Gluconeogenesis Flashcards
What organs do gluconeogenesis?
Major site is the liver, but it can occur in kidney. little gluconeogenesis in brain, skeletal muscle or heart muscle
What is Gluconeogensis?
Synthesis of glucose from non-carbohydrate precursors. in many cases, starting substrate is pyruvate.
Where in the cell does gluconeogenesis happen?
most enzymes are in the cytoplasm
When is gluconeogenesis important?
especially important during fasting or starvation. Glucose is the primary fuel for the brain and the only fuel for red blood cells.
How does insulin/glucagon affect gluconeogenesis
insulin inhibits gluconeogenesis. glucagon activates it
What challenge is there in glyconeogenesis
steps 1,3 and 10 have a big delta G in energy, eneed to covercome this
Oxaloacetate is a precursor for___ and an intermediate of the ___
gluconeogensis/TCA
compartmentalization of OAA
Formation of OAA happens in the mitochondria -> no transporter to transport oxaloacetate.
But there is a transporter for malate.
- Oxaloacetate is REDUCED to malate (malate carries the protons, with NAD+ formed)
(malate dehydrogenase)
- malate is exported to the cytosol
- malate is oxidized to give OAA and NADH
(malate dehydrogenase)
OAA can be then used to synthesis PEP
How to by pass PFK? is this a regulatory step?
F-1-6-BP (fructose 1,6-bisphosphatase) -> fructose 6 phosphate.
Regulatory step
The generation of free glucose only occurs in… (the final step of gluconeogeneiss)
the liver
Where is free glucose formed, in the liver?
Free glucose is not formed in the cytoplasms.
Glucose-6-Phosphate is transported to the lumen of the endoplasmic reticumum.
Glucose-6-phosphatase is an integral membrane protein on the inner surface of the ER, and catalyzes the formation of glucose form glucose-6-phosphate
Why can the liver form glucose?
The liver’s main metabolic duty is to maintain levels of glucose in the blood. So after the action of glucose-6-phosphatase, glucose can exit the liver and transport to tissues that need it.
Why is free glucose not generated in most tissues? What happnes to glucose-6-phosphate?
Most tissues lack glucose-6-phosphatase. so the glucose-6-phosphate is converted into glycogen, storage form of glucose
Is any energy produced during gluconeogenesis?
NO
If glucose is scarce ->
If glucose is abundant or ATP is required
gluconeogeneiss
Glycolysis
How does AMP, fructose 2,6- BP affect glucogensis/glycolysis
when F-2.6-BP is high -> stimulates PFK -> speeds glycolysis (high glucose)
slows down F-1,6B-Pase -> slows gluconeogenesis.
When AMP is high -> stimualtes PFK -> speeds glycolysis (need energy)
AMP slows down F-1,6_pase -> slows gluconeogensis
How does citrate affect mglucogensis/glycolysis
intermediate of TCA cycle -> enough intermediates -> slows down glycolsysi
What is required to start the citric acid cycle
OAA and acetyl coA
What are the fates of oxaloacetate?
GLuconeogeneiss
Citratic acid cycle (along with acetyl CoA -> need to start the cycle)
How does ADP and Acetyl CoA regulate pyruvate carboxylase?
Increase in acetyl coA -> activates pyruvate carboxylase -> produces more OAA (its like it can funnel towards the citric acid cycle)
Increase in ADP -> inhibits Pyr carboxylase slows down gluconeogensesis
What are the regulators for F-1,6-BPases
(-) F-2,6-BP
(-) AMP
(+) Citrate
What are the regulators for PEP carboxyl kinase?
(-) ADP
What are the regulators for pyruvate carboxlylaes
(-) ADP
(+) Acetyl CoA
How does insulin and glucagon control the activities of enzymes
Insulin:
when blood sugar is high -> stimulates insulin secretion (pancreases)
signals cells to absorb glucose out of the blood (glycolysis, glucose -> glycogen)
Glucagon
When blood sugar is low -> glucagon is secreted. in response, the liver releases glucose (glycogen -> glucse) (gluconeogenesis
What is the key regulator of glucose metabolism in the liver
Fructose 2,6 bisphosphate
Fructose 2,6 bisphosphate stimulates phosphofructokinase -> stimulates glycolysis
Fructose 2,6-bisphosphate inhibits fructose 1,6-bisphosphate -> represses gluconeogensis
What enzymes control the accumulation of the regulatory metabolite Fructose-2,6-bisphosphate
PFK-2 and FBPase-2
It turns Fructose-6-phosphate into Fructose-2,6-bisphosphate
Explain the bifunctional enzyme of PFK-2 and FBP-ase-2
PFK-2 and FBPase-2 are encoded by the same gene and are located on the same polypeptide chain.
1 gene = 2 activities
1 bifunctionanl enzyme = 1 mechanism to control activity
When its not phosphorylated -> PFK-2 is ON -> accumulates F-2,6 BP -> stimulates glycolysis.
When it is phosphorylated -> FBPase-2 is ON -> less F-2,6-BP is acccumualted, more F-6-P is accumulated -> stimulates gluconeogensiss
How is phosphorylation of the bifunctional enzyme controlled?
Insulin stimulates dephosphorylation of the bifunctional enzyme -> more F-2,6-P -> stimulates glycolsysi and inhibits gluconeogenesis
Glucagon stimulates phosphorylation of the bifunctional enzyme -> reduces F-2,6-BP -> inhibits glycolysis and stimulates gluconeogenesis.
Do the hormones of act directly on the bifunctional enzymes
No, there are additional kinases that will do the phosphorylation
Under extended muscular activity, oxygen will become limiting in the muscles. How can the muscles respond?
Lactate will accumulate to keep glycolysis running.
Lactate is sent to the liver to be metabolized.
The liver will turn lactate into glucose.
What is the Cori Cycle
Allow sthe recylcing of lactate to produce glucose.
Metabolic pathway in which lactate produced by anaerboic glycolysis is moved to the liver (released into the blood) to be converted into glucose, then is returned to the muscles (releaed back into the blood) and metabolized back into lactate.
Lactate -> pyruvate -> glucose
under normal conditions, how does insulin inhibit gluconeogenesis?
at the metabolite level, by accumulating Fructose 2,6 bisphosphate
How do hormones control glycolysis and gluconeogenesis at the gene expression level
Insulin:
increase expression of genes encoding for glycolytic enzymes
turn off genes for PEPCK
glucagon:
turn off genes for PEPCK: gluconeogenesis
repressor for PK
Explain Type 2 diabetes
Patients have consistnet hyperglycemia. Consistent high blood sugar.
Normally, after eating a meal, there is no need to synthesize glucose -> but in type 2 diabetes, gluconeogensis takes place.
Reason is insulin fails to inhibit the expression of PEPCK => insulin resistance.
liver keeps doing gluconeogenesis -> higher blood glucose -. symptoms
How can type 2 diabetes be controlled?
Therapeutic potential
keep it under control throuhg drugs, exercise iand diet
Which steps require energy in gluconeogenesis
Pyruvate carboxylase step
PEPcarboxylkinase step
and converting from 3-phosphoglycerate -> 1,3-bisphosphogycerate
How is lipids converted to sugars in plants? Full breakdown
- Fats are metabolized into Acetyl CoA in the gyxosome.
- Acetyl CoA enters the glyoxylate cycle, producing succinate.
- Succinate moves to the mitochondira and takes part in the TCA cycle: succinate -> fumerate -> malate
- Malate moves out into the cytosol and is oxidized to OAA
- OAA participates in gluconeogensis (OAA -> PEP -> Glucose)
When microbes are grown without a carboyhydrae source, isocitrate needs to the partitioned between what? What enzymes need to be controlled (the flux of)
isocitrate needs to be partitioned between TCA and the glyoxylate cycle.
Isocitrate lyase and isocitrate dehydrogenase activity
