L2 - Overview of metabolic regulation and integration Flashcards
Core concepts in metabolic integration
1 - Multiple regulatory mechanisms can target a single protein
2 - Single pathway can be regulated at multiple steps (often by different mechanisms)
3 - Control of one protein can have secondary actions
Regulation of opposing pathways: how is it managed without wastefully synthesising and degrading substances and what enzymes must be present for this process?
Reciprocal regulation of opposing pathways occurs - when one pathway is increased the other is reduced
Would not be possible if both pathways were catalysed by the same enzymes - at least one step is catalysed by different enzymes in the catabolic and anabolic directions – regulated separately
Opposing catabolic and anabolic pathways may also occur in different subcellular compartments
Pancreas: what is it, what part of it secretes hormones, and what is the pathway of secreted hormones?
Organ that secretes hormones in response to blood glucose levels
Islets of Langerhans (α/β cells)
Hormones released into the hepatic portal vein – first transported to liver and adipose tissue
Brain
Integrates inputs from surroundings and sends signals to other parts of the body
Liver
- Processes fats, carbohydrates, and proteins from the diet
- Synthesises and distributes lipids, ketones, and glucose
- Converts excess nitrogen into urea
Lymphatic system
Carries lipids from intestines to liver
Adipose tissue
- Synthesises, stores, and mobilises triacylglycerols
- Brown adipose tissue carries out thermogenesis
Skeletal muscle
Uses ATP to contract muscles, resulting in movement
Cardiac muscle
Uses ATP to pump blood around the body
Portal vein
Carries nutrients from intestine to liver
Small intestine
Absorbs nutrients from the diet and transports them into either circulatory or lymphatic system
Hormonal regulation of metabolism
Hormones are carried by the bloodstream to nearby cells or more distant tissues/organs - bringing about metabolic changes in target cells
Insulin: what is it, when is it released, and what does it do?
Peptide hormone
Released by pancreatic β-cells in response to high blood glucose levels
- Stimulates glucose transport into cells
- Stimulates synthesis of fat, glycogen and protein
- Inhibits the breakdown of fat, glycogen and protein
- Essentially causes a coordinated change in metabolism
Glucagon: what is it, when is it released, what does it target, and what does it do?
Peptide hormone
Released by pancreatic α-cells in response to low blood glucose
Liver, primarily
- Inhibits synthesis of fat, glycogen and protein
- Stimulates breakdown of fat, glycogen and protein
- Promotes mobilisation of fuel storage
Epinephrine: what is it, when is it released, what does it target, and what does it do?
Tyrosine-derived peptide hormone (?)
Released by adrenal medulla in response to ‘stress’ (fear, pain, starvation)
Target tissues: muscle, adipose tissue, liver
- Inhibits synthesis of fat, glycogen and protein
- Stimulates breakdown of fat, glycogen and protein
Glucose signalling: how it causes insulin production
- Glucose enters pancreatic beta-cells through the glucose transporter - GLUT2
- Glucose then gets broken down via glycolysis and the citric acid cycle to produce ATP
- ATP binds to ATP-gated K⁺ channels, inhibiting them and causing depolarisation
- Depolarisation causes opening of voltage-gated Ca²⁺ channels, resulting in a Ca²⁺ influx
- Ca²⁺ interacts with insulin granules at the endoplasmic reticulum and causes fusion of vesicles with the plasma membrane, resulting in the secretion of insulin
Glucagon signalling: how it enters cells
- Binds to receptor (GPCR)
- Gs causes adenyl cyclase to be produced
- ATP is converted to cyclic AMP by adenyl cyclase
- cAMP activates protein kinase A
Epinephrine signalling: how it enters cells
- Binds to receptor (GPCR)
- Gs causes adenyl cyclase to be produced
- ATP is converted to cyclic AMP by adenyl cyclase
- cAMP activates protein kinase A
Typical intracellular messengers
cAMP, Ca²⁺, IP₃, etc
Insulin: how does it send signals to cells and what is the process for it?
Using tyrosine kinase receptor
- Insulin receptor binds insulin and autophosphorylates on its C-terminus tyrosine residues
- Insulin receptor’s tyrosine residues are used to phosphorylate insulin receptor substrates (IRS-1)
IRS-1 can then activate PKB/Akt or MAPK to undergo activating various processes
PKB/Akt: what is it, what is it activated by, and what does it do?
Protein kinase B
Insulin/IRS-1
- Phosphorylation of metabolic enzymes (to increase/decrease activity)
- Transcription factors (control of gene expression)
- Activate other regulatory proteins (e.g. phosphatases, translation factors, glucose transporter trafficking)
MAPK: what is it, what is it activated by, and what does it act upon?
Mitogen-activated protein kinase
Insulin/IRS-1
Transcription factors
cAMP: what is it and what does it do?
Cyclic adenosine monophosphate
- Affects gene expression
- Activates cAMP response element binding protein (CREBP)
PKA: what is it and what does it do?
Protein kinase A
- Stimulates gluconeogenesis - Activates FBPase-2, Inhibits pyruvate kinase, and Activates PEP CK
- Stimulates glycogen breakdown - activates glycogen phosphorylase
- Inhibits glycogen synthesis - inhibits glycogen synthase
- Stimulates triacylglycerol (TAG) synthesis - activates HSL, ATGL, and perilipin
- Stimulates FA-oxidation/inhibits FA synthesis - inhibits ACC
ATP/AMP as allosteric effectors: what are the typical cellular concentrations of them and why is there a massive difference in potency between them?
ATP ~ 5mM
AMP ~ 0.1mM
A 10% decrease in [ATP] can greatly affect the activity of ATP utilizing enzymes but results in a 600% increase in [AMP] - AMP can be a more potent allosteric effector
(10% of 5mM is 0.5mM, 0.1->0.6mM is a 600% increase )
AMPK: what is it, what is it activated by, and what does it do?
AMP-dependent protein kinase
- Increased cellular [AMP]
- Reduced nutrient supply
- Increased exercise
- Sympathetic nervous system
- Leptin, adiponectin, etc
Acts as an ‘energy sensor’, has varying functions in different tissues but the effects lead to the same, main function:
Coordinated change to shift metabolism away from energy processes and increases energy generation by using catabolic pathways
MAPK in the heart
Stimulates:
* Fatty acid oxidation
* Glucose uptake
* Glycolysis
MAPK in the brain
Stimulates:
* The desire to eat (hunger)
MAPK in the liver
Inhibits:
* Fatty acid synthesis
* Cholesterol synthesis
* Glycogen synthesis
MAPK in the pancreas
Inhibits:
* beta-cell insulin secretion
MAPK in skeletal muscle
Stimulates:
* Fatty acid uptake/oxidation
* Glucose uptake
* Mitochondrial biogenesis
MAPK in adipose muscle
Inhibits:
* Fatty acid synthesis
* Lipolysis
Glucokinase: what methods of regulation affect it?
- mRNA stability
- Degradation
- Allostery
- Compartmentalisation
- Transcription
What are the advantages of using multiple mechanisms for regulation?
- Failsafe mechanism
- Different signals, different mechanisms - can be regulated by various different things
- Allows different speeds of regulation (transcription, long - phosphorylation, quick)
- Allows degree of regulation?
