Download PG1005 Lecture 11 Glycolysis

PG1005
Lecture 11
Glycolysis
Dr. Neil Docherty
My Teaching Objectives
•  To discuss why when the topic of cellular energy production
is introduced, we use glucose as the fuel of choice for the
generation of ATP.
•  To revise the general mechanisms of glucose uptake.
•  To describe the enzymatic reactions occurring at each step
of glycolysis.
(substrates, enzymes, products, reaction types)
•  To highlight the existence of checkpoints in glycolysis which
permit physiological supervision of flux through the process
Why is ATP The Cellular Energy Source?
•  Many cell processes are not energetically favourable and
are thus require energy input to drive endergonic reaction
The heat energy (free enthalpy)
released from ATP can be
harnessed to give the activation
energy required to drive reactions
This can be the net effect of
heat transfer on protein structure
and/or the effect of the transfer
of the liberated phosphate to
a target protein (kinase activity)
Synthesis requires energy input
Glucose-Origin as a Fuel Source
Dietary Complex Carbohydrate
(starch,glycogen)
Sucrose
Lactose
Salivary and
pancreatic amylase
sucrase
lactase
Disaccharide Trisaccharide Limit dextrin
(maltose)
(maltostriose)
maltase
GLUCOSE
α-glucosidase
α-dextrinase
GLUCOSE
GLUCOSE
GLUCOSE
GALACTOSE
FRUCTOSE
Why Consider Glucose Utilisation?
•  Product of prebiotic chemistry?
•  Due to persistence in ring structure relative to other
carbohydrate, does not modify protein structure
(carbonyl-amino group Schiff base)?
•  The chemical structure is such that its successive
oxidation yields high energy electrons that can be
harnessed to drive ATP synthesis in an energy
efficient manner
Generic Glucose Uptake
•  Distinct from energy dependent sodium glucose
transporters which work against gradient (e.g
small intestine)
•  5 classes (GLUT1-5)
•  12 transmembrane helix structure
•  GLUT 1 and 3 are principal basal entry
pathways
•  Operate by “flipping” glucose across membrane
•  As glucose is consumed intracellularly,
favourable gradient means energy
independence
Glycolysis-Definition
•  A sequence of 10 reactions based on using glucose
as a substrate to generate two molecules of
pyruvate.
•  Anaerobic
•  For each molecule of glucose a net production of 2
ATP occurs.
Lactic acid fermentation
Oxidative phosphorylation
Gluconeogenesis
Adapted from Figure 2-10 Human Physiology Cells to Systems (7th Ed.) Sherwood L. p245
Glycolysis: Stage 1
•  Aim-To trap glucose inside the cell
-In a form readily cleavable to yield two 3-carbon,
phosphorylated intermediates
Modified from http://img.sparknotes.com/figures/
1.1 Hexokinase
-phosphoryl transfer
1.2 Phosphoglucose Isomerase
-isomerisation
6 to 5 membered ring
(Necessary for generation of
3C downstream intermediates)
1.3 Phosphofructokinase
-phosphoryl transfer
Glycolysis: Stage 2
•  Aim-Generation of 3-carbon GAP intermediate
Aldolase
-aldol cleavage
Triosphosphate isomerase
-isomerisation
Entry of
Fructose
As F-1-P
GAP metabolism
drives left to
right reaction
Glycolysis: Stage 3.1
•  Aim-Generation of energy rich 3 carbon phosphate donor used
to drive substrate level generation of ATP
Glyceraldehyde
Phosphate dehydrogenase
(GAPDH)
-oxidation/phosphorylation
oxidation
reduction
Nicotinamide adenine dinucleotide
(B vitamin niacin derivative)
Glycolysis: Stage 3.1 Ctd.
•  Aim-Substrate level generation of ATP
Phosphoglycerate kinase (PGK)
-phosphoryl transfer
N.B.
x2 per molecule
of glucose
Glycolysis: Stage 3.2
Aim. Generation of Pyruvate For Oxidative Phosphorylation
Phosphoglycerate
mutase
-phosphoryl shift
Enolase
-dehydration
Strong phosphate
donor
Pyruvate kinase
-phosphoryl transfer
x2
Stable
Net Glycolytic Reaction
Glucose + 2Pi +2ADP +2NAD+
2 Pyruvate + 2ATP + 2NADH +2H+ + 2H2O
Check Points in Glycolysis
In metabolism, enzymes catalysing irreversible
reactions can become control points
1) PFK-allosterically inhibited by high ATP
2) Backward inhibition of hexokinase
(negative feedback via glucose-6-phosphate)
3) Pyruvate kinase-Allosterically inhibited by ATP
-Activated by F1,6BP
http://faculty.ksu.edu.sa/70917/Pictures%20Library/glycolysis%20pathway.gif
Gluconeogenesis
During fasting and in certain cell types (liver,kidney)
Process aimed at normalising plasma glucose
Essentially synthesis of glucose from non-carbohydrate precursor
GLUCOSE
Glycerol kinase
TAG-Glycerol
DIHYDROXYACETONE
Glycerol phosphate
dehydrogenase
OXALOACETATE
Protein-Amino acid
Lactate
Anaerobic muscle-Lactate
PYRUVATE
dehydrogenase
Combination of
reversible steps of
glycolysis and new
bypass steps
Your Learning From Today
Should focus on being able to;
•  Explain why glucose acts as a fuel of choice for the
generation of ATP.
•  Detail how dietary carbohydrate is digested and the general
mechanisms of glucose uptake in the gut and beyond.
•  List and explain the sequence of enzymatic reactions
occurring at each step of glycolysis.
(substrates, enzymes, products, reaction types)
•  Demonstrate an understanding of the principle of allosteric
control of enzyme activity in glycolysis