SYLLABUS 7: Gluconeogenesis

Question 1

what organs synthesize glucose

Answer 1

mostly liver, also kidney

Question 2

under what conditions is glucose synthesized

Answer 2

conditions of starvation, low carb diet, diabetes

when glucose is needed for quick & rapid energy for muscle

Question 3

primary substrates for synthesizing glucose?

Answer 3

pyruvate, lactate, glucogenic amino acids (18 of the 20 aa in proteins are glucogenic), glycerol from breakdown lf triglyceides

Question 4

why isn’t gluconeogenesis the exact opposite of glycolysis?

Answer 4

there were 3 irreversible steps in glycolysis. to bypass these steps, need special enzymes for gluconeogenesis:

PK : PC

PF-1-K : PEPCK

PFK-1 : F 1,6 bis Pase

GK/HK : G6Pase

Question 5

what are the steps of gluconeogenesis?

Answer 5

1. lactate & alanine make pyruvate
2. Pyruvate Carboxylase converts pyruvate -> OAA in the Mito w/ ATP
3. OAA -> PEP by PEP carboxykinase- PEPCK; in mito or cyto

GTP -> GDP in this step

4. PEP -> Fructose 1,6 bis P easily through series of reversible steps w/ enolase, PG mutase, PG kinase, G3PDH, aldolase
5. F-1,6-bisP becomes F6P by F-1,6-bisPase
6. F6P undergoes isomerase reaction, -> G6P
7. G6Pase hydrolyzes G6P to glucose

Question 6

what is the effect of glucagon/epi and insulin on the enzymes of gluconeogenesis?

Answer 6

they are

increased by glucagon/epi

decreased by insulin

Question 7

where does the 1st 2 steps of gluconeogenesis occur

Answer 7

in the mito

Question 8

what’s the relationship between F-1,6-bisphosphatase and PFK?

Answer 8

they have the opposite regulatory properties

F 1,6 bis P is inhibited by AMP, Pi, NH4+ (ammonia) and stimulated by high energy signals: ATP, citrate, glucagon, epi

Question 9

what does G6Pase do?

what upregulates G6Pase?

Answer 9

converts G6P to glucose, last step of gluconeogenesis

glucagon and epi transcriptionally upregulate it

Question 10

how does Pyruvate become PEP?

Answer 10

undergoes 2 reactions

alanine -> pyruvate by transamination reaction

pyruate enters the mito, since pyruvate carboxylase is there for the TCA cycle

1) pyruvate -> OAA by pyruvate carboxylase rxn in Mito

OAA -> Malate by Malate DH

Malate can leave the Mito, and in the Cyto, -> OAA by Malate DH

OAA -> PEP by PEPCK in the Cyto

2) but, PEPCK can be in the mito or in the cyto

If PEPCP is in the Cyto, then in the Mito, OAA -> Malate, which leaves mito by carriers 2, 3, 4; in the Cyto, Malate -> OAA again, also releasing NADH

If PEPCK is in the cyto, Pyruvate -> OAA -> Asp which leaves mito on carrier -> OAA in cyto and there it undergoes PEPCK rxn

Question 11

what are the 2 net reactions converting pyruvate to PEP

Answer 11

1) Pyruvate + ATP + CO2 -> OAA + ADP + Pi = Pyruvate Carboxylase Rxn
2) OAA + GTP -> PEP + CO2 + GDP = PEPCK Rxn

NET:

Pyr + ATP + GTP -> PEP + ADP + Pi + GDP

Question 12

what is the effect of glucagon/epi on PEPCK and pyruvate carboxylase?

Answer 12

they INCREASE levels of these gluconeogenic enzymes

Question 13

what is acetyl CoA effect on pyruvate carboxylase?

Answer 13

stimulates pyruvate carboxylase

inhibits pyruvic kinase

Question 14

how does PEP then become F 1,6 bis P

Answer 14

through reversal of:

enolase, phosphoglyceromutase, phosphoglycerokinase, G3PDH, and aldolase

Question 15

how many PEPs make 1 F 1,6 bis P

Answer 15

2 PEPs are needed to make 1 F 1,6 bis P

Question 16

when is ATP needed in gluconeogenesis

Answer 16

glycerol -> Glycerol 3 Phosphate, the phosphoglycerokinase step step

Question 17

when is NADH needed in gluconeogenesis

Answer 17

at the G3PDH step

Question 18

how many ATP equivalents are needed to synthesize glucose from 2 pyruvates?

Answer 18

6 ATP equivalents:

3 to convert pyruvate to G3P

2 pyruvates per glucose

Question 19

what does F 1,6 bis phosphatase do?

what regulates F1,6 bis phosphatase?

Answer 19

converts F1,6 bis P to F6P

**stimulated by ATP and citrate **

**inhibited by AMP, Pi, NH4+ **

Question 20

what is the relationship between F 2,6 bis P and F 1,6 bis Pase? how do glucagon/epi regulate their relationship?

how does insulin regulate their relationsihp?

Answer 20

F2,6 bis P is a critical allosteric inhibitor of F1,6 bis Pase

glucagon and epi lower F2,6 bis P levels; they thus stimulate F1,6 bis Pase and gluconeogenesis

insulin elevates F2,6 bis P levels; it thus inhibits F1,6 bis Pase and gluconeogenesis

Question 21

describe the G6Pase reaction

Answer 21

final reaction of gluconeogenesis

G6P reacts w/ Pi and G6Pase to become glucose

glucose then leaves the liver, and can be fuel for other tissues

Question 22

how do glucagon/epi and insulin regulate G6Pase?

Answer 22

insulin inhibits G6Pase

glucagon/epi stimulate G6Pase

this is the opp of how they act on glucokinase

Question 23

how are amino acids glucogenic?

Answer 23

alanine, serine, glycine, cysteine, others

they produce pyruvate

pryuvate undergoes gluconeogenesis

Question 24

how are amino acids that feed into the TCA cycle glucogenic?

Answer 24

they feed in to TCA cycle at level of aKg, succinyl CoA, fumarate, OAA

OAA so produced is glucogenic via PEPCK rxn

Question 25

how is glycerol from triglyercides’ breakdown glucogenic?

Answer 25

from triglyceride breakdown in adipose tissues and liver

can enter gluconeogenesis after conversion to aGP -> DHAP -> F1,6 bis P

Question 26

what are futile cycles

Answer 26

cycles that would occur if the irreversible steps of glycolysis and gluconeogenesis weren’t regulated, so they were going on simultaenously in the liver

Question 27

what enzyme does the Pyruvate <-> PEP conversion?

what would occur if the Pyruvate <-> PEP conversion weren’t regulated?

how is it regulated?

Answer 27

PK in glycolysis; PC + PEPCK in gluconeogenesis

if simultaneous, GTP would be hydrolyzed to GDP + Pi; energy lost

reciprocal control, where when 1 enzyme is activated, the opposing is inactivated, prevents this:

GLUCAGON increases PEPCK and PC, inhibits PK

INSULIN increases PK, decreases PEPCK

HIGH ENERGY SIGNALS stimulate PC, inhibit PK

ATP is needed for PC, inhibits PK

Question 28

what futile cycle would occur if PFK and F1,6 bis Pase weren’t regulated?

what impacts each?

Answer 28

if unregulated, ATP would be hydrolyzed to ADP + Pi

GLUCAGON increases F1,6 bis Pase, INHIBITS PFK via F2,6 bis P cycle

INSULIN decreases F1,6 bis Pase, increases PFK by the F2,6 bis P cycle

ATP and CITRATE stimulate F1,6 bis Pase; inhibit PFK

AMP, Pi, NH4 inhibit F1,6 bisPase, stimulate PFK

Question 29

how are the hexokinase/glucokinase vs G6Pase rxn kept out of a futile cycle?

what regulates them?

Answer 29

if unregulated, ATP would be hydrolyzed to ADP + Pi

GLUCAGON increase G6Pase activity, inhibits glucokinase

INSULIN inhibits G6Pase but increase glucokinase activity

G6Pase has a high Km for G6P, so functions when glucose is low; Glucokinase has high Km for glucose, so functions when glucose is high

Question 30

where does the Cori Cycle occur

what is its major action

Answer 30

btwn RBC or exercising muscle and liver

converts lactate in the RBC back to glucose in the liver