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Biochemistry II > Exam 1 Regulation of Glycolysis and Gluconeogenesis > Flashcards

Exam 1 Regulation of Glycolysis and Gluconeogenesis Flashcards

1
Q

what is the normal blood glucose level?

A

4-8mM

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2
Q

what are the four glucose transporters?

A

GLUT1, GLUT3, GLUT2, GLUT4

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3
Q

what tissue/cell types is GLUT1 found in?

A

most tissues/cells

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4
Q

what is the Km for glucose for GLUT1?

A

1mM

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5
Q

what tissue/cell types is GLUT3 found in?

A

neuronal tissues/cells

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6
Q

what is the Km for glucose for GLUT3?

A

1mM

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7
Q

what tissue/cell types is GLUT2 found in?

A

hepatocytes, pancreatic beta cells

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8
Q

what is the Km for glucose for GLUT2?

A

20mM

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9
Q

what tissue/cell types is GLUT4 found in?

A

skeletal myocytes, cardiomyocytes, adipocytes

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10
Q

what is the Km for glucose for GLUT4?

A

5mM

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11
Q

what occurs when you eat a donut? (glucose transporters)

A

GLUT2 senses glucose intake, triggers pancreatic beta cells to make insulin, GLUT4 then senses the insulin increase and puts more GLUT4 on cell surface to increase insulin uptake

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12
Q

which glucose transporter is sensitive to blood glucose concentration?

A

GLUT2

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13
Q

which glucose transporter’s presence on the cell surface is insulin-dependent?

A

GLUT4

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14
Q

what occurs to GLUT4 when insulin levels increase?

A

GLUT4 vesicles fuse with cell membrane

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15
Q

what occurs to GLUT4 when insulin levels decrease?

A

GLUT4 is sequestered inside the cell in internal vesicles

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16
Q

which glucose transporters are near their max rate regardless of glucose concentration?

A

GLUT1 and GLUT3

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17
Q

what is an appropriate glucose transporter for cells charged with blood glucose concentration regulation?

A

one that is sensitive to change in glucose concentration in the blood

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18
Q

which two glucose transporters are the least sensitive to glucose concentration?

A

GLUT1 and GLUT3

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19
Q

without a follow up step, once glucose concentration equilibrates across the membrane, net transport stops. How does glucose affect net transport?

A

if glucose is modified after making the cell, net transport in remains favorable.
if glucose is generated from an internal source (G6P dephosphorylation), glucose export can become favorable

therefore, transport is connected to irreversible processes (HK and/or glucose-6-phosphatase)

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20
Q

what type of step is hexokinase?

A

irreversible; committed step in metabolism (must use the glucose)

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21
Q

what is the Km for Hexokinases I-III?

A

0.1mM

completely insensitive to blood glucose concentration
always going at their max rate (similar theme to GLUT1 and GLUT3)

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22
Q

what tissue/cell types are Hexokinases I-III found in?

A

most cell types

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23
Q

what is hexokinase I-III inhibited by?

A

glucose-6-phosphate

cell’s internal condition entirely controls withdraw of glucose from blood.
if need for glucose internally decreases, glucose-6-phosphate accumulates and glucose concentration equilibrates across the membrane transport stops.
as long as an internal need exists, glucose will be obtainable because of GLUT1/GLUT3 and HKI-III combo

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24
Q

what is Hexokinase IV also called?

A

glucokinase

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25
Q

what is the K0.5 of Hexokinase IV in glucose?

A

10mM

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26
Q

hexokinase IV

A
  • allosteric enzyme (its rate shows a sigmoidal response to glucose concentration
  • K0.5 corresponds to the physiological range of blood glucose concentration (very sensitive to changes to the physiological glucose concentration)
  • NOT inhibited by glucose-6-phosphate
27
Q

what is HK IV expressed by?

A

hepatocytes and pancreatic beta cells

28
Q

what does HK IV (also) produce?

A

glucokinase regulatory protein (GKRP)

29
Q

hepatocytes, glucose, and HK IV relationships:

A

glucose and GKRP compete for HK IV
HK IV is inactive and is moved to the nucleus
when glucose concentration increases, it competes with GKRP; HK IV is then released to the cytosol in its active form

increase in glucose —> increase HK IV active in cytosol
decrease in glucose —> increase HK IV inactive in nucleus

30
Q

HK IV expression

A

insulin signaling increases HK IV signaling
glucagon signaling decreases HK IV signaling

31
Q

what is the last step of gluconeogenesis?

A

glucose-6-phosphatase

32
Q

what cell types is glucose-6-phosphatase?

A

only found in a couple of cell types; hepatocytes account for 90% of cell types

33
Q

glucose-6-phosphate during glucose-6-phosphatase

A

glucose-6-phosphate from gluconeogenesis is transported to hepatocyte ER, it removes phosphate, glucose crosses ER and plasma membranes through GLUT2

34
Q

glucose-6-phosphatase substrate-level control

A

increased glucose-6-phosphate concentration —> increased rate

35
Q

glucose-6-phosphatase transcriptional-level control

A

increased glucagon concentration —> increased expression
increased insulin concentration —> decreased expression

36
Q

allosteric enzymes

A
  • characterized by intraenzyme communication via protein confirmational changes
  • rates are influenced by binding of molecules (substrate and/or non-substrate) to sites separate from the active site
  • large majority (not all) have quaternary structure (they are multisubunit systems); often subunits are highly similar or identical
  • multiple active sites for S binding
37
Q

what do allosteric enzymes typically not follow?

A

Michaelis-Menten kinetics

38
Q

allosteric enzymes - what does a sigmoidal response to [s] indicate?

A

“positive cooperativity”: binding/processing of S at one active site facilitates or enhances binding/processing at another active site(s)

39
Q

what is a model for understanding the cooperative effect?

A

symmetry model

40
Q

each subunit in an allosteric enzyme can have one of two conformations…

A

T (tight): interacts poorly with substrate
R (right): interacts well with substrate

  • for each enzyme molecule, all subunits with either be T or R, not a mix of both!*
41
Q

when are T and R in equilibrium?

A

in the absence of substrate

[T]&raquo_space; [R] (i.e. [T]/[R] = L = large positive value)

42
Q

dissociation constant for [R]

A

Kr= [R][S]/[RS]

43
Q

dissociation constant for [T]

A

Kt= [T][S]/[TS]

44
Q

is Kr is really small, then ?

A

Kr &laquo_space;Kt

45
Q

the presence of S does what?

A

since S associates so favorable with the R form, S shifts equilibrium to the R state

46
Q

inhibition of allosteric enzymes is not like that of M-M enzymes

A
  • inhibitor does not necessarily resemble the substrate (or transition state) for an enzyme-catalyzed reaction
  • inhibitor binds preferentially to the T state therefore inhibitor increases the cooperative effect (makes even more S necessary to overcome the bias toward the T state)
47
Q

Allosteric activators bind how?

A

preferentially to the R state

  • presence of A shifts equilibrium toward the R state
  • therefore, R diminishes the cooperative effect
  • therefore, less A is required to overcome the bias toward the T state
  • if enough A is present relative to its dissociation constant, allosteric enzyme will act like a M-M enzyme (there is no cooperativity)
48
Q

PFK-1 T and R active sites

A

Glu —> to active site for “T”
Arg —> to active site for “R”

49
Q

Allosteric effectors of PFK-1

A
  • ATP = substrate and an inhibitor
  • AMP activates-reverses ATP-dependent inhibition
  • PEP (phosphoenol pyruvate) = inhibits PFK-1 (if pyruvate kinase is inhibited, PEP accumulates and inhibits PFK-1
  • citrate = inhibits (citrate accumulation indicates that there are sufficient sources elsewhere for ATP production so using glucose is not necessary)
  • fructose-2,6-bisphosphatase (VERY POTENT) = activator (as little as 1 micrometer is sufficient to remove the inhibitory effect of ATP and remove the cooperative effect
50
Q

Override Effect

A

fructose-2,6-bisphosphatase counteracts effect of phosphoenol pyruvate on PFK-1

51
Q

what is fructose-1,6-biphosphatase (FBPase-1) inhibited by?

A

AMP and fructose-2,6-bisphosphatase

(fructose-2,6-bisphosphatase enhances effect of AMP on FBPase-1)

52
Q

Fructose-2,6-bisphosphatase

A

major regulator of glycolysis and gluconeogenesis

fructose-6-phosphate + ATP —> fructose-2,6-bisphosphate + ADP (enzyme: PFK-2)

fructose-2,6-bisphosphate + H20 —> fructose-6-phosphate + Pi (enzyme: FBPase-2

53
Q

PFK-2/FBPase-2 structure (all one polypeptide)

A
  • two domains of a single polypeptide (N-terminal: PFK-2, C-terminal: FBPase-2)
  • there are several isozymes (expression = tissue-specific, regulation mechanism = tissue-specific)
54
Q

PFK-2/FBPase-2 regulation

A
  • regulated by covalent modification (phosphorylation/dephosphorylation)
  • the details are major distinguishing features of isozymes (tissue specificity)
55
Q

hepatocyte PFK-2/FBPase-2 regulation

A

(look at drawing)
- insulin —> inactivation of PKA, activation of PPP-1 (hepatocytes = acting as glucose consumers!!) (therefore increase in fructose-2,6-bisphosphate concentration, increase in PFK-1 activity and decrease in FBPase-1 activity, increase in glycolysis and decrease in gluconeogenesis
- glucagon —> activation of PKA, inactivation of PPP-1 (therefore, decreased fructose-2,6-bisphosphate, decreased PFK-1 activity and increased FBPase-1 activity, decreased glycolysis and increased gluconeogenesis (hepatocytes acting as glucose producers!!)
- epinephrine —> same response as glucagon

56
Q

cardiomyocyte PFK-2/FBPase-2 regulation

A
  • default = operate primarily using fatty acids and fatty acid-derived metabolites (ex. ketone bodies) (glycolysis will be more or less active depending on overall needs… gluconeogenesis doesn’t figure into cardiomyocite metabolism)
57
Q

what are the two circumstances where glycolysis will be upregulated in cardiomyocytes?

A
  • fight or flight response
  • well-fed state (i.e. insulin signaling)
58
Q

glycolysis upregulation in cardiomyocytes- fight or flight response

A

look at drawing
- Protein Kinase A and Phosphoprotein phosphatase-1
- epinephrine signaling activates PKA and inactivates PPP-1

59
Q

glycolysis upregulation in cardiomyocytes- well-fed state

A
  • Protein Kinase B (Akc) (Wortmannin-sensitive, insulin-stimulated, protein kinase AKA WISK), and Phosphoprotein phosphatase-2
  • activity decreases as insulin signaling decreases
  • with either epinephrine or insulin: increased fructose-2,6-bisphosphate concentration therefore increased glycolysis in cardiomyocytes
60
Q

what is pyruvate kinase activated by?

A
  • AMP (tells us glycolysis is being done because AMP is formed form/by ATP)
  • fructose-1,6-bisphosphate (if something activates PFK-1, pyruvate kinase will be stimulated, too)
61
Q

what is pyruvate kinase inhibited by?

A
  • ATP
  • acetyl-CoA (indicates that ATP can be generated from other sources)
  • alanine (other sources of pyruvate are available)
62
Q

Pyruvate Kinase regulation in hepatocytes

A

pyruvate kinase isozyme expressed by hepatocytes is also regulated by covalent modification (phosphorylation/dephosphorylation)

63
Q

Pyruvate Carboxylase

A
  • biotin-dependent enzyme
  • activated by acetyl-CoA (essentially inactive without it)
64
Q

PEP Carboxykinase (PEPCK)

A
  • expression levels are regulated by glucagon and insulin
  • well-fed state: increased insulin and decreased glucagon —> decreased PEPCK gene transcription
  • fasting state: decreased insulin and increased glucagon —> increased PEPCK gene transcription

Biochemistry II (4 decks)

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