Transcript L02_IntroMetab

Introduction to Metabolism
Lecture 2
A/Prof Gareth Denyer
[email protected]
Metabolism
• The chemical reactions of life
– The reactions which happen inside our cells
• Divided into:
– Anabolism
• the reactions that build things up
– Catabolism
• the reactions that break things down
MACROMOLECULES
BUILDING BLOCKS
Amino acids, sugars, nucleotides, fatty
acids
SIMPLE INORGANICS
Water, carbon dioxide, ammonia
CATABOLIC
ANABOLIC
Proteins, DNA, fats, polysaccharides
Linking Anabolism and Catabolism
• Anabolic reactions require an input of
energy
• Energy is produced by the breakdown of
building blocks
– The catabolic reactions!
• The linkage is ATP
• “The Energy Currency of Life”
Adenosine Triphosphate
PPP
ribose
Adenine base
• A tri-phosphonucleotide
• Energy released when terminal
phosphates are hydrolysed
• ATP  ADP releases energy
• Energy released as heat…
UNLESS we can trap it do do
something useful
– Like anabolic reactions!
– But also ANYTHING that requires
the input of ‘energy’
ATP facts I
• The “Energy Intermediary” of our cells
– Made by catabolic reactions (but not macromolecular
conversion to building blocks)
– Used by anabolic reactions (and any ‘work’)
• We don’t store much of it
– Cell [ATP] is about 5 mM (well, 4.8 mM )
• Cellular [ATP] must not dip below 3 mM
– Or the cell will die..
– ATP is continually being used for lots of essential
‘housekeeping’ roles (eg, maintaining ion gradients)
• In context: 5 mM = 5 umol/g tissue
– and exercising muscle can use ATP at 3 umol/s/g
– So there’s only 1-2 seconds ‘store’ in muscle
ATP facts II
• TURNOVER is massive in comparison to store size
– Total amount of ATP in whole body is about 50 grams
– Total production and destruction of ATP is about 65 kg/day
(about 1g/kg body weight/day)
• We don’t have a ‘store’ of ATP
– We can only store it ‘indirectly’ as fuels like fat and
carbohydrate
– Can’t ‘make’ ATP and store it somewhere for later
• ATP levels are pretty tight balancing act! Wallet analogy!
– Imagine trying to ‘balance’ a wallet that was only allowed to
contain $30-50 at any given time
– But with a throughput of money of $65,000 per day!
– Imagine how tightly you’d have to regulate the flow in/out of
the wallet
• The rate of ATP generation must be ABSOLUTELY
matched to the rate of ATP consumption
ATP facts III
• ATP is quite stable
– Will not spontaneously hydrolyse
• Hydrolysis is under enzyme control
– Makes sense for an energy currency to be under
some sort of control
– Don’t want something explosive!
• ATP is not THE most energy-containing
molecule in metabolism
– Something has to MAKE it, of course!
– ATP is intermediate in energy content – perfect for its
role as ‘mediator’ between the arms of anabolism
and catabolism
Strategies for making ATP
• Fuel molecules are the ‘building blocks’
– Fatty acids and sugars
• Will be broken down by catabolic
reactions
– To water and carbon dioxide
– These are OXIDATION reactions
Fuel Molecules
Fatty acids – long hydrocarbon chain with carboxylic acid group on the end
CH3CH2 CH2CH2CH2CH2
CH2COOH
Most of the fatty acids that we experience are even numbered
with 2-26 carbon atoms
Carbons in the fatty acid are generally -(CH2 )nContains a lot of hydrogens!
Carbohydrates – also contain lots of hydrogens
But this time, each carbon atom is -(CHOH )- ‘hydrated carbon’!
And one carbon has an aldehyde/ketone group
Biochemists Redox!
• Oxidation
– Addition of oxygens
– Removal of hydrogens
– Removal of electrons
• Reduction
– Addition of hydrogens
– Addition of electrons
– Removal of oxygens
• Under those definitions
– Carbon dioxide is the most oxidised form of carbon
– Conversion of –CH2- or –CHOH- to CO2 is OXIDATION
Fuel Oxidation
• Oxidising fuels releases energy
– But the trick is to TRAP the energy as
chemical energy as ATP
– And the ATP can later be used to do
something useful
• Compare with the lack of trapping when
fuels just burn on a fire
– All the energy is lost as heat and light
Oxidation of Fatty Acids
Fatty acids
Coenzyme A
Simple
diffusion*
Fatty acylCoA
Fatty acids
blood
cytoplasm
A large
charged
molecule
Need to be
trapped to
stop them
getting back
out
Trapping involves a
small investment of
energy (use of ATP)
mitochondria
carnitine
CoA
Swapping the CoA for
carnitine allows the FA
to get into the
mitochondrial matrix
Inside the matrix, the CoA is put back onto the FA, thus
trapping the FA in the matrix and releasing the carnitine
which can go back into the cytoplasm
Note – there is an intra-mitochondrial pool of CoA
carnitine
Fatty acylcarnitine
FAcarnitine
matrix
Fatty acyl-CoA
Betaoxidation!!