L13: PPP, Glycogen Metabolism, and Alcohol Metabolism Flashcards
main functions of pentose phosphate pathway
- bypass first step in glycolysis
- generate NADPH
- generate ribulose-5-phosphate
- provide precursors for nucleotide biosynthesis
NADPH role
- reductive reactions required for biosynthesis
- protection against oxidative stress
- fatty acid synthesis
- glutathione reduction
ribulose-5-phosphate role
- nucleotide biosynthesis
oxidative phase
- oxidation of glucose-6-phosphate to ribulose-5-phosphate
- via glucose-6-phosphate dehydrogenase
- produces 2 NADPH
non-oxidative phase
- ribulose-5-phosphate to fructose-6-phosphate
- produces glycolytic pathway intermediates
Phase I regulation of PPP
- high NADPH inhibits glucose-6-phosphate dehydrogenease
Phase II regulation of PPP
- controlled by substrate availability
cancer cells and PPP
- need nucleotides for DNA and RNA synthesis
- so need ribose-5-phosphate
- need NADPH for fatty acid synthesis
Why do we use glycogen for storage?
- glucose cannot be stored by itself because it would disrupt the osmotic balance of the cell
alpha 1,4 linkage in glycogen
- joins the glucose molecules in a linear molcule
alpha 1,6 linkage in glycogen
- results in branches
why do we have branches in glycogen?
- makes it much easier for enzymes involved in degradation to find something to degrade
function of glycogen in the muscle
- serves as a fuel source
function of glycogen in the liver
- serves as a good source of blood glucose for other tissues
energy requirements in glycogen synthesis versus breakdown
- synthesis requires energy
- breakdown does not
glycogenolysis step 1
- via phosphorylated glycogen phosphorylase
- cleaves alpha 1,4 bonds, adds a phosphate
- releases glucose-1-phosphate residues until only 4 residues remain
glycogenolysis step 2
- transferase removes outer 3 glucose residues from a branch and transfers them to another chain
glycogenolysis step 3
- alpha-1,6-glucosidase (branching enzyme) cleaves alpha-1,6 bond on the single residue
glycogenolysis step 4
- glucose-1-phosphate converted to glucose-6-phosphate by phosphoglucomutase
liver versus muscle in glucose-6-phosphatase
- liver breaks down glucose-6-phosphate to glucose via glucose-6-phosphatase in ER membrane
- muscle uses glucose-6-phosphate to generate ATP
- does not have phosphatase
important component of glycogen degradation
- glycogen phosphorylase
hormones that control glycogen degradation
- glucagon in the liver
- epinephrine in the muscle
- signal through GCPR pathway
when glucose levels are low
- glucagon and epi released
- GCPR pathway
- cAMP made from ATP
- activate PKA
- activate phosphorylase kinase
- inactivates glycogen synthase
- phosphorylation of glycogen phosphorylase (a form) initiates glycogen degradation
step 1 of glycogen synthesis
- glucose-6-phosphate -> glucose-1-phosphate
- via phosphoglucomutase
step 2 of glycogen synthesis
- glucose-1-phosphate -> UDP-glucose
- via UDP-glucose pyrophosphorylase
step 3 of glycogen synthesis
- glycogenin primes the initial synthesis of a short glucose chain using UDP-glucose as a substrate
step 4 of glycogen synthesis
- glycogen chain extended with more glucose
- via glycogen synthase and UDP-glucose
step 5 of glycogen synthesis
- glycogen branches creating by transferase (branching enzyme)
- breaks 1,4 links and forms 1,6 links
- occurs about every 12 residues
important hormone in glycogen synthesis
- glycogen synthase
insulin signaling and glycogen storage
- insulin released from pancreas
- activates glycogen synthase kinase (a form)
- activates phosphatase 1
- removes phosphate from glycogen synthase, which activates it
Type I glycogen storage disease
- Von Gierke
Von Gierke cause
- defect in glucose-6-phosphatase
- glucose can’t be transported from liver
- glycogen accumulates in liver
- excess glucose-6-phosphate results in high rates of glycolysis with high levels of lactate and pyruvate in the blood
Von Gierke symptoms
- massive liver enlargement
- hypoglycemia
- weakness
Type II
Pompe Disease
Pompe disease cause
- defect in lysosomal alpha glucosidase that breaks down glycogen in lysosomes
- leads to increased membrane bound glycogen
Pompe disease symptoms
- muscle and nerve damage
Type III
- Cori disease
Cori disease cause
- defect in debranching enzyme
- increase of glycogen with short outer branches
- can’t break down well
- only a limited amount of glucose can be released
Cori disease symptoms
- like Von Gerke but milder
Type IV
- Andersen disease
Andersen disease cause
- defect in branching enzyme
- keep making longer branches
Andersen disease symptoms
- usually fatal
- liver can’t handle longer branches of glycogen
Type V
- McArdle disease
McArdle disease cause
- defect in muscle glycogen phosphorylase
- no glycogen metabolized
McArdle disease symptoms
- exercise induced muscle pain
- cramps
- weakness
type VI
- Hers disease
Hers disease cause
- defect in liver glycogen phosphorylase
Hers disease symptoms
- mild hypoglycemia
- hepatomegaly
two pathways of alcohol metabolism
- alcohol dehydrogenase - modest levels of ethanol
- MEOS - high levels of ethanol
alcohol dehydrogenase system
- alcohol dehydrogenase in liver oxidizes ethanol to acetaldehyde and generates NADH
- acetaldehyde is converted to acetate by acetaldehyde dehydrogenase and generates NADH
- acetate released into bloodstream for use by tissues
acetaldehyde and drinking
- acetaldehyde is the negative effects of drinking
- nausea, etc
alcohol dehydrogenase
- low Km for ethanol
- active at low ethanol concentrations
ALDH2 human variants
- have acetaldehyde dehydrogenase with low Km and low activity (Vmax)
- low levels of ethanol result in nausea
disulfiram
- inhibits acetaldehyde dehydrogenase
- used to treat alcoholism
MEOS system
- metabolizes alcohol to acetaldehyde requiring NADPH
- highest activity is CYP2E1
CYP2E1
- high affinity
- functions at high levels of alcohol consumption
- results in increased production of free radicals and tissue damage
result of NADH buildup in liver
- fatty acid oxidation is inhibited
- fat accumulation in liver
- acetyl CoA shifted away from TCA cycle toward ketone body production
- lactate dehydrogenase reaction shifted toward lactate production
lactate dehydrogenase reaction shifted toward lactate production
- lactic acidosis
- lactic acid competes with uric acid in kidney for excretion
lactic acid competes with uric acid in kidney for excretion
- decrease in uric acid excretion
- uric acid crystals
- gout!
