biochem lecture 9 pt 1 Flashcards
(221 cards)
1
Q
glwhat molecules can be used to synthesize glucose via gluconeogenesis
A
pyruvate, lactate, etc.
2
Q
gluconeogenesis
A
synthesis of glucose from non carbon precursors
3
Q
what are glycolysis and gluconeogenesis
A
opposite pathways
4
Q
what do both pathways have in common
A
reciprocally regulated
5
Q
what do mammals require to sustain us
A
carbs
6
Q
where do we get carbs
A
diet, glycogen stores (liver and muscle), gluconeogenesis
7
Q
absorptive phase
A
immediate access of glucose from the things we eatt
8
Q
post-absorptive phase
A
short term starvation conditions; we rely on glycogen stores to provide glucose source
9
Q
what do we rely on for glucose in short-term starvation conditions
A
glycogen stores
10
Q
what happens if we don’t get more glucose (no more from diet or we’ve depleted stores)
A
we begin gluconeogenesis
11
Q
how does gluconeogenesis initiate/progress
A
initiates slowly overtime, gradually increases to sustain organ function
12
Q
what happens when you go beyond intermediate starvation to prolonged starvation (many days)
A
we see decrease in gluconeogenesis
13
Q
why is there decrease in gluconeogenesis after a while
A
cuz there is a lack of carbon skeletons necessary to provide glucose via gluconeogenesis
14
Q
what do you need in order to sustain life
A
supplementation of carbs
15
Q
main sources of glucose needed to sustain life
A
dietary/exogenous, glycogen stores, and gluconeogenesis
16
Q
when are glucose stores depleted
A
periods of starvation, fasting beyond a day
17
Q
gluconeogenes invovles
A
pyruvate –> glucose
18
Q
how many pyruvates do we need to make 1 glucose
A
2 pyruvates
19
Q
what is required
A
2 NADH, 4 ATP, 2 GTP
20
Q
glucogenic molecule
A
any molecule that can be converted into pyruvate
21
Q
examples of glucogenic molecules
A
lactate, AAs, glycerol
22
Q
so what does that mean if a molecule is glucogenic
A
can derive gluocse from that precursors
23
Q
what are glycerol again
A
backbone of neutral fats
24
Q
what are bypass reactions
A
unique to gluconeogenesis
25
describe bypass rxns
diff enzymes that catalyze a step in glycolysis, deff enzymes catalyzing the reverse step
26
what are irreversible glycolytic enzymes
hexokinase, PFK, pyruvate kinase
27
what are enzymes of gluconeogenesis
pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphate, glucose-6-phosphate
28
what are irreversible steps in glycolysis
exergonic
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what are these steps then in other drxn
exergonic
30
each of these bypass rxns enzyme catalyzes what
an exergonic step
31
are these steps reversible or irreversible
technically reversible, but its mostly unidirectional so irreversible
32
what is importance of having unique enzymes
is something is unidirectional, then we can't have the same enzymes
33
in order to have each of those steps occurring in one direction, and not influenced by flux, what do you need
need a different enzyme
34
how are the 3 glycolytic and 4 gluconeogenic enzymes controlled
reciprocally controlled by same hormones insulin and glucagon
35
describe example of this reciprocal control
if you're stimulating glycolysis, means that 3 enzymes that catalyze 3 exergonic steps are gonna be active, while simultaneous inactivation of gluconeogenic bypass rxn enzymes
36
what is understanding the importance of bypass rxns crucial force
understanding how we have reciprocal control in a seemingly reversible process (glycolysis vs. gluconeogenesis)
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what are key points of regulation going to involve
these bypass reactions
38
what 4 enzymes are bypass reactions in gluconeogenesis catalyzed by
pyruvate carboxylase, phosphoenolpyruvate carboxylase, fructose-1,6-bisphosphatase, glucose-6-phosphotase
39
why is it 4 steps instead of 3
process for PEP to pyruvate conversion in glycolysis is one step BUT pyruvate to PEP is two step process (via formation of oxaloacetate)
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what catalyzes the first step in pyruvate to PEP
pyruvate carboxylase
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what catalyzes the 2nd step
phosphoenolpyruvate carboxylase
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what enzyme catalyzes the bypass of pyruvate kinase
pyruvate carboxylase
43
what do carboyxlaes do
tack on carbons to structures
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what do decarboxylases do
remove carbons from structure
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what does pyruvate carboxylase do
addition of carbon in form of bicarbonate to pyruvate, generates oxaloacetate
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what rxn does pyruvate carboxylase do
pyruvate --> oxaloacetate
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what rxn (thermodynamically speaking) is pyruvate carboxylase catalyzing
exergonic or irreversible step
48
what cofactor requirement do carboxylases have
biotin
49
what activates carboxylase
acetyl CoA
50
what is acetyl CoA an indicator of
low E state in the cell;
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what is acetyl CoA serving as low E indicator important for
important for catalyzing synthesis of glucose
52
what kinda rxn is this first bypass step
anaplerotic rxn
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what is an anaplerotic rxn
rxns that replenish intermediates in a pathway
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what is oxaloacetate synthesized for
final product in TCA: in order to keep eTCA going, we have synthesis of oxaloacetate thru this bypass rxn
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what does the second enzyme do
oxaloacetate --> phosphoenolpyruvate
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what enzyme for second one
phosphoenolpyruvate carboxykinase (PEPCK)
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when does PEPCK synthesis increase
increases in fasting
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where does first bypass step occur
pyruvate to oxaloacetate conversion is in mitochondrial matrix
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where does second bypass step occurs
in cytosol
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so what is needed in order for gluconeogenesis to occur
oxaloacetate needs to go thru interconversion steps involving malate formation
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describe thermodynamics of pyruvate carboxylase
metabolically irreversible
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what does pyruvate use as a cofacto
biotin
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what is pyruvate carboxylase allosterically activated by
acetyl CoA
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what kinda rxn is pyruvate carboxylase step
anaplerotic for TCA cycle
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how is pyruvate carboxylase anaplerotic for TCA cycle
cuz it replenishes oxaloacetate for TCA cycle
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where does pyruvate carboxylase step occur
mitochondria
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what is biotin utilized by
carboxylase
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how is biotin utilized
covalently associated to specific lysine residue in active site of carboxylase
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what happens to pyruvate and where
pyruvate is carboxylated into oxaloacetate, by pyruvate carboxylase, in mitochondria
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what is needed for pyruvate to enter gluconeogenic pathway
needs to enter mitochondrial matrix
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how does pyruvate get into mitochondrial matrix
specific transporters
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basically what is needed for pyruvate to go into TCA cycle
needs to get into mitochondrial matrix
73
what happens to pyruvate in mitochondria
converted to oxaloaecetate by pyruvate carboxylase
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what happens to oxaloacetate in mitochondria
converted to malate
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who does oxaloacetate --> malate
malate dehydrogenase
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what does oxaloacetate to malate conversion allow for
export of carbon skeletons originally derived from pyruvate back into cytosol from mitochondrial matrix
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sum up conversion step in first two bypass rxns
pyruate --> oxaloacetate (in mitochondria) --> malate (shuttled out of mitochondria) --> oxaloacetate
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why do we need to do a bunch of conversion reactions
becuase there is no oxaloacetate transporter, so it can't be shuttled out of mitochondria
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what enzyme carries out this interconversion
malate dehydrogenase
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sum up what malate dehydrogenase does
oxaloacetate --> malate (by malate dehydrogenase), malate shuttled out of mitochondria into cytosol, then cytosolic malate dehydrogenase which does malate --> oxaloacetate
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what enzyme does oxaloacetate --> malate
malate dehydrogenase
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what enzyme does malate --> oxaloacetate
cytosolic malate dehydrogenase
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what happens once we get malate --> oxaloacetate
we can continue on w/ gluconeogenesis
84
what is 3rd bypass rxn
fructose -1,6-bisphosphate --> fructose-6-phosphate
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what enzyme for 3rd bypass rxn
fructose-1,6-bisphosphatase
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what kinda rxn (thermodynamically) is fructose-1,6-bisphosphatase
metabolically irreversible rxn
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what are allosteric inhibitors of F-1,6-BPase
AMP, fructose-2,6-bisphosphate
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what is the glycolytic counterpart for this 3rd bypass rxn
conversion of F6P into F,1-6-BP
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what enzyme in glycolysis
PFK-1
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why do we require diff enzymes
both exergonic steps but occurring in opposite directions, so diff enzymes needed
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describe reciprocal control in gluconeogenesis and glycolysis
if one enzyme active other one is gonna be shut down
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what is fructose-2,6-bisphosphate important for
reciprocal regulation of these two enzymes
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what is final bypass step of gluconeogenesis
glucose-6-phosphate --> glucose
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what enzyme catalyzes final bypass step
glucose-6-phosphatase
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describe thermodynamics of this final bypass rxn
irreversible
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what kinda rxn is G6P to glucose
hydrolysis rxn
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where is glucose-6-phosphatase found
only liver and kidney
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so only which tissues can serve as as source of glucose from gluconeogenesis
liver and kidney
99
what enzyme catalyzes the glycolytic counterpart
hexokinase
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what are we doing to glucose-6-phosphate to glucose
dephosphorylating it
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why do we phosphorylate glucose to G6P
traps it inside cell
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what would happen without glucose-6-phosphatase in gluconeogenesis
that glucose would be trapped in cell, can't go to other parts of body; so we need to dephosphorylate it
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what is main source of glucose via gluconeogenesis
liver, little bit from kidney
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what is glucose-6-phosphate a precursor for
glycogen and glucose synthesis
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where is glucose-6-phosphatase found in
only liver and kidney
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where is glucose-6-phosphatase hgihly regulated
in liver
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what is glucose-6-phosphate a starting point for
pentose phosphate pathway
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is glucsoe-6-phosphatase expressed in every tissue or only limited ones
limited tissue expression; only liver and kidney
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where are major contributions/release of glucose into blood gonna come from
liver mainly
110
so why is liver strictly regulating glucose-6-phosphatase enzyme
because major contributions/release of glucose come from the liver
111
how many NTPS (so like ATP/GTP) does it take to synthesize glucose
6 NTPs
112
how many NTPs are generated from glycolysis
2 nucleotide triphosphate molecules
113
is gluconeogenesis favorable or unfavorable
unfavorable (because we are synthesizing something)
114
how much extra high phosphoryl transfer potential molecules does it take to drive this unfavorable gluconeogenesis pathway
4 extra
115
how many pyruvates required to make glucose
2 pyruvates
116
what does gluconeogenesis require
some investment of ATP E
117
why do we need an input of E to synthesize glucose
because it's endergonic
118
does that E needed to synthesize glucose only come from ATP
no; body needs additional E sources
119
where is flux through a pathway controlled at
rate-limiting steps
120
how can flux thru the rate determining steps be altered
allosteric control, covalent modifications, substrate cycles/futile cycles, genetic control (regulate transcription/translation of enzymes)
121
what can you do when you have 2 directly opposing pathways
reciprocal control
122
why can we control flow of intermediates thru these pathways at these exergonic rate limiting steps
because these steps are unidirectional; by limiting or depleting reactant of that step, you can limit the amount of byproduct produced in that step
123
what are reciprocally regulated in the liver
glycolysis and gluconeogenesis
124
what does this reciprocal regulation allow
prevents both pathways from operating at the same time
125
what does high. [AMP] indicate for glycolysis and gluconeogenesis
low energy state; need ATP
126
what does high [ATP] mean
high E state, intermediates are abundant
127
what is another allosteric regulator of gluconeogenesis/glycolysis
citrate concentration
128
high [citrate] means
high energy state, abundant intermediates
129
what does insulin stimulate
glycolysis
130
what does glucagon stimulate
gluconeogenesis
131
what are allosteric regulators
AMP, ATP, citrate
132
what is liver a major site for
major site for carb metaboism
133
what does insulin promote
glucose uptake and storage in liver, thus glycolysis
134
what does insulin do in other tissues
inhibits glycolysis
135
what does insulin do in liver
stimulates glycolysis; important for generating ATP E, necessary to fuel glycogenolysis, etc.
136
what does glucagon stimulate
gluconeogenesis
137
when is glucagon activated
intermediate starvatino conditions
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what do the points of control for allosteric regulation primarily involve
bypass reactions
139
what are indicators of a high E state in the celly
acetyl CoA, ATP, citrate
140
what do high E state indicators stimulate
gluconeogenesis
141
what are low E state indicators
AMP, ADP
142
what do low E state indicators do
inhibit gluconeogenesis
143
what does high AMP indicate
energy state is low, so we need ATP
144
what does low E state do
stimulates glycolysis while reciprocally inhibiting gluconeogenesis
145
what does a lot of ATP, TCA cycle intermediates (citrate, acetyl CoA) mean
high E state
146
what are allosteric regulators here
ATP/ADP/AMP, TCA cycle intermediates (citrate/acetyl CoA)
147
what does ATP and TCA cycle intermediates do
inhibits glycolysis and stimulate gluconeogenesis
148
describe futile cycle
what happens if both gluconeogenesis and glycolysis were activated; gluconeogenesis: fructose-1,6-bisphosphate -->fructose-6-phosphate, and then fructose-6-phosphate --> fructose-1,6-bisphosphate in glycolysis. if both enzymes active at the same time, it would be a futile cycle
149
is futile cycle actually happening
nope; whenever one enzyme is active, the reciprocal enzyme is inactive
150
what is a big part to understanding what futile cycles are
understanding that they do reciprocal regulation of enzymes catalyzing the opposing step in that cycle
151
consider FBP-ase 1 (gluconeogenic enzyme) and PFK-1 (glycolytic enzyme). what is an important regulator for both enzymes
fructose-2,6-bisphosphate
152
what is fructose-2,6-bisphosphate
isomer of fructose-1,6-bisphosphate
153
is F-2,6-BP a player in gluconeogenesis/glycolysis?
no; it is not serving as an intermediate in either of these 2 pathways
154
what is fructose-2,6-bisphosphate form important for
reciprocal regulation of PFK-1 and FBPase-1
155
what does fructose-2,6-bisphosphate serve as
allosteric regulator of these two enzymes
156
what does fructose-2,6-bisphosphate do to PFK-1 and FBPase-1
activates PFK-1 (glycolysis) while simultaneously inhibiting FBPase-1 (gluconeogenic enzyme)
157
what do high levels of F26BP favor
activation of PFK-1
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what does activation of PFK-1 favor
glycolysis
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what kind of regulation is that of PFK-1 and FBPase 1 by F-2,6-BP
reciprocal regulation
160
what does F26BP's regulation of PFK-1 and FBPase-1 involve
two more enzymes
161
what are these 2 more enzymes called
PFK-2 and FBPase-2
162
are PFK-2 and FBPase-2 the same as PFK-1 and FBPase-1
nope
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what does PFK-2 correspond to
formation of F-26-BP
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what does FBPase-2 correspond to
reduction in F-2,6-BP levels
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so what are these enzymes with 2 in their names involved in
regulation or control of level of F,2-6-BP
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what does active PFK-2 favor
formation of fructose-2,6-bisphosphate
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what does increase in fructose-2,6-bisphosphate do
activates PFK-1 while inhibiting FBPase-1
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what does activates PFK-1 while inhibiting FBPase-1 do
favors glycolysis
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basically what does PFK-2 being active do
increase in F-2,6-BP, increases PFK-1, inhibits FBPase-1, which favors glycolysis
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what does FBPase-2 do
dephosphorylates fructose-2,6-bisphosphate do
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what does de-phosphorylating fructose-2,6-bisphosphate do
lowers levels of F-2,6-BP
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what does lowering F26BP do
less activation of PFK-1 (so less PFK1) and less inhibition of FBPase-1 (so more FBPase-1)
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what does less PFK1 and more FBPase-1 do
favors gluconeogenesis and inhibits glycolysis
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basically what does active FBPase-2 do
decrease in F-2,6-BP, so decrease PFK-1, increasees FBPase-1, which favors gluconeogenesis
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can hormones stimulate futile cycle
yes
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what does glucagon do
stimulates gluconeogenesis
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what does glucagon in liver do
inhibits glycolysis
178
how does glucagon work in futile cycle
simulates cAMP, activates PKA, phosphorylates FBPase-2 and PFK2
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what does PKA do to FBPase-2 and PFK-2
phosphorylates them
180
what does phosphorylating FBP-ase 2 do
activates it
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what does phosphorylating PFK-2 do
inhibits it
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so describe what glucagon does in futile cycle
glucagon --> cAMP --> PKA --> activates FBPase2, inhibits PKA-2 --> lowers F-2,6-BP --> inhibits PFK-1 and activates FBPase-2 --> favors gluconeogenesis and inhibits glycolysis
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if glucagon is active, does that mean higher or lower levels of fructose-2,6-bisphosphate
lower levels of f-2,6-bp
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what does glucagon do
stimulates gluconeogenesis
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how does glucagon stimulate gluconeogenesis in liver
lby lowering F-26-BP, activates FBPase-1 and inhibits PFK-1, activating gluconeogenesis
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what does insulin do
favors glycolysis, inhibits gluconeogenesis
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what other enzyme is at play in futile cycle
PP2
188
how does insulin work in futile cycle
insulin activates PP2
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what does PP2 do to PFK2 and FBPase-2
dephosphorylates them
190
what does dephosphorylating of PFK-2 by PP2 do
activates PFK-2
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what does dephosphorylating FBPase-2 by PP2 do
inactivates FBPase-2
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what does PP2's dephosphorylating activity do to F-26-BP
activates it
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so what does insulin do to f-26-bp
increases fructose-2,6-bp
194
what does increasing f-26-bp do
activates PFK-1, inhibits FBPase-1, favors glycolysis over gluconeogenesis
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what does insulin do in futile cycle (full pathway)
insulin --> PP2 --> inactivates FBPase2, activates PKA-2 --> increases F-2,6-BP --> increases PFK-1 and decreases FBPase-2 --> favors glycolysis and inhibits gluconeogenesis
196
what does cori cycle involve
interconversion of waste products, their recycling to synthesize more glucose in liver via gluconeogenesis
197
what was one of the issues with gluconeogenesis
we don't have enough NTP equivalence from glycolysis to fuel gluconeogenesis
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what would we end up with if we just relied on glycolysis to fuel gluconeogenesis
energy deficiency
199
corci cycle
describes interconnectedness b/w glycolysis and gluconeogenesis, specificaly where ATP needed to drive gluconeogenesis comes from
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where does ATP oxidation needed to drive gluconeogenesis come fom
beta oxidation of fats in liver
201
overall what happens in cori cycle
pyruvate (lactic acid) generated thru fermentation accumulates in muscle, travels to liver, converted back to pyruvate, and goes thru gluconeogenesis to synthesize glucose
202
what can happen in intermediate starvation conditions
that glucose can be used in glycolysis, like in muscle, brain, etc.
203
what is gluconeogenic pathway coupled to
some ATP generated via oxidation of fatty acids
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what is cori cycle important for understanding
important in understanding linkage and thus how gluconeogenesis and glycolysis are regulated
205
what happens as a result of liver being a major organ for intermediary metabolism
a lot of blood flow into and out of liver
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how are energy rich molecules and nutrients available from diet made available
partial digestion in stomach and upper parts of intestines
207
where do those energy rich molecules go
transported to liver
208
how are E rich molecules transported to liver
via blood flow via hepatic portal system
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how are those products from liver distributed to various parts of body
byproducts of the various metabolic processes that occur from liver leads to its distribution
210
what does massive amount of bloodflow into and out of liver allow
means you can distribute intermediates of carb metabolism AND fatty acid metabolism, protein metabloism
211
what is liver a big time player in
distribution of various types of dietary fuels, receiving waste products and intermediates that can be used in recycling pathways (like in cori cycle)
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what is cori cycle interaction b/w
interaction of glycolysis and gluconeogenesis
213
describe cori cycle step 1
lactate from peripheral tissues goes to liver and made to glucose (lactate --> glucose in liver)
214
cori cycle step 2
glucose goes back to peripheral tissues (like muscle)
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cori cycle step 3
uses lipid for energy
216
talk about placement of liver in circulation
first pass at removing nutrients absorbed from intestine, makes nutrients available to other tissues
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what does liver participate in
interconversion of all types of metabolic fuels (carbs, AAs, fatty acids)
218
what does liver regulate
distribution of dietary fuels, supplies fuel from its own reserves
219
where does liver supply fuel
from its own reserves
220
what does cori cycle do
generates ATP
221
how does cori cycle make ATP
(lactate --> glucose --> lactate) thru this interconversion
