Transcript Document

Regulation of Metabolism
All metabolism is regulated to do
one thing – maintain the brain!
What are we trying to regulate by
altering the flux of fuels through
these pathways?
1.Fuel supplies (blood glucose in particular)
2.Free energy
Why do you think these pathways
are regulated at these points?
1. Big losses of free energy at these steps
2. Branch points in the pathway
What kind of regulation might be
taking place?
1. Regulation of enzymes through
• Allosteric regulation
• Covalent modification (phosphorylation)
If you want to slow glucose
utilization which enzymes are
likely to be highly regulated?
1
2
Free Energy Changes
Rxn# Enzyme
DG°'(kJ/mol)
1
Hexokinase
-16.7
2
Phosphogluco-isomerase
+1.7
3
Phosphofructokinase
-14.2
4
Aldolase
+23.9
5
Triose phos. Isomerase
+7.6
6
G-3-PDH
+12.6
7
Phosphoglycerate kinase
-37.6
8
Phosphoglycerate mutase
+8.8
9
Enolase
+3.4
10
Pyruvate kinase
-62.8
3
4
5
6
7
8
9
10
If you need glucose for the blood, which metabolic pathways are
likely to be activated?
The means for regulating what goes on in the cell requires
communication between different parts of the body.
How will the cell know what to do unless it has information about
other processes taking place?
The main mechanisms for cell-to-cell communication are: the nervous
system, the endocrine system, and local cell communication.
Endocrine regulation of metabolism
Blood glucose is regulated by controlling enzymes that either help use
glucose when energy is needed, or enzymes that help store glucose
when it is in excess. This is typically done via hormonal control.
Hormone =
Types:
• peptide or protein = at least 3 amino acids
• steroid = derived from cholesterol
• amine = derived from single amino acids (tryptophan,
tyrosine)
Peptide Hormones
Synthesis/transport/half-life =
Storage?
Multiple processing patterns for protein hormones
Because peptides are
impermeable, they must use
membrane receptors and
second messenger signal
transduction mechanisms to
produce the desired effects.
Most use g-protein coupled
receptors, but some use
tyrosine kinase type
receptors (i.e. insulin)
Steroid Hormones
Steroid hormone synthesis/storage/half-life
Mechanism of cellular activation?
Amine hormones
Two Alternatives for Glucose Metabolism (and indirectly fat and
protein metabolism):
1. Lots of glucose – indicates need for storage, energy for
anabolic reactions (building proteins, fats, other tissues) is
present. Principal hormone involved – insulin.
2. Low glucose – indicates stress conditions, low energy, anabolic
reactions should wait, alternative fuels should be used to
replace or make glucose. Principal hormones involved –
glucagon, cortisol, epinephrine.
• After a meal blood glucose is high
• Cells in the pancreas sense [glucose] and release the peptide hormone insulin
• Insulin circulates in the blood and attaches to receptors on target cells
• Receptors translate insulin binding into an appropriate cellular response (lower blood
glucose) via a second messenger signaling pathway.
• In the case of insulin, the response is to insert glucose transporter proteins into the cell
membrane so that glucose can enter the cell. Overall, the response helps to stop the initial
signal. In this case, by moving glucose out of the blood, it stops the release of insulin from
the pancreas.
Regulation of Metabolic Enzymes
•When enzymes need to be regulated
(i.e. when we need more energy to
run away from a bear or to store
excess glucose), a signal transduction
cascade is activated by a hormone.
•The hormone that signals storage of
glucose is insulin. The enzymes that
help regulate glucose storage (i.e.
glycogen synthesis) or fat production
(if you are really in excess) are in the
“on” mode when insulin is present.
•The hormones that signal low blood
glucose are glucagon, cortisol, and
epinephrine.
•Most of these hormones (not
cortisol) work on cells via second
messenger signaling cascades called
G-protein linked cAMP cascades.
• Cyclic AMP (cAMP) is made from ATP by the enzyme adenylyl cyclase.
• In the cAMP signal transduction cascade, as long as the signaling hormone is
bound to the receptor, adenylyl cyclase will continue to make cAMP. Generally,
ONE molecule of hormone binding can result in hundreds of cAMP molecules
being produced inside the cell. This is called AMPLIFICATION.
•When the hormone is removed from the receptor, another enzyme,
phosphodiesterase, converts cAMP back to AMP. This turns off the signal
transduction when it isn’t needed.
In the case of glucagon, and
epinephrine, most cells with receptors
respond to hormonal activation by
phosphorylating (activating) target
enzymes. In the case of glucagon, the
enzymes are involved in fat and
protein catabolism, and
gluconeogenesis. Epinephrine
enhances these effects but also targets
key enzymes in glycolysis, producing
a quick burst of energy (to run away
from the bear).
Phosphorylation of target proteins
•Cortisol is a steroid hormone that targets gene
transcription.
•One of its main functions with regard to glucose
metabolism is to cause cells to make more of the
enzymes involved with the catabolism of protein.
•Those break down proteins into amino acids, which
feed in to gluconeogenesis or provide ketones for
alternative fuel source.
Tissues can be targeted by multiple hormones.
How is this possible?
Hormones can act synergistically, permissively, or antagonistically
Synergistic effects of
hormones on blood
glucose concentration