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