T04 - Pentose Phosphate Pathway Flashcards
What are the primary products of the PPP? (3)
NADPH
ribose
5 or 7-carbon carbonhydrates
Why is NADPH important? (2)
primary reducing power for biosynthetic pathways
protects against oxidative stress
Pompe disease results from
recessively-inherited deficiency in alpha-glucosidase
What is the function of the enzyme alpha-glucosidase?
digests glycogen to glucose
What are the effects of Pompe disease?
buildup of glycogen in lysosomes, leading to muscle weakness and organ damage
fatal in infants if not treated within 2 years
What are the linkages within glycogen?
glycosidic alpha-1,4 and alpha-1,6 linkages
The alpha-glycosidic bonds within glycogen cause it to adopt what shape?
forms helical-like configuration
What are the advantages of branches within glycogen? (2)
increased solubility
rapid release of glucose from glycogen
What enzyme is responsible for releasing glucose from glycogen?
glycogen phosphorylase
What enzyme is responsible for adding glucose to glycogen?
glycogen synthase
What is the primary function of liver glycogen?
maintain blood glucose levels
(T/F) Glycogen granules are absent from cells after a 24-hour fasting period.
True. Glycogen granules exist to maintain blood [glucose] between meals. If there are no meals, the glycogen granules are depleted.
What is the primary function of muscle glycogen?
provide source of ATP in muscle
What is the major limitation of muscle glycogen?
muscle glycogen is not available to other tissues because muscle cells don’t have glucose-6-phosphatase, which is required to make free glucose
What molecule is the primer for glycogen synthesis?
the protein glycogenin is the primer/initiator of glycogen synthesis
What molecule is the template (note: distinct from primer) for glycogen synthesis? Explain how this molecule forms.
glycosylated glycogenin is the template for glycogen synthase
“plain” glycogenin self-glycosylates by attaching glucose from UDP-glucose to its tyrosine residue
What molecule is the building block for glycogen synthesis?
UDP-glucose
Explain the difference between UDP-glucose and glucose.
UDP-glucose is an activated form of glucose because of high-energy diphosphate linkage → makes polymerization more energetically favorable
How is UDP-glucose synthesized? What drives this synthesis forward?
UTP + G-1-P → UDP-glucose + PPi, catalyzed by UDP-glucose pyrophosphorylase
irreversible hydrolysis of pyrophosphate drives reaction forward
Which enzymes are responsible for the alpha-1,4 and alpha-1,6 linkages?
glycogen synthase adds in alpha-1,4 fashion
branching enzyme breaks alpha-1,4 linkages and replaces it with alpha-1,6 linkage
In order for glycogen synthase to add UDP-glucose units, what structure must first exist in the glycogen molecule?
short pre-existing glucose polymer (4 units), which is synthesized by glycogenin
Describe how the branching enzyme of glycogen synthesis operates.
transfers block of 7 residues to interior site
breaks alpha-1,4 bond and replaces it with alpha-1,6 linkage
interior site is located at least 4 residues from another branch site
[tip: think “July 4th” for 7 residues/4 residues]
Write out the chemical equation for glycogen degradation/glycogenolysis.
(glycogen)n + Pi → (glycogen)n-1 + G-1-P
What enzyme breaks alpha-1,4 glycosidic linkages in glycogen?
glycogen phosphorylase
(T/F) G-1-P can freely diffuse across cell membranes.
False. It, like G-6-P, can’t cross cell membranes because of the negative charge of the phosphate.
How is G-1-P liberated from glycogen made available for metabolic processes?
phosphoglucomutase converts G-1-P to G-6-P, which is the molecule at the center of glucose metabolism
What enzyme breaks alpha-1,6 glycosidic linkages in glycogen?
debranching enzyme
Describe how the debranching enzyme operates.
moves chain of 3 glucose residues to end of an adjacent glycogen branch
breaks alpha-1,6 linkage of remaining residue
remaining residue liberated as free glucose
The debranching enzyme is an example of what kind of enzyme?
debranching enzyme = example of bifunctional enzyme
What is the effect of epinephrine on glycogen? (2)
stimulates glycogenolysis in liver and muscle
[tip: think fight or flight]
Draw out the cascade of events that occurs when glucagon activates protein kinase A.
glucagon → adenylate cyclase → cAMP → active PKA → active phosphorylase kinase → active phosphorylase a → glycogenolysis
What is the effect of glucagon on glycogen?
glucagon stimulates glycogenolysis (to ensure there is adequate glucose for all tissues)
Which form of glycogen synthase is active — phosphorylated or dephosphorylated?
dephosphorylated is active
[opposite of glycogen phosphorylase]
Which form of glycogen phosphorylase is active — phosphorylated or dephosphorylated?
phosphorylated form is active
[opposite of glycogen synthase]
The low glucagon and epinephrine levels in the period after eating a meal activate what protein?
protein phosphatase 1 (PP1)
Protein phosphatase 1 (PP1) is activated/expressed in what period of time?
period of time after eating a meal, when glucagon and epinephrine levels are low
What is the function of protein phosphatase 1 (PP1)?
activates glycogen synthase (by dephosphorylation)
inhibits glycogen phosphorylase (by dephosphorylation)
[yes, both mechanisms are by dephosphorylation]
What does the term “favism” refer to?
refers to people who can’t tolerate Fava beans
Favism results from what defect?
deficiency in G-6-P dehydrogenase (G6PDH)
What is the significance of the enzyme G6P dehydrogenase (G6PDH)?
rate-limiting enzyme of PPP
What is the rate-limiting enzyme of the PPP?
G6P dehydrogenase (G6PDH)
What happens if a patient with favism eats fava beans?
most likely, acute hemolysis
What are the symptoms of favism? (3)
jaundice
black urine
tired all the time
What is a benefit of favism?
malaria resistance, because RBC membrane is too compromised to allow propagation of malaria parasite
(T/F) Relatively speaking, the PPP consumes more glucose than glycolysis or glycogen synthesis.
False. The PPP consumes relatively smaller amounts of glucose compared to glycolysis or glycogen synthesis.
Write out the overall reaction for the PPP.
G6P + 2 NADP+ → ribulose-5-phosphate + 2 NADPH + CO2
Draw out the three steps of the PPP.
How does NADPH maintain the reductive environment of the cytosol? (2)
glutathione reductase uses NADPH to reduce glutathione dimers to just glutathione
glutathione breaks disulfide bonds and maintains protein in reduced (-SH) state
How is NADPH utilized in anti-bacterial mechanisms?
NADPH provides electrons for generation of ROS by phagocytic cells (NADPH oxidase) to kill invading bacteria
How does NADPH protect cells from oxidative damage? Draw a diagram to support your answer.
glutathione peroxidase uses NADPH to convert H2O2 into water, which protects cells from oxidative damage
The PPP is most active in tissues involved in…
Give three examples of such tissues.
fatty acid and steroid synthesis
for example:
liver
adrenal gland
adipose tissue
Why is the PPP important in the eye?
cornea and lens lack mitochondria (therefore no TCA cycle) and have limited blood supply, so they use the PPP to metabolize glucose
Why is the PPP important in RBCs? (2)
RBCs lack mitochondria (so no TCA cycle), making the PPP the only source of NADPH in RBCs
RBCs are susceptible to oxidative damage, which the PPP can help prevent
What is the most common enzyme disorder in the world?
G6P dehydrogenase deficiency
What is the most abundant small peptide in human cells?
glutathione
What is the treatment for Pompe disease?
myozyme (recombinant acid alpha-glucosidase)
Which two tissues have the highest concentration of glycogen in the body?
liver (5-10% of wet weight)
muscle (1-2% of wet weight)
(T/F) Fat can be converted to glucose.
False
In the polymerization reaction of glycogenesis, what serves as the leaving group?
UDP
Write out the net chemical equation for glycogenesis/glycogen synthesis.
G6P + ATP + (glycogen)n + H2O → (glycogen)n+1 + ADP + 2 Pi
How does glycogen phosphorylase break alpha-1,4 glycosidic linkages in glycogen?
uses inorganic phosphate to cleave the alpha-1,4 linkages
What is the defect in Von Gierke’s disease?
glucose-6-phosphatase mutation
What are the effects of von Gierke’s disease?
hypoglycemia
increased glycogen storage → hepatomegaly
lactic acidosis
What is the most common treatment for von Gierke’s disease?
daily cornstach intake to prevent hypoglycemia
Where in the cell does the PPP take place?
cytoplasm
Does the PPP require ATP?
No.
