Transcript lect11

BIOC/DENT/PHCY 230
LECTURE 11
How long will glucose reserves last?
 glucose requirements:
160g/day whole body
(120g/day brain)
 glucose reserves:
190g glycogen
20g in body fluids
 need to synthesise glucose during prolonged
periods of fasting
Gluconeogenesis
 synthesis of glucose from a variety of
non-carbohydrate metabolites
 lactate, glycerol and the carbon skeletons of
certain amino acids can all be used as substrates
(propionyl-CoA can also be used)
 most of the reactions of
gluconeogenesis are simply
the reverse of the
corresponding steps in
glycolysis
hexokinase
phosphofructokinase
(PFK)
 however those reactions
which represent
irreversible steps in
glycolysis need to be
by-passed
pyruvate kinase
By-passing pyruvate kinase
Converting pyruvate back to phosphoenolpyruvate (PEP)
is a two step process
Reaction 1: pyruvate + CO2 + H2O + ATP
oxaloacetate + ADP + Pi + 2H+
 catalysed by pyruvate carboxylase
 mitochondrial reaction
 oxaloacetate transported out of mitochondria as
malate
 allosterically activated by acetyl-CoA
 there is no mitochondrial
transporter for oxaloacetate
 oxaloacetate is converted
to malate which can be
transported out of the
mitochondria
 the reverse reaction occurs
in the cytoplasm
Reaction 2:
oxaloacetate + GTP
PEP + CO2 + GDP
 DG’ = -25kJ/mol for the combined reactions
 catalysed by phosphoenolpyruvate carboxykinase
(PEPCK)
 synthesis of PEPCK is stimulated by glucagon
By-passing phosphofructokinase
fructose-1,6-bisphosphate + H2O
fructose-6-P + Pi
 DG0’ = -16.3kJ/mol
 catalysed by fructose-1,6-bisphosphatase
 allosterically inhibited by fructose-2,6-BP and AMP
PFK-1
PFK-2
P
[F-2,6-BP] increases as [F-6-P] increases
Glucose
-
hexokinase
Glucose-6-P
Fructose-6-P
Fructose-2,6-BP
+
PFK
Fructose-1,6-BP
By-passing glucokinase
Glucose-6-phosphate + H2O
glucose + Pi
 DG0’ = -12.1kJ/mol
 catalysed by glucose-6-phosphatase
 most tissues lack this enzyme
 primarily expressed in liver
 allows liver to release glucose into the bloodstream
A comparison of energy
input and output from
glycolysis and
gluconeogenesis
Whilst the DG’ for both
glycolysis and
gluconeogenesis is
negative, gluconeogenesis
is a net consumer of
energy
Entry points into
gluconeogensis
glycerol
amino acids
lactate
lactate
amino acids
glycerol
TAG
DHAP
NAD+
DAG
G-3-P DHase
glycerol-3-phosphate
glycerol kinase
glycerol
Ketone Bodies
 ketone bodies are synthesised from acetyl-CoA
 they represent a means of using the energy available
in fatty acids for tissues that may not be able to use
fatty acids themselves
 particularly important for the brain, as water soluble
ketone bodies can cross the blood-brain barrier
 help supplement the energy requirements of brain,
which may not be met solely by glucose during prolonged
fasting
Ketone Bodies
Synthesis of ketone bodies
 occurs primarily
in liver mitochondria
Degradation of ketone
bodies
 in mitochondria of target
tissues
Ketoacidosis
What do I need to study for the final
exam?
You do not:
 need to memorise pathways
 need to memorise structures
 need to learn the names of all the intermediates and
enzymes involved in the various pathways
 need to understand the regulation mechanism for
glycogen phosphorylase
 know which specific amino acids are glucogenic and
which are ketogenic
You do not:
 need know equations for whole pathways
 reaction mechanisms
You do need to know:
 the logic of pathways
eg.
Why does flux through glycolysis decrease in the
presence of oxygen?
What is the significance of the LDH isozymes and
the reactions they catalyse?
Why is b-oxidation a cyclic series of reactions?
 how pathways are regulated and linked
eg.
What are the regulatory steps of pathways?
What are the key enzymes and how are they
regulated?
Is the pathway regulated by substrate supply or
subcellular location?
Is there hormonal regulation of the pathway?
Are the products of one pathway used in another?
 how is metabolism integrated between tissues
eg.
How are muscle and liver metabolism linked?
How are liver and brain metabolism linked?
What effect does any given hormone have on
various tissues?
 be able to describe the metabolism of the fed and
fasted state
How are these states regulated by hormones?
What are the features of fuel synthesis and
degradation that characterise each state?
How do tissues co-operate in these states?
How are pathways that carry out opposite sets of
reactions reciprocally regulated?
LOGIC/INTEGRATION/REGULATION