Gluconeogenesis Flashcards
What is gluconeogenesis?
Gluconeogenesis is the reverse of glycolysis except at rate-limiting steps
-need to “bypass” the 3 rate-limiting steps in glycolytic pathway in order to go in opposite direction
What are the glycogen in solutions?
- primary source is amino acids
- lactate
- glycerol
Are there reactions that are unique to gluconeogenesis ?
7 f the reactions in glycolysis are reversible- used in synthesis from lactate or pyruvate
-3 glycolytic reactions are irreversible and are substituted by 4 reactions unique to gluconeogenesis
Explain the first step of gluconeogenesis
Pyruvate —> oxaloacetate (OAA) -carboxylation by Pyruvate carboxylase
Biotin is a coenzyme
Biotin is bound to apoenzyme of Pyruvate carboxylase through an E-amino group of a lysyl residue to form biocytin
Cleavage of ATP drives formation of apoenzyme-biotin- CO2 intermediate
-intermediates carboxylase Pyruvate to form OAA
Where is Pyruvate carboxylase found?
Pyruvate carboxylase round in mitochondria of liver and kidney cells but not muscle
Explain the second step for gluconeogenesis
B: transport of oxaloacetate to the cytosol
- OAA is produced in mitochondria but subsequent gluconeogenesis reactions occur in the cytosol
- OAA is converted to a late for transport to cytosol
- Recall this is one of the shunts for transport of reducing equivalents between mitochondria and cytosol
What is the third step of gluconeogenesis ?
C: Decarboxylation of cytosolic oxaloacetate
OAA—> PEP by decarboxylation and phosphorylation by PEP-carboxykinase (PEPCK) using hydrolysis of GTP.
This represents a thermodynamically favorable path from Pyruvate to PEP
PEP is then converted through reverse glycolysis reactions up to fructose 1,6-bisphosphate
What is the 4th step of gluconeogenesis?
D: Dephosphorylation of fructose 1,6-bisphosphate
- Conversion of fructose 1,6-bisphosphate —> fructose 6-phosphate cannot use phosphofructokinase 1(irreversible in opposite direction - glycolysis)
- The enzyme fructose 1,6-bisphosphate is used instead
- Important regulatory site for gluconeogenesis
What is the 5th step of gluconeogenesis ?
- Hexokinase/Glucokinase reaction in glycolysis reaction irreversible
- Glucose 6-phosphatase converts glucose 6-phosphate —> glucose
- Found in liver and kidney but not muscle(like pyruvate carboxylase)
- In liver, if the enzyme glucose 6-P phosphatase is defective, it results in a glycogen storage disorder (glycogen storage disease type 1: Von Gierke’s disease)
Define and differentiate the glucose 6-phosphate deficiencies
Type 1a: Von Gierke’s disease (glucose 6-phosphatase deficiency )
Type 1b: Glucose 6-Phosphate translocase deficiency
What are the glucose 6-phosphatase deficiencies, what can they cause?
Type 1a: Von Gierke’s disease (glucose 6-phosphatase deficiency )
Type 1b: Glucose 6-Phosphate translocase deficiency
- Affects liver and kidney
- Fasting hypoglycemia- severe
- Fatty liver, hepato- and renomegaly
- Progressive renal disease
- Growth retardation and delayed puberty
- Hyperlacticacidemia, hyperlipidemia, and hyperuricemia
- Normal glycogen structure, increased glycogen stores
Describe treatment of glucose 6-phosphate deficiency
Type 1a: von Guerke’s disease( glucose-6 phosphatase deficiency )
Type 1b: glucose 6-phosphate translocase deficiency
Treatment: Nocturnal gastric infusions of glucose or regular administration of uncooked cornstarch
How does glucagon regulate gluconeogenesis ?
Stimulates gluconeogenesis by 3 mechanisms
- changes in allosteric effectors: lowers levels of fructose 2,6-bisphosphate
- Covalent modification of enzyme activity
- Induction of enzyme synthesis: it increases transcription of the gene for PEPCK
How does glucagon use covalent modification to regulate enzyme activity ?
- elevates cAMP levels
- cAMP-dependent protein kinase converts Pyruvate kinase to a phosphorylated inactive form
- This decreases conversion of PEP to pyruvate switching off glycolysis and switching on gluconeogenesis
Outline the step by step process of glucagon regulating gluconeogenesis
- High glucagon/insulin ratio causes elevated cAMP and increased levels of active protein kinase A
- Increased protein kinase A activity favors the phosphorylated form of the PFK-2/FBP-2 complex
- Phosphorylated PFK-2 is insctive, whereas FBP-2 is active; this impedes formation of fructose 2,6-bisphosphate
- Decreased levels of fructose 2,6-bisphosphate decreases the inhibition of FBP-1, which leads to an increased rate of gluconeogenesis
