gluconeogenesis

define gluconeogenesis
synthesizng glucose from non-carbohydrate precursors
what are some examples of non-carbohydrate precursors used in gluconeogenesis?
pyruvate, alanine (by transamination), lactate (by LDH, lactate dehydrogenase), propionate, glycerol, (important in starved state), and gluconeogenic amino acids, (anything that feeds into the pyruvate/TCA cycle such as aspartate)
what tissues perform gluconeogenesis?
liver, (major, kidney, and small intestine epithelia, (minor)
what is the purpose of gluconeogenesis?
supporting the plasma glucose level
what are the enzymes of the 3 irreversible steps that gluconeogenesis needs to bypass in re-tracking glycolysis?
pyruvate kinase, PFK-1, and gluokinase
where does glycolysis take place?
in the cytosol
how many net ATP are generated in glycolysis?
2
how many steps/enzymes are there in glycolysis, how many are reversible?
10. 7
what is the first enzyme/step/barrier that must be overcome in gluconeogenesis?
pyruvate -> PEP, (PK catalyzed step in glycolysis) – requires several steps
how is pyruvate converted to oxaloacetate in the first step of gluconeogenesis?
first the pyruvate must be brought into the mitochondria from the cytosol. once there, pyruvate carboxylase adds a bicarbonate using ATP and biotin as a cofactor. 3C molecule – 4C
what else can oxaloacetate be used for, other than gluconeogenesis?
addition back into the TCA cycle to make citrate.
what does PEP stand for?
phosphoenolpyruvate
what are the two ways that oxaloacetate can be made into PEP? how often does the body use either process?
in the mitochondria or in the cytosol. each happens about 50% of the time
how is oxaloacetate made into PEP in the mitochondria?
mitochondrial PEP carboxykinase uses a GTP to convert oxaloacetate into PEP, giving off a CO2
how is oxaloacetate made into PEP in the cytosol?
there is no oxaloacetate transporter from the mitochondria to the cytosol, so oxaloacetate has to be converted to malate, transported,converted back to oxaloacetate, then converted to PEP by cytosolic PEP carboxykinase, using 1 GTP, and giving off a CO2. (transamination to aspartate instead of malate is also possible)
what energy molecules/enzymes are needed to get pyruvate to PEP?
ATP, (pyruvate carboxylase), and GTP, (PEP carboxykinase)
in comparison to glycolysis, which gives 2 pyruvates, and one enzyme producing net 1 ATP each, gluconeogenesis uses 2 enzymes 2x to create 2 PEPs, how many ATP/GTP does this require
2 ATP, 2 GTP
what is one benefit of using malate in the process of converting OAA -> PEP?
OAA to malate makes NADH -> NAD+ in the mitochondria, and malate to OAA in the cytosol makes NAD+ -> NADH, bringing more reducing equivalents to the cytosol which will be helpful later
what rxns need biotin? what is an example?
carboxylation rxns, such as pyruvate -> oxaloacetate
what molecules allosterically activate pyruvate carboxylase? why is this helpful?
acetyl CoA, and other acyl CoAs. one reason for this is acetyl CoA and pyruvate are both substrates of the TCA cycle, which requires oxaloacetate to make citrate, (start of TCA). acetyl CoAs need OAA in the process of breaking down fats
what is the next 2 steps/barriers/enzymes to overcome in gluconeogenesis after pyruvate kinase?
PFK-1 and hexokinase.
how is the glycolytic PFK-1 step overcome in gluconeogenesis?
PFK-1 uses an ATP to make F6P -> F1,6bisP. so in gluconeogenesis, fructose 1,6-bisphosphatase uses a water and takes off a Pi, (no energy involved)
how is the glycolytic hexokinase step overcome in gluconeogenesis?
hexokinase uses an ATP to convert glucose to G6P, so glucose 6 phosphatase takes the Pi off using a water, (no energy involved)
which 2 amino acids are completely ketogenic?
lysine, leucine
what does it mean that almost all the amino acids are gluconeogenic?
glucose is very important
what is the cori cycle?
RBCs, (and to some extent muscles) produce lactate, (pyruvate -> lactate by LDH, using one NADH) for the 2 ATP from glycolysis. the lactate is then brought back to to the liver and can be used in gluconeogenesis
what is the alanine cycle?
the alanine cycle is muscle running glycolysis and then transaminating the pyruvate to alanine, this is used to either save an NADH that the cori cycle would have used, or to transport N back to the liver. alanine can then be either transaminated to pyruvate in the liver and run through gluconeogenesis, or excreted as urea
where does the energy driving gluconeogenesis come from?
fatty acid catabolism, (acetyl CoA)
what are the 2 major products from beta-oxidation, (fatty acids catabolism)?
acetyl CoA and NADH
what do the products of beta oxidation do in terms of regulating gluconeogenesis, (in terms of the pyruvate kinase step of glycolysis)?
NADH and acetyl CoA both inhibit pyruvate dehydrogenase, (tells liver to stop making more acetyl CoA, b/c now its coming from fats), and acetyl CoA activates pyruvate carboxylase.
what does pyruvate dehydrogenase do?
catalyzes the conversion of pyruvate to acetyl CoA
what does pyruvate carboxylase do? is it inducible?
catalyzes conversion of pyruvate to oxaloacetate. it is inducible by glucagon.
what does pyruvate kinase do?
makes pyruvate from PEP
what ratio of insulin/glucagon correlates with gluconeogenesis?
low insulin/high glucagon
how does the higher level of glucagon regulate gluconeogenesis, (in terms of the pyruvate kinase step of glycolysis)?
glucagon stops pyruvate kinase from making more pyruvate from PEP, (futile cycle). glucagon also activates AND INDUCES PEP carboxykinase, which catalyzes the conversion of oxaloacetate to PEP
how does glucagon regulate the PFK step of glycolysis in gluconeogenesis in terms of covalent modification?
glucagon activates a kinase that phosphorylates PFK-2 and fructose 2,6 bisphosphatase. this inactivates PFK-2, which then cannot make F2,6bisP, (allosteric activator of PFK-1). also, this activates fructose 2,6 bisphosphatase, which changes F2,6bisP -> F6P. thus, glucagon favors gluconeogenesis
how does insulin regulate the PFK step of glycolysis in gluconeogenesis in terms of covalent modification?
insulin activates a phosphatase that dephosphorylates PFK2 and F2,6,bisPase. this activates PFK2, allowing it to make F2,6 bisP and inactivates F2,6 bisPase, (stopping conversion of F6P -> F2,6,bisP). thus, insulin favors glycolysis
what enzymes are inducible by glucagon?
PEP-CK, F1,6bisphosphatase, and G6phosphatase
how does glucagon regulate the PFK step of glycolysis in gluconeogenesis in terms of enzyme induction?
glucagon can induce PEP-CK, the enzyme that catalyzes the conversion of OAA -> PEP
how does glucagon affect glucokinase? how does this further the purpose of gluconeogenesis?
it activates it’s translocation into the nucleus, and therefore when glucose is produced it can go into the bloodstream from the liver w/out risk of it being brought into glycolysis
what ratio of ATP to AMP allosterically activates gluconeogenesis? where does the ATP come from?
high. from fat breakdown

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