biochemistry lecture 11. gluconeogenesis metab 1 ab metab 2 xy -metabolic pathways are irreversible...
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Biochemistry
Lecture 11
Gluconeogenesis
Gluconeogenesis
Metab1
A B
Metab2
XY
-Metabolic Pathways are Irreversible∆G between the 1st & last metabolite is large & neg.
- If 2 metabolites are interconvertible (metab 1 metab 2), the path from Metab 1 Metab 2 must be different from that of Metab 2 Metab 1
1. Carboxylation of pyruvate to oxaloacetate √
2. Transport of oxaloacetate out of mitochondriamitocyto Oxaloacetate
Malate
NADH + H+
NAD+
Malate
Oxaloacetate
NADH + H+
NAD+
Inner mito. Memb.
A. Circumventing Pyruvate Kinase - Conversion of Pyruvate to Phosphoenolpyruvate
3. PEP Carboxykinase: decarboxylates and adds phosphate
• Dephosphorylation is not phosphorylation in reverse!• Reverse Phosphorylation of ADP by F1,6 BP to
generate F6P (and ATP) would be steeply uphill:
F1,6 BP + ADP F6P + ATP ∆G° = +3.4 kcal/mol
• Instead, dephosphorylation is carried out:
F1,6 BP + H2O F6P + PO4 ∆G° = -3.9 kcal/mol
• Reverse Phosphorylation would be mediated by PFK
• Dephosphorylation is mediated by F1,6BPase
B. Circumventing PFK – dephosphorylation of F1,6BP
C. Circumventing Hexokinase – dephosphorylation
of G6P
• Mediated by G6Pase• G6Pase is present only in liver and
kidney• Hence, these are the only tissues that
can synthesize and secrete glucose into the blood
The Gluconeogenic Response is Activated Largely by the State of
Feeding/Fasting
Glycogen
Glucose
Pyruvate
Acetyl CoA
Blood Glucose
Alanine
FA’s
Blood Glucose
Blood Glucose
The Cory Cycle
Gluconeogenesis & Glycolysis can Occur at the Same Time in Different
OrgansIN LIVER
Glucose Glucose
IN MUSCLE
B L OO D
PyruvatePyruvate
LactateLactate
Alanine
GlycolysisGluconeogen.
RED BLOOD CELLS
Glucose
Pyruvate
Lactate
Alanine
*** The main substrate here is LACTATE***
Regulation of Metabolism
Overview of Energy Metabolism
FATS POLYSACCHARIDES PROTEINS
Fatty Acids, Glucose and Amino Acids
Glycerol other sugars
Stage I Digestion
Acetyl CoA
Stage II Anaerobic
TCA cycle CO2
CoA
e-
ADPATP
O2Oxidative
Phosphorylation
Stage III Aerobic
Principles of Regulation• The flow of metabolites through the
pathways is regulated to maintain homeostasis
• Sometimes, the levels of required metabolites must be altered very rapidly– Need to increase the capacity of glycolysis
during the action
– Need to reduce the capacity of glycolysis after the action
– Need to increases the capacity of gluconeogenesis after successful action
Rates of a Biochemical Reaction
• Rates of a biochemical reaction depend on many factors• Concentration of reactants
• Activity of the catalyst– Concentration of the enzyme
– Intrinsic activity of the enzyme
• Concentrations of effectors– Allosteric regulators
– Competing substrates
– pH, ionic environment
• Temperature
Reactions Far From Equilibrium are Common Points of Regulation
Hexokinase
• Isozymes are different enzymes that catalyze the same reaction
• They typically share similar sequences
• Their regulation is often different
P
eg. G6P is structurally similar to glucose, and competes with glucose for active site of hexokinase
AMP
ATP
F6P
Active site
Allosteric site
PFK
Fructose-2,6-bisphosphate
Two Alternative Fates for Pyruvate
• Pyruvate can be a source of new glucose– Store energy as glycogen– Generate NADPH via pentose phosphate
pathway• Pyruvate can be a source of acetyl-CoA
– Store energy as body fat– Make ATP via citric acid cycle
• Acetyl-CoA stimulates glucose synthesis by activating pyruvate carboxylase
Pancreas
Glucagon
Liver
Glycogen
Glucose
F6P
F1,6BP
Pyruvate
PK
F2,6BP
PFK
Glucose(Blood)
Brain
Epinephrine
Adrenal Medulla
Glucose
Muscle
Glycogen
F6P F2,6BP
PFK
F1,6BP
Pyruvate
PK
+
+
+
+++
+
+
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