Flashcards in Carbohydrate Metabolism Deck (107):
What is the only fuel that RBCs can use? This is also the only fuel that the brain uses under non-starvation conditions
De novo synthesis
Gluconeogenesis in liver
Why can’t glucose cross the cell membrane?
It is polar, so there are specialized glucose transporters located in the cell membrane
High in RBCs and brain
Skeletal muscle, heart, adipose tissue
What type of diffusion is the uptake of glucose an example of?
Facilitated diffusion, since transporters are used
Which glucose transporter has the lowest affinity (highest Km) for glucose?
Describe how GLUT4 is insulin dependent
GLUT4 is a protein made in ribosomes that is then sequestered in vesicles in cells
Insulin signaling causes fusion of these vesicles with the plasma membrane, which allows GLUT4 to take up glucose
Glycolysis includes a sequence of reactions that metabolizes ______ and generates _______
1 molecule of glucose (6C) to 2 molecules of pyruvate (3C)
2 ATP and 2 NADH
Under aerobic conditions, glycolysis can yield ____ ATP, which then go on to the TCA cycle in mitochondria
Where does glycolysis occur?
There are 3 phases of glycolysis: investment, splitting, and recoup/payoff. Describe briefly what occurs in each
Investment: requires 2 ATP
Splitting: one 6C molecule into two 3C molecules
Recoup/payoff: 4 ATP molecules generated (2 net)
What is the net yield of products in glycolysis?
2 ATP, 2 NADH, 2 pyruvate
The first phase of glycolysis, investment, can be broken down further into 3 steps:
1. Phosphorylation of glucose to G6P
2. Isomerization of G6P to F6P
3. Phosphorylation of F6P to fructose 1,6-biphosphate
In glycolysis, glucose must be trapped in the cell. Describe how/when this occurs
This occurs during the phase 1 of glycolysis, when glucose is phosphorylated to G6P
The enzymes involved are hexokinase, Glucokinase (pancreatic beta cells)
This is an important regulatory step
What/when does the rate limiting step occur in glycolysis?
The rate-limiting step occurs in the first phase of glycolysis, investment
It is when F6P is phosphorylated to fructose 1,6-biphosphate
The second phase of glycolysis, splitting, can be further broken down into:
4. Cleavage of F1, 6BP
What catalyzes the cleavage of F1, 6BP in the splitting phase of glycolysis?
The third phase of glycolysis, recoup/payoff, can be further broken down:
6. Phosphorylation of G3P
7. Conversion of 1,3-BPG to 3-PG
8. Formation of pyruvate
What step of glycolysis is irreversible?
The formation of pyruvate, which converts ADP to ATP
What occurs when 1,3-BPG is converted to 3-PG in the recoup/payoff phase of glycolysis?
ADP is converted to ATP
What occurs when G3P is phosphorylated in the recoup/payoff stage of glycolysis?
NAD+ is reduced to NADH
What are the checkpoints that help regulate glycolysis? What enzymes are they catalyzed by? What influences these enzyme’s activity?
3 irreversible phosphorylation steps
Hexokinase/glucokinase, phosphofructokinase-1, pyruvate kinase
ATP (low ATP = glycolysis), AMP, glucose, INSULIN & GLUCAGON!!!!
Catalyze the phosphorylation of glucose to G6P (helps trap glucose inside cells)
Has a high affinity for glucose and is functional even at low levels
Inhibited by G6P (product)
Low affinity for glucose
Most active when glucose is high
At low F6P, it translocates to nucleus
What is the rate limiting enzyme in glycolysis? What does it do? Does increased or decreased activity of it favor glycolysis?
Catalyze the conversion of F6P to F1,6BP
High insulin/low glucagon
Citrate (TCA cycle)
High glucagon/low insulin
Catalyzes the conversion of PEP into pyruvate and ATP
Activates pyruvate kinase
Inhibits pyruvate kinase
At rest, a negative feedback loop is created in glycolysis when:
G6P accumulates, so hexokinase stops wanting to make it
Also a precursor for the pentose phosphate pathway to produce ribose and NADPH
(Converted to G1P for galactose metabolism, glycogen synthesis, ironic acid pathway)
What is the fate of pyruvate in RBCs and muscle cells?
Reduced to lactate, which regenerates NAD+
What is the fate of pyruvate in the mitochondria?
It is oxidized in the TCA cycle to acetyl CoA and then CO2
Pyruvate can be converted to this amino acid
Which cells are most impacted by disorders of glycolysis?
Those that lack mitochondria— RBCs (most defects cause hemolytic anemias)
Also brain cells
Mutations in this enzyme affect the protein’s folding and activity and lead to nonspherocytic hemolytic anemia and neurologic impairment
Mutations in these enzymes cause hemolytic anemia
Mutations in this enzyme cause intermediate enzyme deficiency and are associated with neonatal onset hemolytic anemia and neurologic dysfunction
Triose phosphate isomerase
Where does the brain obtain glucose from during starvation?
Note: glucose is one of the only fuel molecules that can cross the blood brain barrier (BBB)
From the liver via gluconeogenesis
Can also utilize ketone bodies
Summarize carbohydrate metabolism in the fed state
Increased rates of glycolysis, production of glycogen
Summarize carbohydrate metabolism in the fasting state
Increase in gluconeogenesis and glycoogenolysis
Diabetes due to loss off pancreatic beta cells
Diabetes due to insulin resistance that progresses to loss of beta cell function
Inherited defects in RBC membranes
Nutritional deficiencies in these 3 can cause hemolytic anemia
Iron, folate, vitamin B12
What are 2 clinical marketers of hemolytic anemia?
Elevated lactate dehydrogenase, unconjugated bilirubin
In this disease, the patient is deficient in PFK-1 (rate limiting step) and experiences exercise-induced muscle cramps and weakness and high bilirubin and jaundice
Tarui disease (GSD VII)
How much glucose does the whole body need a day?
How much glucose is present in body fluids? How much is readily available from glycogen?
Where and when does gluconeogenesis occur?
In the liver, kidney, and small intestine
Occurs when glucose and glycogen stores are depleted
What does gluconeogenesis do? What are the major precursors?
Converts pyruvate into glucose
Lactate, amino acids, and glycerol
Does gluconeogenesis directly yield ATP?
No, it makes glucose
List the positive regulators for gluconeogenesis
Glucagon, citrate, cortisol, thyroxine, acetyl CoA
List the positive regulators for glycolysis
Glucose, insulin, AMP, Fru2,6-BP, Fru1,6-BP
List the negative regulators for gluconeogenesis
ADP AMP, Fru2,6-BP
List the negative regulators for glycolysis
Glucagon, ATP, citrate, G6P, F6P, alanine
Gluconeogenesis bypasses the 3 irreversible steps of glycolysis by using 4 enzymes not present in glycolysis. These are:
A mitochondrial enzyme that forms oxaloacetate from pyruvate in step 1 of gluconeogenesis
Has biotin as a cofactor
Pyruvate carboxylase (PC)
OAA is reduced to malate by ______. It is then transported to the cytoplasm and re-oxidized to OAA by _______
Step 2 of gluconeogenesis
Mitochondrial malate dehydrogenase
Cytosolic malate dehydrogenase
In step 3 of gluconeogenesis, OAA is ddecarboxylated and phosphorylated to PEP by
Phosphoenolpyruvate carboxykinase (PEPCK)
The 4th, and rate limiting, step of gluconeogenesis
The 5th step of gluconeogenesis, where _____ dephosphorylates G6P to form glucose
Glucose-6-phosphatase (located in the lumen of the ER)
Links the lactate produced from anaerobic glycolysis in RBCs and exercising muscle to gluconeogenesis in liver
Glucose from liver is transported back to RBC and muscle to prevent lactate accumulation and regenerate glucose
Lactate —> pyruvate —> gluconeogenesis
3 important precursors of gluconeogenesis
Galactose, fructose, lactate (monosaccharides)
Deficiency in glucose-6-phosphatase causes this disease
It is caused by a mutation in a catalytic site
This means no free glucose is formed and leads to symptoms like fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, and retarded growth
Von Gierke disease
Takes up fructose
Takes up galactose and glucose
Caused by GLUT2 mutation
Unable to take up glucose, fructose, and galactose
Symptoms: failure to thrive, hepatomegaly
Rx: vitamin D and phosphate, uncooked corn starch
Reduces glucose to sorbitol
Oxidizes sorbitol to fructose
Cells that lack this can have water influx and swelling —> retinopathy, cataracts, peripheral neuropathy
Why is fructose easier to convert to fat?
It bypasses the rate limiting step of glycolysis d/t absence of PFK1
Describe galactose metabolism
Glucose 1p uriddyltransferase (GALT) converts galactose to G1P to G6P where it can enter glycolysis
Results from a deficiency in glucose 1P uridyltransferase (GALT), which leads to an accumulation of galactitol —> cataracts in babies
Can also result from a deficiency in galactokinase
Produces the sugar for DNA and RNA formation as well as NADPH, but does not produce energy
Pentose phosphate pathway (PPP)
Where does the PPP take place?
Oxidation of G6P to ribulose 5P and 2 NADH
Irreversible oxidative and reversible non-oxidative steps
Summarize the oxidative phase of PPP, which involves the oxidation of G6P
-produce 2 NADPH and 1 CO2
-G6P dehydrogenase: rate-limiting step —> NADP+ to NADPH
-NADPH regenerates glutathione, an antioxidant
G6PD deficiency presents as hemolytic anemia and affects those from _____ descent
If thee cells have a high demand for ribose 5P (synthesize DNA), what phase of PPP is favored?
Oxidative phase to produce ribulose 5P
What occurs in PPP if there is a high cellular demand for NADPH?
Non-oxidative products are channeled into gluconeogenesis
There is very high PPP activity in what type of cells?
Homopolymer of glucose
What type of bond links together the glucose molecule within a chain of glycogen?
A-1,4 glycosidic bonds
What bonds form the branch points in glycogen?
A-1,6 glycosidic bonds
Contain a terminal glucose with a free hydroxyl group at carbon 4
Non-reducing end of glycogen
Glucose monomer connected to a protein called glycogenin
Reducing end of glycogen
From which end is glycogen degraded and extended?
How glycogen is stored in the liver and muscle; contain also enzymes needed for glycogen metabolism
Regulates blood glucose
Reservoir of fuel (glucose) for physical activity
There are 3 key steps in glycogenesis:
1. Trapping/activation of glucose (glucokinase/hexokinase phosphorylated glucose to G6P —-> phosphoglucomutase to G1P)
2. Elongation of a glycogen primer
3. Branching of glycogen chanins
What is the rate limiting enzyme in glycogenesis?
What is the rate limiting enzyme in glycogenolysis?
Glycogen phosphorylase (B6 is a cofactor)
Glycogen synthase is active in the _____ form.
Glycogen phosphorylase is active in the ______ form
Does glucagon act on muscle?
Disorders that affect glycogen breakdown lead to:
Hepatomegaly and hypoglycemia
Disorders that affect glycogen synthesis lead to:
Patients dependent on glucose
Defective enzyme: glycogen synthase
Pathway affect: glycogenesis— chain elongation
Pathway affected: lysosomal glycogenolysis— release of glucose
GSD II / Pompe disease
Defective enzyme: glucosyl (4:6) transferase
Pathway affected: glycogenesis— chain branching
Long chain glycogen
Enlargement of liver and spleen, cirrhosis, death by 5
GSD IV / Andersen disease
Defective enzyme: muscle glycogen phosphorylase
Pathway affected: glycogenolysis— G1P release
Unable to supply muscles with enough glucose
Weakness, muscle cramps
Myoglobin in urine
GSD V / McArdle disease
Defective enzyme: liver glycogen phosphorylase
Pathway affected: glycogenolysis— G1P release
Prevents glycogen breakdown in liver —> hepatomegaly
Low blood glucose levels
GSD VI / Hers disease