Gluconeogenesis - Abali 3/7/16 Flashcards
gluconeogenesis
- definition
- requirements and sources
synthesis of new glucose molecules from simple C precursors
involves enzymes in both mitochondria and cytosol
requires: energy source and source of C
- energy provided from FA metabolism
- C skeletons from:
- lactate (→ pyruvate → enters TCA cycle in gluconeogenic direction)
- glycerol (liberated from TAGs in lipolysis)
- glucogenic amino acids (Ala)
housekeeping fx of gluconeogenesis
gluconeogenesis is upregulated during extended fast/starvation
also has housekeeping fx : clearance of lactate and glycerol from blood
gluconeogenic organs
- liver is the major workhorse
- kidney picks up approx 10% glucose synth fx in ext starvation
-
muscle is not a contributor to gluconeogenesis
- can provide Ala to the pathway, but can’t make glucose
glycolysis vs gluconeogenesis
glycolysis
- occurs in muscle and brain
- 3 irreversible rxns (gluco/hexokinase, PFK1, PK)
gluconeogenesis
- occurs in liver
- 4 irreversible rxns (pyruvate carboxylase, PEP carboxykinase, fructose 1,6 bisphosphatase, glucose-6-phosphatase)
**note that the irreversible rxns of gluconeogenesis are in place to get back to reactants used by the irreversible rxns of glycolysis (and vice versa)
key enzymes of gluconeogenesis
- names, locations
1. pyruvate carboxylase (mitochondria)
2. PEP carboxykinase (mito/cytosol)
- which isozyme depends on which precursor you’re using
3. fructose 1,6 bisphosphatase (cytosol)
4. glucose-6-phosphatase (ER)
pyruvate carboxylase
- action
- regulation
bicarbonate + pyruvate → oxaloacetate
- cofactor: biotin [raw eggs: avidin can bind and block biotin activity]
- energy req: ATP → ADP
- regulation: acetyl CoA is the obligate activator (accumulates during beta-ox of FA)
*is an ABC carboxylase (require ATP, biotin, CO2)
PEP carboxykinase
- action
- determinantion of whether cPEP-CK or mPEP-CK is used
oxaloacetate + GTP → phosphoenolpyruvate
- energy req: GTP → GDP
- produces 1 CO2
*is an ABC carboxylase (require ATP, biotin, CO2)
two locations: mitochondria and cytosol
which one is used depends on the gluconeogenic precursor being used
NADH is required for a downstream rxn (1,3BPG → G3P)…
- if lactate is the starting substrate, NADH is generated as part of the lactate → pyruvate rxn [lactate DH], and mPEP-CK is used
- if Ala or pyruvate is the starting substrate, need NADH to be moved from mito to cytosol : use the malate shuttle! and then cPEP-CK is used
fructose 1,6 bisphophatase
fructose 1,6 bisphosphate → fructose 6-phosphate
- regulated hormonally and allosterically
allosteric :
- AMP inhibits
- fructose 2,6-bisphosphate inhibits
how does this link to the hormonal regulation?
- PFK2 is complex, has two activities: kinase/phosphatase activity
- when fasting/starving: glucagon released: cAMP → PKA pathway activated : PFK2 phosphorylated
- can’t make fructose 2,6 bisphosphate, which would inhibit gluconeogenesis (by inhibiting activity of FBP-1)
i. e. by downregulating fructose 2,6 bisphosphate production (via PFK2), you upregulate gluconeogenesis
(mech: inhibiting formation of the inhibitor of FBP-1)
glucose 6-phosphatase
glucose 6-phosphate → glucose
glucose 6-phosphatase is part of an ER-bound complex (incl 3 transport proteins: G6P, glucose, Pi)
- expressed in liver (not muscle) - allows for regulation of blood sugar by liver
- after glucose is created, it’s released from liver into bloodstream through GLUT2
overall eqn of gluconeogenesis
(starting: lactate or pyruvate)
2 lactate + 4 ATP + 2 GTP + 6 H20 → glucose + 4 ADP + 2 GDP + 6 Pi + 6H
- consumes energy (from FA metabolism! bc this is a response to low glucose)
regulation of gluconeogenesis
upregulated in fasting/starved state
hormonal control
- : glucagon (PEP-CK, FBP1 indirect through PFK2, G6Pase)
- : cortisol (PEP-CK)
- : CREBP, cAMP-response-element binding protein (PEP-CK)
allosteric control
- : acetyl CoA (pyruvate carboxylase)
- : increase in a.a.s (Ala, Gln, etc)
FBP-1 deficiency
- approx 50% of cases present with hypoglycemia, severe lactic acidosis in first few days of life
- lack of FBP-1 impairs formation of glucose from precursors
- maintenance of blood glucose is entirely dependent on glucose intake and glycogen breakdown
tx: frequent feeding with carbs
- frequency of attacks decreases with age, kids have normal psychomotor devpt
a.a.s in gluconeogenesis
- exceptions
- essential a.a.s
18/20 a.a.s are able to donate their C backbones to gluconeogenesis
exceptions: Leu, Lys [breakdown ltd to acetyl CoA → ketogenesis]
*critical for starvation: Asp → OAA
recall: essential a.a.s : HILK MV FTW
Cori cycle
means of recyling lactate
liver picks up lactate, converts it to glucose through gluconeogenesis
lactate from active muscle or RBC pulled from circulation into liver
→ liver converts it into glucose through gluconeogenesis and pushes it back into circ
→ glucose can be used again (anaerobic respiration)
→ repeat
Cahill cycle
aka alanine-glucose cycle
- converts alanine released during muscle breakdown (active muscle, fasting) to glucose in the liver which can be released into bloodstream and used again
- allows cells to shuttle NH3 to the liver on alanine, which is stripped of the NH3 (saved for urea cycle) and converted to glucose
