Possible sources of gluconeogensis
And explain pathway of each to glucose
AA (feeding into the Kerbs cycle and directlyinto pyruvate), lactate pyruvate, propoionate, and glycerol. ALso galactose and fructose
Exception leucine and lysine CANNOT be use for gluconeogensis (because these two can't yield pyruvate or OAA) and CANNOT use regular even number fatty acids because The acetyl CoA they form can't make pyruvate
Why are children more susceptible to hypoglycemia than adults?
What children are most susceptible?
Because they have a large brain/body ratio and the brain is using disproportionally amounts of glucose.
Newborns have a limited capacity for ketogenesis because transport of long fatty acids into liver is poorly developed, so they have very little glucose to spare by using ketone bodies.
Also newborns can't synthesis glucose from lactate and alanine because they rate limiting step require phosephoenolpyruvate carboxykinase which is low in the first hours after birht
Premature and smlal for gestintatioanl age are most suseptible because their liver storage of glycogen is smaller
Explain the recyclnig of the end products of glycolysis
Peripheral tissue release ALANINE (Alanine Cycle pyruvate from muscles) and LACTATE (-Cori Cycle RBC, muscles) and they return to the liver by blood where they enter gluconeogenesis
What is happening in the cori cycle
Lactate (end product of glycolysis) travels to the liver where is it converted to glucose and sent out into blood stream for use
Not actually a cycle because many organs (all lactate producing cells) are invovled
Equation for GLuconeogensis
2-lactate + 6 ATP + 6H2O---> glucose + 6 ADP + 6 Pi
Note that it take SIX ATPS for gluconeogensis from lactate
What enzymes aren't the same in glycolysis and gluconeogensis? What replaces those enzymes
1. Hexokinase- glucose 6 phosphate
2. PFK-1-- Fructose 1, 6 biphosphatase
3. Pyruvate kinase- pyruvate carboxylas
and an additional one that take pyruvate to Oxaloactetae is PEP carboxykinase
What are the first 3 steps of gluconeogenesis from lactate
1 Lactate is converted to pyruvate by Lactate dehydorgenase making NADH which is needed later (this is just reversed in anerobic glycolyssi)
2. Pyruvate wants to become 2-phosphenolpyruvate by cant do so directly so we use 2 ATPs (4/glucose) to to convery pyruvate to 2- oxaloacetate with pyruvate carboxylase then the Oxaloacetate becomes 2-Phosphophenolpyruvate (PEP) by the PEP carboxykinase
Majr difference in going from phoshenolpyruvate to pyruvate and the oppoiste
In glycolysis it's a direct step and you producse ONE ATP
In gluconeogenosis you have 2 other steps and use FOUR ATP/glucose
MEchanism of pyrvuate to PEP
1. Cytosolic pyruvate enters mitochondria b/c that where pyruvate carboxylase is
2. Pyrvuate---- pyrvuate carboxylase(use biotion as cofactors for transfer of CO2---> Oxaloacetate-CO2
3. Oxaloactete can't pass the membrance so it's converted to malate
4. In cytosol malate back to OAA and OAA----PEP---> Pyruvate
What is special about the steps fom PEP to fructose 1-6 biphophate...list them with enzyme
They are just the reverse of glycolysis
PEP---- enolase--> 2- phospholycerate---- phosphyglyerate mutase--->3- phosphoglycerate--- phosphoglycerate kinase--- 1-3 BPG
Last three steps of gluconeogenosis
Fructose 1-6 biphosphate--- fructose 1, 6 bisphosphate---> Fructose 6-P (irreversible hydrolysis)
Fructose 6-P---phosphoglycoisomerase--> Glucose 6-P (reversible)
Glucose 6-P-- Glucose 6-phosphatase---> glucose (this is irreversible hydrolytic reaction)
What is imporatnt about amonia and gluconeogensis
Liver cells need to be able to get rid of amonia so the urea cycle is always run when gluconeogensis is running to remove ammonia to make urea (which we can secrete)
Where does Oxacloacetae come from? What step is it important in?
Oxalacetate Intermediate from pyruvate to PEP in gluconeogensis
Comes from different AA and odd 0carbon fatty acids after they are chopped off by beta oxidation
What steps require ATP/GTP in glucogenosis
Where does this energy come from
Pyruvate to OAA
OAA to PEP
2 phosphoglycerate-- to 1-3 phosphoglycerate
Getting energy from Beta oxidation- from fatty acids
Explain what happens when pyruvate carboxylase deficieincy symptoms
No gluconeogenisis (between pyruvate and OAA)- hypoglycemia
But also needed in TCA (running from fatty acid normally but when enzyme is gone poor energy gerneration
1. HIgh pyruvate- can't go into gluconeogensis so it backs alanine up
2. So alanine is high
3. Now pyruvate can't do to gluconeogensis so it goes to lactic prouction which further inhibits gluconeogensis because it's using the lactate
Treatment of this is limited until the enzyme is picked
Where is glucose 6 phosphotase located?
What organs and what organelle?
In the ER of liver and kidney.
1. A translcocase is require to put the G6P enzyme from the cytosol to the ER
2. then GLUT-7 takes the glucose out from the ER to cytosol
3. and then GLUT 2 from cytosol to membrane.
Why would there be a build of glycogen in the liver
A deficienty in the translocase (move Glucose 6- phophatase) from Cytosol to ER for phosphatase attack.
A defiicney in the translocase or the phosphtase
Define anaplerotic reactions
Reactions that lead to the net synthesis of TCA cycle intermediates
They also support gluconeogensis because they make OAA
Why cant leucine and lysine function ascarbon sources for gluconeogensis
They are ketogenic (make keteon bodies) and not gluocogenic. They make Acetyl CoA and acetoacetaate and this CAN"T MAKE PYRUVATE OR OOA. Acetyl CoA is catalyzed by PDH and that is irreversible.
Which enzymes are both glucogenic and ketogenic
Dicuss glucose synthesize and fatty acids
Stright-even chain fatty acids can't produce glucose
Fatty acids with methyl branches or odd number of carbons yield oropionyl CoA which is a precursor of OAA
Propionate --> Propionyl CoA --> Methylmalonyl CoA --> Succinyl CoA --> ½ glucose
Triacylglyerols when liberated from adipose storage can make glyercol which is a substrate for gluconeogensis
Steps in which glucose is synthezied by fructose
↓ Aldolase B
DHAP + Glyceraldehyde
Hwo is galactose used to synthezied glucose
Galactose--- Galactokinase---> Glucose 1-P----> glucose 6-P---> Glucosse
Cost of glucogenosis from 2lactate?
What provides this energy?
Lactate is 6 ATPS and 2 NADH
Alanine is 10ATPS and 2 NADH
This cost comes from fatty acids running int he TCA cycle
Enzymes that regulate gluconeogeniss
1. Pyruvate carboxylase (stimulated by Acetyl CoA) and
2. PEP carboxykinase (glucagon induces synthesis of the enzyme)
3. Fructose 1-6 biphosphatase (AMP, F2,6-BP inhibit; glucagon stimulatesby upregulating enzyme protein synthesis)
6. Glucose 6 phophtases
When glycolysis is upregulated glucogenosis is down regulated
Hormonal control of gluconeogenosis
Stimulated by glucagon by making less fructose 2-6 biphosphate in the liver
Insulin inhibits glucongeogensis but mechanisms not well understood
What does glucagon up and down regulate?
Glucagon up regulates PEP carboykinase, fructose 1-6 biphophatase and glucose 6-phosphatase
Down regulates Pyruvate kinase PFK 1 and glucokinase
how does insuling work?
At the gene level-- Insulin opposes the action of glucagon by activating an insulin response element binding protein (IREB), which binds to an insulin response element (IRE) and inhibits
Relationship between alcohol intake and gluconeogensis
Alcohol inhibts gluconeogensis. The NADH made from alcohol oxidation is transferred into the malate asparate shuttle and it drives LDH and MDH towards lactate and malate so we limit glucogensosi by limiting OAA and pyruvate