Introduction to MetabolismLecture 2

A/Prof Gareth Denyer

gareth@usyd.edu.au

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

Proteins, DNA, fats, polysaccharides

Amino acids, sugars, nucleotides, fatty acids

BUILDING BLOCKS

SIMPLE INORGANICS

Water, carbon dioxide, ammonia

AN

AB

OLI

CC

AT

AB

OLIC

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

• 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’

PPP

Adenine base

ribose

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

CH3CH2 CH2CH2CH2CH2 CH2COOH

Fatty acids – long hydrocarbon chain with carboxylic acid group on the end

Carbons in the fatty acid are generally -(CH2 )n-

Contains a lot of hydrogens!

Most of the fatty acids that we experience are even numbered with 2-26 carbon atoms

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

blood

cytoplasm

Fatty acids

Simple diffusion*

Need to be trapped to stop them getting back out

Fatty acyl-CoA

Coenzyme AA large charged molecule

Trapping involves a small investment of energy (use of ATP)

carnitine

Fatty acyl-CoA

Fatty acyl-carnitine

FA-carnitine

CoA

matrix

mitochondria

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

Beta-oxidation!!

carnitine

Note – there is an intra-mitochondrial pool of CoA