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gluconeogeneis/PPP

Terms in this set (60)

blood glucose is
5 mM after overnight fasting
CANNOT make glucose from
acetyl coa or FA
gluconeogenesis
process of making glucose from non-carb intermediates (pyruvate, glycerol, AA, TCA intermediates, lactate)
only exception is odd chain FA
free energy changes in glycolysis (large delta G)
(the big 3 enzymes)
1. hexokinase
3. PFK
10. PK
these are metabolically irreversible- and regulated
pyruvate kinase replaced with
pyruvate decarboxylase/ PEP carboxykinase
PFK replaced with
fructose-1,6-bisphosphatase
hexokinase replaced with
glucose-6-phosphatase
can synthesize glucose from noncarb precursors such as lactate and alanine
liver and kidney
gluconeogenesis supplies almost all of the body's glucose under this condition
fasting
2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H2O + 2 H+
Glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi
pyruvate carboxylase
converts pyruvate to oxaloacetate
requires ATP and bicarbonate HCO3-
(biotin covalently linked to active site lysine, acetyl coa is allosteric activator)
pyruvate carboxylase regulation
when acetyl coa or ATP high, pyruvate enters gluconeogenesis
anapleurotic
refilling TCA intermediates
pyruvate carboxylase reaction
activate CO2 by phosphorylating it then add it to pyruvate
(become anapluerotic=OA feeds into TCA
pyruvate carboxylase is compartmentalize
pyruvate makes OA (but cannot be transported through mitochondrial membrane, so converted to malate, goes through membrane to cytosol, then oxidized back to OA)
Phosphoenolpyruvate carboxykinase (PEPCK)
decarboxylation rxn in which GTP donates phosphoryl group
(OA to PEP)
this rxn requires alot of energy: comes from
1. GTP
2. decarboxylation is a favorable rxn
Fructose-1,6-bisphosphatase
fructose 1,6-bisphosphate to fructose 6-phosphate
thermodynamically favorable in the liver
Fructose-1,6-bisphosphatase regulation
allosteric regulation
inhibited by:
-AMP
-fructose-2,6-bisphosphate
activated by:
-citrate
Glucose-6-phosphatase
glucose 6-phosphate to glucose
present in the liver and kidneys
G-6-P hydrolyzed as it passes through ER
glucose enters into ER vesicles and diffuse into into bloodstream
lactate recyling
how the liver helps during exercise
-vigorous exercise=build up of pyruvate and NADH due to O2 shortage.. requiring for glycolysis
-NADH can reoxidized during reduction of pyruvate to lactate
-lactate returned to liver to be reoxidized to pyruvate by liver LDH
-liver provides glucose to muscle and reprocesses lactate to glucose
cori cycle
working out creates lactate (glycolysis->pyruvate->anaerobic processes=lactate) which feeds into the liver.
lactate->pyruvate-> glucose via gluconeogenesis= glucose feeds back into the muscle
gluconeogenesis regulation
glycolysis and gluconeogenesis are opposite.. one off/one on
cell energy status high:
-glycolysis is off, pyruvate used for synthesis or storage of glucose
cell energy status low:
-glucose should be rapidly degraded to provide energy
hexokinase
inhibited by glucose-6-phosphate
PFK
Inhibited by ATP, citrate.
Activated by ADP, AMP, cAMP, F2,6-bisphosphate.
Catalyzes the second irreversible step of glycolysis.
Determines the [G6P] available for glycogen synthesis.
Fructose-1,6-bisphosphatase regulation
inhibited by:
-AMP
-fructose 2,6-bisphosphate
activated by:
-citrate
pyruvate kinase
inhibited by:
-acetyl coa
-ATP
-alanine
-cAMP dependent phosphorylation
activated by:
-F-1,6 BP
pyruvate carboxylase is activated by
Acetyl CoA
gluconeogesis regulation II
glucose-6-phosphatase is under substrate-level control
Km for G-6-P is higher
hypoglycemia and etoh intoxication
-etoh inhibits liver gluconeogenesis
-liver cannot metabolize reducing equivalents (NADH) made by oxidizing ethanol
-this blocks the conversion of lactate to glucose, promotes alanine production
-liver needs to reduce NAD to NADH to produce lactate to pyruvate, cannot do this bc everything is reduced to NADH
-no production of glucose=hypoglycemia
glucose storage
polymerize into long chains (glycogen or starch) and add branches so it can be broken down more quickly
glycogen
animal storage of glucose
-long chains connected alpha 1,4 bonds
-branches connected alpha 1,6 bonds
starch
plant form of glucose storage
catabolism of glycogen
-a-amylase is endoglycosidase (cleaves 1,4 linkages)
-active on either side of branches but reduced activity near branch site
debranching enzyme moves 3 of the last 4 sugars near the branch site over to the long chain, the last sugar remaining on the branch site is the limit dextrin cleaved by 1,6 glucosidase
metabolism of tissue glycogen
-DIGESTIVE breakdown is unregulated-100%
-TISSUE glycogen is important energy reservoir-carefully controlled
-PHOSPHOROLYSIS breaks down glycogen using phosphate to break bonds
glycogen synthesis
activated by:
-acetyl-coa
-biotin

activate sugars by adding UDP-glucose pyrophosphorylase
glycogen synthase
-forms a-1,4 linkages in glycogen
-glycogenin is a primer for synthase to form linkages (GS cannot begin from scratch, needs glycogenin to start it off >4 glucose molecules)
-GS transfers glucosyl units from UDP glucose to C-4 hydroxyl at nonreducing end of glycogen strand
glycogen formation/activation
-glucose-1-P needs to be transformed to UDP-glucose to become activated
-now glycogen synthase can work on adding glucose to the polysaccharide chain
glycogenin
uses UDP glucose to start the primer
first glucose linked to tyrosine -OH
branching vs debranching
-glycogen is found in granules within the cytoplasm
-since cytoplasm is most water (polar)
-branching increases the solubility of glycogen in cytoplasm
-branching increases rate of glycogen synthesis and degradation by increasing the number of terminal glucose residues
-branching is better
terminal nonreducing residue
free hydroxyl group on C-4 at the terminal end
glycogen metabolism controlled
reciprocal control of glycogen phosphorylase and sythase
-GP activated by AMP, inhibited by ATP, glucose-6-P, caffeine
-GS activated by glucose-6-P
hormonal regulation
hormones activate adenyl cyclace=cAMP
-cAMP activates kinases and phosphatases that control phosphorylation of GP and GS
glucagon and epinepherine stimulate
glycogen breakdown
glucagon is secreted from
pancreas
glucagon acts in
liver and adipose tissue only
Epinephrine acts on
liver and muscles
phosphorylase cascade
amplifies signaling
where does NADPH come from
pentose phosphate pathway
glucose-6-P is precursor for
-glucose-1-P-> glycogen (storage)
-fructose-6-P->pyruvate (glycolysis)
-6-phosphogluconate->ribose-5-P (reducing power)
Pentose Phosphate Pathway (PPP)
-provides NADPH for biosynthesis
-produces ribose-5-P
-TWO OXIDATIVE PROCESSES followed by 5 non-oxidative steps
-OPERATES MOSTLY IN CYTOPLASM OF LIVER AND ADIPOSE CELLS
-NADPH IS USED IN CYTOSOL FOR FA SYNTHESIS
glucose-6-P to 6-phosphogluconate to ribulose-5-phosphate
oxidative process
produces 2 NADPH
Oxidative steps of PPP
Glucose-6-P Dehydrogenase (G6PD)*
-irreversible 1st step-highly regulated
6-Phosphogluconate Dehydrogenase
-oxidative decarboxylation
G6PD deficiency
Low NADPH leads to premature hemolysis (hemolytic anemia)
Fava beans, sulfonamides, primiquine, dapsone
X-linked recessive
most common genetic defect found in humans- high levels of oxidative stress
G6PD
committed step in PPP
phosphopentose isomerase
converts ketose to aldose
phosphopentose epimerase
converts xylulose 5-phosphate to ribulose 5-phosphate
transketolase
Transfers a two-carbon keto group
Transaldolase
Transfers a three-carbon aldo group
glucose-6-P feeds into PPP
to produce more glucose-6-P and12 NADPH OR
fructose-6-P feeds into PPP
to produce ribose-5-P
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