what organs synthesize glucose
mostly liver, also kidney
under what conditions is glucose synthesized
conditions of starvation, low carb diet, diabetes
when glucose is needed for quick & rapid energy for muscle
primary substrates for synthesizing glucose?
pyruvate, lactate, glucogenic amino acids (18 of the 20 aa in proteins are glucogenic), glycerol from breakdown lf triglyceides
why isn't gluconeogenesis the exact opposite of glycolysis?
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
what are the steps of gluconeogenesis?
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
what is the effect of glucagon/epi and insulin on the enzymes of gluconeogenesis?
increased by glucagon/epi
decreased by insulin
where does the 1st 2 steps of gluconeogenesis occur
in the mito
what's the relationship between F-1,6-bisphosphatase and PFK?
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
what does G6Pase do?
what upregulates G6Pase?
converts G6P to glucose, last step of gluconeogenesis
glucagon and epi transcriptionally upregulate it
how does Pyruvate become PEP?
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
what are the 2 net reactions converting pyruvate to PEP
1) Pyruvate + ATP + CO2 -> OAA + ADP + Pi = Pyruvate Carboxylase Rxn
2) OAA + GTP -> PEP + CO2 + GDP = PEPCK Rxn
Pyr + ATP + GTP -> PEP + ADP + Pi + GDP
what is the effect of glucagon/epi on PEPCK and pyruvate carboxylase?
they INCREASE levels of these gluconeogenic enzymes
what is acetyl CoA effect on pyruvate carboxylase?
stimulates pyruvate carboxylase
inhibits pyruvic kinase
how does PEP then become F 1,6 bis P
through reversal of:
enolase, phosphoglyceromutase, phosphoglycerokinase, G3PDH, and aldolase
how many PEPs make 1 F 1,6 bis P
2 PEPs are needed to make 1 F 1,6 bis P
when is ATP needed in gluconeogenesis
glycerol -> Glycerol 3 Phosphate, the phosphoglycerokinase step step
when is NADH needed in gluconeogenesis
at the G3PDH step
how many ATP equivalents are needed to synthesize glucose from 2 pyruvates?
6 ATP equivalents:
3 to convert pyruvate to G3P
2 pyruvates per glucose
what does F 1,6 bis phosphatase do?
what regulates F1,6 bis phosphatase?
converts F1,6 bis P to F6P
stimulated by ATP and citrate
inhibited by AMP, Pi, NH4+
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?
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
describe the G6Pase reaction
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
how do glucagon/epi and insulin regulate G6Pase?
insulin inhibits G6Pase
glucagon/epi stimulate G6Pase
this is the opp of how they act on glucokinase
how are amino acids glucogenic?
alanine, serine, glycine, cysteine, others
they produce pyruvate
pryuvate undergoes gluconeogenesis
how are amino acids that feed into the TCA cycle glucogenic?
they feed in to TCA cycle at level of aKg, succinyl CoA, fumarate, OAA
OAA so produced is glucogenic via PEPCK rxn
how is glycerol from triglyercides' breakdown glucogenic?
from triglyceride breakdown in adipose tissues and liver
can enter gluconeogenesis after conversion to aGP -> DHAP -> F1,6 bis P
what are futile cycles
cycles that would occur if the irreversible steps of glycolysis and gluconeogenesis weren't regulated, so they were going on simultaenously in the liver
what enzyme does the Pyruvate PEP conversion?
what would occur if the Pyruvate PEP conversion weren't regulated?
how is it regulated?
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
what futile cycle would occur if PFK and F1,6 bis Pase weren't regulated?
what impacts each?
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
how are the hexokinase/glucokinase vs G6Pase rxn kept out of a futile cycle?
what regulates them?
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
where does the Cori Cycle occur
what is its major action
btwn RBC or exercising muscle and liver
converts lactate in the RBC back to glucose in the liver