Carbohydrate Metabolism: Gluconeogenesis Flashcards
What is glucongeogensis?
Synthesis of glucose
Where is gluconeogenesis most active in animals?
Most active when glycogen stores in the liver and muscle has been depleted
Which organ is most responsible for gluconeogenesis?
It is mostly the liver’s job as it is unselfish and gives it to those in need
The muscle is selfish as it stores its own glucose
What are the 4 major carbon sources for glucose synthesis?
Glycerol
Amino acids
Lactate
CO2 fixation (in plants)
How is glycerol a major carbon source for glucose synthesis?
Triglycerides (fats) are converted into glycerol, which can be converted to DHAP (Dihydroxyacetone phosphate)
How are amino acids a major carbon source for glucose synthesis?
Nutrient limitation increases the conversion of amino acids into pyruvate or citrate cycle metabolites
How is lactate a major carbon source for glucose synthesis?
Anaerobic respiration increases the pool of lactate, which can be converted into pyruvate for entry into the gluconeogenic pathway
How is CO2 fixation (in plants) a major carbon source for glucose synthesis?
Plants use gluconeogenesis to synthesize glucose from triose phosphates generated from CO2 fixation, which is used to produce sucrose and starch for energy storage
Compare and contrast between glycolysis and gluconeogenesis.
Glycolysis is the breakdown of glucose while gluconeogenesis is the synthesis of glucose
They are opposing pathways - end product of one is the starting point of the other
They share 7 enzymes (those that catalyze reversible reactions)
- The direction of the reversible reactions is simply a response to the relative concentrations of metabolites
Main determinants of the flux through either pathway are the IRREVERSIBLE reactions
Name 4 gluconeogenic enzymes that bypass 3 exergonic reactions in glycolysis.
Pyruvate carboxylase and Phosphoenolpyruvate (PEP) carboxykinase in gluconeogenesis bypass Pyruvate kinase in glycolysis
Fructose-1,6-bisphosphate-1 in gluconeogenesis bypass Phosphofructokinase-1 in glycolysis
Glucose-6-phosphate in gluconeogenesis bypass Hexokinase in glycolysis
Describe the reaction of Pyruvate to Phosphoenolpyruvate.
Requires two energy-consuming steps
1st step: pyruvate carboxylase converts pyruvate to OAA (oxaloacetate)
- Carboxylation using a biotin cofactor
- Requires transport of pyruvate into the mitochondria
2nd step: PEP carboxykinase converts OAA to PEP
- Phosphorylation and decarboxylation
- Occurs in mitochondria or cytosol depending on aerobic vs. anaerobic conditions
Describe the synthesis of oxaloacetate.
Biotin = an important cofactor for pyruvate carboxylase
Covalently linked to the e amino acid group on Lys in the active site
Biotinylated Lys functions as a swinging arm in the reaction to carry a carboxyl group from one region of the active site to another
What is Biotin?
CO2 Carrier; long biotinyl-Lys tether moves CO2 from site 1 to site 2
A vitamin required in the human diet; abundant in many foods; also synthesized by intestinal bacteria
Is biotin deficiency rare?
Yes its rare, but can be caused by a diet rich in raw eggs
What is the relation between eggs and biotin?
Eggs have a protein called avidin, which binds biotin and prevents its absorption (which will also affect the synthesis of oxaloacetate)
In cooked eggs, avidin is denatured and inactivated
Describe the steps of oxaloacetate to phosphoenolpyruvate.
Decarboxylation leads to rearrangement of electrons
Facilities attack of the carbonyl oxygen of the OAA on the y phosphate of GTP
In humans, the reaction can either happen in the mitochondrial matrix or cytosol depending on whether we have aerobic or anaerobic metabolism
In aerobic metabolism, how is OAA converted to PEP?
OAA –> Malate in mitochondrial matrix
Malate transported to cytosol
Malate brings OAA in the cytosol
- produces NADPH in the cytosol
- needed for GAPDH (as if there is not enough NADPH, this reaction of 1,3BPG to G3P will not occur)
OAA –> PEP in the cytosol
PEP –> 1,3BPG
1,3BPG –> G3P by GAPDH (enough NADPH is needed) (GAPDH = glyceraldehyde-3-P dehydrogenase)
G3P –> gluconeogenesis
In aerobic metabolism, how is OAA converted to PEP?
During vigorous exercise, lactate produced in muscle cells is transported to the liver
Lactate –> Pyruvate by lactate dehydrogenase
Under these conditions cytosolic NADH levels are maintained by the lactate dehydrogenase reaction
Mitochondrial PEPCK converts OAA to PEP (PEPCK = phosphoenolpyruvate carboxykinase)
PEP is exported out to the cytosol (PEP –> G3P by GAPDH)
What bypasses the other two irreversible glycolytic reactions?
F1,6-BP + H2O –> F6-P + Pi
- by Fructose-1,6-bisphosphate-1
- coordinately/oppositely regulated with PFK-1 (glycolysis)
G6P + H2O –> Glucose + Pi
- by glucose 6-phosphatase
- coordinately/oppositely regulated by hexokinase (glycolysis)
Where is glucose-6-phosphatase localized?
Glucose-6-phosphatase is localized to the lumen of the endoplasmic reticulum
Found in hepatocytes, renal cells and epithelial cells of small intestine
NOT found in other tissues
How can glucose leave to the extracellular space?
By glucose transporter 2 (GLUT2)
What are the metabolic control points of glycolysis?
Reaction of Fructose-6-P –> Fructose-1,6-BP:
PFK-1
- positive regulators = Fructose-2,6-BP and AMP
- negative regulators = ATP and citrate
Reaction of 2 PEP –> Pyruvate
Pyruvate kinase
- positive regulator = Fructose-2,6-BP
- negative regulators = ATP, Alanine
What are the metabolic control points of gluconeogenesis?
Pyruvate –> OAA
Pyruvate carboxylase
- positive regulator = Acetyl-CoA
- negative regulator = ADP
OAA –> PEP
PEPCK
- negative regulator = ADP
Fructose-1,6-BP –> Fructose-6-P
FBPase-1
- positive regulator = citrate
- negative regulator = Fructose-2,6-BP and AMP (not enough AMP, means you can’t do gluconeogenesis, sign just means the energy change)
What is the different regulation of PFK-1 and FBPase-1?
PFK-1 and FBPase-1 are RECIPROCALLY REGULATED in response to energy needs of the cell
By:
AMP (+ glycolysis, - gluconeogenesis)
Fructose-2,6-BP (- glycolysis, + gluconeogenesis)
Citrate (+ glycolysis, - gluconeogenesis)
