biochemistry lecture 11. gluconeogenesis metab 1 ab metab 2 xy -metabolic pathways are irreversible...
TRANSCRIPT
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Biochemistry
Lecture 11
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Gluconeogenesis
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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
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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
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• 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
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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
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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
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The Cory Cycle
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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***
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Regulation of Metabolism
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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
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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
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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
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Reactions Far From Equilibrium are Common Points of Regulation
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Hexokinase
• Isozymes are different enzymes that catalyze the same reaction
• They typically share similar sequences
• Their regulation is often different
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P
eg. G6P is structurally similar to glucose, and competes with glucose for active site of hexokinase
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AMP
ATP
F6P
Active site
Allosteric site
PFK
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Fructose-2,6-bisphosphate
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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
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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
+
+
+
+++
+
+