gluconeogenesis
formation of glucose from noncarbohydrate sources (lactate, pyruvate, glycerol, and AA's)
Which cells can undergo gluconeogenesis?
liver or kidney cells
lactate is produced by
active skeletal muscles that undergo fermentation
lactate is then moved to liver cells where it is converted to pyruvate by lactate dehydrogenase
glycerol is produced from
the breakdown of triglycerides in adipose tissue
it then enters the bloodstream and travels to liver cells where it is converted to DHAP
amino acids are obtained from
hydrolysis of protein in our food
under starvation conditions we obtain AA from protein in skeletal muscles
some AA's are converted to pyruvate and some to oxaloacetate
Why is gluconeogenesis important?
some tissues depend only on glucose for fuel and so is an emergency supply of G
human daily G requirement = 160g (75% of which is used by the brain)
human G reserves = 20g in body fluid + 190g in glycogen
after a little over a day we would run out of our
Is gluconeogenesis the reverse of glycolysis?
no, because glycolysis is a very exergonic RXN
in glycolysis, 3 irreversible steps release the majority of the E; that means that for gluconeogensis to be an effective process, it must somehow by pass these steps in the conversion of pyruvate to glucose
step 10 of glycolysis is bypassed via
a 2-step pathway that involves an oxaloacetate intermediate
Pyruvate + ATP + GTP + H2O --->
PEP + ADP + GDP + Pi + 2H+
step 3 of glycolysis is bypassed via
the exergonic hydrolysis of F 1,6-BP to F6P
F 1,6-BP + H2O --->
F6P + Pi
step 1 of glycolysis is bypasses via
the hydrolysis of G6P to glucose
G6P + H2O --->
Glucose + Pi
Step 1 of the Step 1 bypasses of gluconeogenesis
carboxylation of pyruvate:
(1) ATP activates CO2 by forming carboxyphosphate
HCO3- + ATP <--> HOCO2-PO3^-2 + ADP
(2) phosphorylated CO2 can now attached onto biotin of enzyme and form carboxybiotin-enzyme intermediate; this bond is very unstable
enzyme-bi
pyruvate carboxylase
consists of 4 identical subunits that each have
- a domain that has a covalently attached biotin prosthetic group that binds CO2 and brings it closer to the active site of the enzyme
- a domain that binds ATP needed to activate CO2 (uses ATP hydrolysis to
malate dehydrogenase
oxaloacetate must be converted into malate and transported across the mito membrane and into cytoplasm where it is then converted back into oxaloacetate
oxaloacetate + NADH + H+ ---> malate + NAD+
*redox RXN
Step 2 of the Step 1 bypasses of gluconeogenesis
PEP carboxykinase converts oxaloacetate into PEP
in this step the highly endergonic phosphorylation is coupled to the highly exergonic decarboxylation
oxaloacetate + GTP <--> PEP + GDP + CO2
once PEP is formed
the reverse steps of glycolysis are followed until F1,6-BP is formed
these steps (3-7) are at equilibrium and will readily occur under conditions that favor G formation
upon reaching F 1,6-BP a different reaction pathway is followed because the reverse gl
once F 1,6-BP is formed
the enzyme F 1,6-bisphosphatase (allosteric E that is also used in gluconeogensis regulation) catalyzes the exergnoci hydrolysis of the ester bond at C1 of F 1,6-BP forming F6P
once F6P is formed
it undergoes step 9 which is the reverse of step 2 in glycolysis
G6P is then converted to G in the lumen of the ER
gluconeogenesis net reaction
2pyruvate + 4ATP + 2GTP + 2NADH + 6H2O --->
glucose + 2ADP + 2GDP + 6Pi + 2NAD+ + 2H+
3 fates of pyruvate
(1) lactate (muscles)
(2) acetyl CoA (TCA/oxidative phosphorylation)
(3) oxaloacetate (forms glucose in liver via gluconeogenesis or can enter TCA)