxide to water by donating H’s
-NADPH regenerates glutathione by replacing the donated H’s
Oxidative phase regulation:
G6P => R5P
Rate limiting step:
G6P => 6-phosphoglucono-δ-lactone
Enzyme: glucose-6-phosphate-dehydrogenase (G6PD)
Regulated by: ratio of NADPH & NADP+
-high ratio of NADPH & NADP+, inhibits G6PD
-inhibited by high levels of acetyl CoAs:
-Upregulated by insulin
G6PD deficiency is an _____________ trait.
x-linked
More common in men.
Highest prevalence: middle eastern, mediterranean, & tropical african or asian descent.
What does G6PD deficiency result in?
hemolytic anemia when an individual is exposed to an oxidant stress.
ex) some drugs, infections, fava beans
Non-oxidative phase of pentose phosphate shunt:
Riboluse -5-P => ribose-5-P: participates in the synthesis of nucleotides, coenzymes, energy metabolism, & cellular redox balance.
or
Riboluse-5-P => glycolytic intermediates
-G6P
-F6P
Glucose is stored in polymeric form as glycogen mostly in the ________ & ____________.
liver & skeletal muscle
High glucose/ energy levels will trigger ____________________.
Glycogen synthesis:
Glycogenesis
Glucose can be rapidly delivered to the bloodstream when needed by degradation of glycogen in the __________
Liver
(Glycogenolysis)
Glucose is transferred onto a growing chain of glycogen as a ___________
UDP-glucose
(Glycogenesis)
UDP-glucose is added to an existing strand of glycogen by the enzyme ______________.
glycogen synthase
_____________ catalyzes the transfer of 4-8 glucose residues to a branch point.
Branching enzyme: amylo-α(1,4=>1,6) glucosyl transferase
Glycogenolysis:
Glycogen synthase cannot initiate a new glycogen chain de novo, it requires a primer:
Primer contains ore-formed (alpha1=>4) polyglucose chain with at least 4-8 glucose residues
Found within glycogenin: contains the primer and the enzyme needed to build the primer.
Glycogenolysis is a ___________ progress
catabolic progress:
-Breakdown of glycogen into glucose units
-Occurs in the liver & muscle
Glycogenolysis:
Glucose is removed from non-reducing ends of glycogen:
Enzyme: glycogen phosphorylase
-sequentially cleaves α (1=>4) linkages from the non reducing ends until 4 units away from a branch point (glucose is released as G1P)
-Once all chains degraded to within 4 units of the branch point, the molecule is called a limit dextrin
Glycogenolysis:
A de-branching enzyme has two functions:
1) transfers the outer 3 glucose residues from the branch to another non-reducing end (leaving only 1 reside behind as the branch point)
-aka: Oligo-α(1,4)-α(1,4)glycotransferase
2) Removes the final glucose residue in the alpha (1=>6) linkage
-aka: amylo-α(1,6)-glucosidase
Glycogenolysis:
Glucose-1-P is converted to glucose-6-P by the enzyme:
Phosphoglucomutase
(same enzyme in the first step of glycogenesis)
Glycogenolysis:
After glucose-1-P is converted to Glucose-6-P by phosphoglucomutase, The liver can then convert G6P to glucose with ____________.
Glucose-6-phosphatase
(primarily found in ER)
Muscles do not have G6P, Why? and what do they use instead?
Because muscles have no need to regulate blood glucose levels.
Instead they use G6P for ATP (energy production)
________________ & __________________ are the two regulated enzymes in glycogen metabolism.
Glycogen synthase & glycogen phosphorylase
Glycogen synthase regulation:
Allosterically activated by glucose-6-P
Glycogen phosphorylase regulation:
Allosterically inhibited by:
-G6P
-ATP
-Free glucose (liver only)
-Allosterically activated by AMP (muscle only)
Glycogen synthase and glycogen phosphorylase can also be regulated by covalent modification:
Glycogen synthase:
Glycogen phosphorylase:
Glycogen synthase: de-activated by phosphorylation
Glycogen phosphorylase: Activated by phosphorylation
-Phosphorylation is catalyzed initially by the same protein, protein kinase A (PKA)
-This prevents both pathways from running at the same time.
Glycogen metabolism regulation-Hormonal:
Covalent modification of glycogen metabolism is under hormonal control.
Inhibition:
In the presence of glucagon & epinephrine =>
-Glucagon binds to its GCPR
-Gα_s activates adenylyl cyclase => cAMP levels rise
-PKA phosphorylates glycogen synthase, rendering it INACTIVE (glycogenesis is inhibited)
Glycogen metabolism regulation-Hormonal:
Covalent modification of glycogen metabolism is under hormonal control.
Activation:
In the presence of glucagon & epinephrine =>
-PKA phosphorylates glycogen phosphorylase kinase, rendering it ACTIVE
-Glycogen phosphorylase kinase phosphorylates glycogen phosphorylase, rendering it ACTIVE
-Glycogenolysis is promoted
Glycogen metabolism regulation-Hormonal:
Covalent modification of glycogen metabolism is under hormonal control.
Activation:
In the presence of Insulin =>
-Insulin promotes the breakdown of cAMP and thus inactivation of PKA
-Insulin activates protein phosphatase 1, which removes the phosphate group from glycogen synthase, rendering it ACTIVE
-Glycogenesis is promoted
Glycogen metabolism regulation-Hormonal:
Covalent modification of glycogen metabolism is under hormonal control.
Inhibition:
In the presence of Insulin =>
-Insulin promotes the breakdown of cAMP and thus inactivation of PKA
-Insulin activates protein phosphatase 1, which removes the phosphate group from:
-Glycogen phosphorylase kinase
-Glycogen phosphorylase
Rendering both INACTIVE
-Glycogenolysis is INHIBITED
