Gluconeogenesis Flashcards
Mobilization of liver glycogen stores helps to maintain adequate glucose supply, but these storescan
be fully depleted in
24 hours
The synthesis of new glucose from simple carbon-skeleton precursors,
also helps maintain bloodglucose levels, and can serve this function for up to several weeks
Gluconeogenesis
Occurs not only during periods of extended fasting/starvation, but at all times
Gluconeogenesis
Critical for the clearance of blood lactate produced by tissues and cells performing anaerobic glycolysis, such as rapidly exercising muscle and RBCs
Gluconeogenesis
Most of the bodies gluconeogenesis occurs in the
Liver
Can contribute up to 10% of the body’s gluconeogenesis but only in the later stages of a fast
Kidneys
Not able to perform gluconeogenesis, though it provides important substrates for this process
Muscle
Requires chemical energy in the form of ATP and NADH
Gluconeogenesis
Are able to perform gluconeogenesis even during the lean times of an extended fast because they are simultaneously also able to oxidize fatty acids for the production of ATP and NADH
Liver and Kidney
The metabolic conditions that call for accelerated gluconeogenesis include the mobilization of fatty acids for
Catabolism
Several compounds may contribute their carbon skeletons to glucose synthesis. These include all the glycolytic and TCA cycle intermediates with the significant exception of
Acetyl CoA
18 of the 20 amino acids, as well as a few other compounds such as propionate and glycerol can also contribute their carbon skeletons to
Gluconeogenesis
The product of anaerobic glycolysis, produced in tissues during periods of high energy demand but low oxygen supply
Lactate
Also produced in specialized cells which lack mitochondria, such as RBCs
Lactate
Summarizes the principal means by which lactate is cleared from the body
The Cori Cycle
Reversible depending on the concentration of pyruvate and lactate, and the NADH/NAD+ ratio
The lactate dehydrogenase reaction
The oxidation of lactate occurs in the cytoplasm and produces
Pyruvate and NADH/H+
Two moles of lactate are recruited for the formation of
One mole of glucose
Pyruvate is then transported into mitochondria where we see the first reaction unique to
Gluconeogenesis
Our goal is the production of
-can not be produced by reversing the pyruvate kinase reaction
Phosphoenolpyruvate (PEP)
The first gluconeogenic ‘detour’ is a two-step process, beginning with the conversion of pyruvate to the TCA cycle intermediate oxaloacetate (OAA) by
Pyruvate carboxylase
CO2 and ATP are required in this reaction, and a critical cofactor for pyruvate carboxylase is
Biotin
The conversion of pyruvate to oxaloacetate by pyruvate carboxylase is stimulated by high levels of
Mitochondrial acetyl CoA
Muscle tissues lack the enzyme
Pyruvate carboxylase
Oxaloacetate cannot be transported across the mitochondrial membrane, so,it is carried across the mitochondrial membrane by either
Malate or aspartate
Conversion of malate to OAA produces NADH, therefore whether OAA uses malate or aspartate shuttle depends on the need for reducing equivalents in the
Cytosol
Used to convert 1,3-
bisphosphoglycerate to glyceraldehydes 3-phosphate during gluconeogenesis
NADH
Cytoplasmic oxaloacetate is then converted to PEP by
PEP-carboxykinase
The formation of PEP-carboxykinase
- ) Consumes 1?
- ) Releases 1?
- ) GTP
2. ) CO2
Each of the first two reactions unique to gluconeogenesis are driven energetically by the hydrolysis of a high energy
Phosphodiester bond
This makes these reactions
Irreversible
We now take advantage of five consecutive reversible reactions of glycolysis to convert two moles of PEP into one mole of
Fructose 1,6-bisphosphate
Along the way we consume another pair of ATP molecules with the conversion of two moles of 3-phosphoglycerate to
1,3-bisphosphoglycerate
The conversion of two moles of 3-phosphoglycerate to 1,3-bisphosphoglycerate consumes another pair of ATP molecules. This reaction is catalyzed by
3-phosphoglycerate kinase
In the next reaction, catalyzed by glyceraldehyde 3-phosphate dehydrogenase, we oxidize the
-produced in the original oxidation of lactate
NADH/H+
With fructose 1,6-bisphosphate we return to a familiar area in glycolysis, and to the highly regulated enzyme
PFK-1
That reaction, with the consumption of an ATP, is irreversible, so a second detour is taken with the gluconeogenic enzyme
Fructose 1,6-bisphosphatase-1 (FBP-1)
This enzyme removes the phosphate on carbon #1 of fructose 1,6-bisphosphate to produce fructose 6-phosphate
FBP-1
Are an enzyme pair for glycolysis/gluconeogenesis in the same way that glycogen synthase and phosphorylase are for glycogen metabolism
PFK-1 and FBP-1
Allosteric regulation of fructose 1,6-bisphosphatase is effected by
AMP and Fructose 2,6-bisphosphate
Serves as a local signal of energy need
AMP
Gluconeogenesis is an energy requiring process, so AMP inhibits the
FBP-1
Fructose 2,6-bisphosphate allosterically inhibits
FBP-1
The principal regulatory site in the glycolysis/gluconeogenesis story
PFK-1/FBP-1
Remember that insulin and glucagon also regulate
Pyruvate kinase
Glucagon-mediated phosphorylation of this enzyme prevents the conversion of
-conserves it for gluconeogenesis
PEP
The final step in gluconeogenesis is the conversion of glucose 6-phosphate to free glucose, but we are unable to use the ATP-consuming enzyme
Glucokinase
Instead, a membrane-bound complex of proteins catalyzes this step. This complex of proteins includes the enzyme
Glucose-6-phosphatase
This reaction takes place in the
ER
Glucose 6-phosphate is transported into the ER, where it reacts with the membrane-bound
Phosphatase
Genetic deficiency for glucose 6-phosphatase in liver has been characterized extensively and is referred to as
Von Gierke’s Disease, also called Type 1 Glycogen Storage Disease)
Gluconeogenesis is an energy consuming process. In order to convert lactate to glucose, the liver (and kidney) must consume the equivalent of
6 ATPs (4 ATP and 2 GTP)
While ATP has no direct allosteric effect on gluconeogenic enzymes, it inhibits two
Rate-limiting glycolytic enzymes
In this way, high levels of ATP help to stimulate net
Gluconeogenesis
In this way, high levels of ATP help to stimulate net gluconeogenesis by ensuring the inhibition of the counter directional enzymes
Pyruvate kinase and PFK-1
An intermediate of the TCA cycle that inhibits PFK-1
Citrate
It is principally at the fructose 6-phosphate/fructose 1,6-bisphosphate stage of things that we see control via
Glucagon and insulin
Liver interprets high insulin/glucagon ratios as a sign of carbohydrate energy abundance, and inhibits
Gluconeogenesis
Conversely, it treats low insulin/glucagon ratios as a signal of carbohydrate energy deficiency, and therefore throttles up
Gluconeogenesis
Functions to clear the lactate that is produced by anaerobic glycolysis
The Cori Cycle
Has one end point and many potential start points
Gluconeogenesis
Eighteen of the twenty common amino acids are able to donate their carbon
skeletons to
Gluconeogenesis
Integral to this is the disposal of the amine nitrogen on amino acids, tightly linking gluconeogenesis via amino acids to the process of
Urea Production (I.e. The Urea Cycle)
The use of substantial quantities of amino acids for gluconeogenesis is reserved, in large part, to the circumstance of an
Extended fast
What are the only two amino acids that are unable to participate in gluconeogenesis?
Leucine and Lysine
Leucine and lysine are “ketogenic”, meaning their catabolism leads only to
Acetyl CoA
Similarly, fatty acids composed of an even number of carbons produce only
- Via the process of B-oxidation
- Cannot participate in gluconeogenesis
Acetyl CoA
Not a tenable source of carbon atoms for gluconeogenesis
Acetyl CoA
Acetyl CoA and OAA combine to produce
Citrate
Acetyl CoA doesn’t contribute net carbon atoms to the ensemble of
-Thus why it can not contribute to gluconeogenesis
TCA cycle intermediates
Contrasting this, those 18 glucogenic amino acids are able to contribute to the pools of TCA cycle intermediates without consuming a TCA cycle intermediate. Such a contribution is referred to as an
Anapleurotic reaction
When there is net production of a TCA cycle intermediate, there is no problem in feeding OAA into
Gluconeogenesis
Free glycerol, produced when the three fatty acids of a TAG are released, is taken up by the liver and in two reactions, catalyzed by
Glycerol Kinase and Glycerol-3-phosphate dehydrogenase
In this process, glycerol is converted into
Dihydroxyacetone phosphate
Has a number of metabolic sources, including catabolism of valine and isoleucine, and the conversion of cholesterol to bile salts
Propionate
Also derives from fatty acids with branch structures and from fatty acids with an odd number of carbons
Propionate
Following a carboxylation reaction, propionate donates its carbons to the synthesis of
-another example of an anapleurotic reaction
Succinyl CoA
The neonate’s liver glycogen stores are typically
Modest
Its ability to metabolize certain types of fatty acids for energy is also markedly reduced, compared to even slightly older babies
Neonates
Also, the neonate’s brain to body ratio is the largest it will ever be and hence the brain places a disproportionate demand on the child’s
Glucose supply
The matter is compounded by the fact that in the newborn, a critical liver enzyme in gluconeogenesis is in very low levels. This enzyme is
PEP carboxykinase (PEPCK)
As limited glycogen stores are depleted in the first few hours after birth, gluconeogenesis must step in to fill the gap. In the absence of adequate levels of PEP carboxykinase, we may see
Hypoglycemia
