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2 Activation of fatty acids and transport to the mitochondrion

Carnitine acyltransferase acyl group transferred to carnitine, after transport across the outer
mitochondrial membrane
Acylcarnitine transported into mito. Matrix in exchange for free carnitine; carnitine then
replaced again with CoA by second acyl transferase
An unusual aspect: energy of thioester bond in acyl-CoA sufficiently well preserved in ester bond
of acyl-carnitine to allow exchange reaction to be reversed inside mito.
o Carboxyl esters dont have this

10.3.3 Reactions in B-oxidation

A- carbon right beside a functional group; B-carbon is the second carbon from the thioester,
where axn is in B-oxidation
The reactions are:
o Acyl-CoA dehydrogenase dehydrogenates the fatty acyl-CoA molecule between the
alpha and the beta carbon atoms
o Enoyl-CoA hydratase hydrates the trans double bond just created; alpha carbon now
once more fully reduced
o Hydroxyacyl-CoA dehydrogenase beta hydroxyl group is converted to a keto group;
NAD+ accepts the hydrogen and the product is beta-ketoacyl-Coa
o Thiolase introduces a new molecule of CoA to cleave the beta-ketoacyl-CoA, which
releases acetyl-CoA and a new, shortened acyl-CoA that enters the next cycle of beta-
Process repeated until fatty acid completely broken down
Acyl chains with even #s of carbons yield acetyl-CoA only
Those with odd numbers of carbons yield one molecule of propionyl-CoA (special pathway to
deal with this CoA type) in the final thiolase step

10.3.4 Shared reaction patterns in beta-oxidation and TCA cycle

* write down table*


10.3.5 The reaction mechanism of thiolase

* draw a mechanism*
Not very many features to rxns seen so far, but there a few familiar features:
o Cysteine thiolate performs nucleophilic attack in active site on carbonyl group in
substrate yields covalent intermediate also occurs with G-3-P dehydrogenase
o Acid-base catalysis breaks a C-C bond next to carbonyl bond; thiolate rxn reversible so
making of a C-C bond adjacent to carbonyl group via acid base catalysis occurs in reverse
rxn seen in citrate synthase rxn
o Creation of one thioester at expense of another occurs in 2nd step of PDH reaction

10.3.6 Utilization of propionate

Draw reaction
Fatty acids with odd #s of carbons yields one propionyl-CoA as final degradation product,
which has an elaborate degradative pathway:
o First, propionyl-CoA carboxylase converts propionyl-CoA
o Methylmalonyl-CoA racemase converts S-methylmalonyl-CoA to its enantiomer R-
o Finally, methylmalonyl-CoA mutase transplants one carboxyl group within molecule
to yield succinyl-CoA, it requires Vitamin B12 in form of adenosylcobalamin as a
When vitamin is lacking methylmalonyl-CoA backs up and is hydrolyzed to free
methylmalonate which may inhibit gluconeogenesis
Succinyl-CoA - a TCA cycle intermediate so it can enter gluconeogenesis so that propionyl-CoA is
an exception to the rule that carbon from fatty acids cannot be used for gluconeogenesis but
not very important in odd numbered fatty acids as they amount to a small fraction of all fatty
10.5.5 Fatty Acids Synthesis (2)

6. Hydroxyacyl dehydratase eliminates water

7. Enolyreductase reduces ensuing double bond; step 6 & 7 yield butyrate

8. Ketoacyl Synthase acquires butyrate, freeing up ACP

9. Malonyl-acetyltransferase acquires next malonyl residue from malonyl-CoA supplied by

acetyl-CoA reductase

Cycle then repeats from here on; KS decarboxylates malonate and forms bext beta- keto
acid, KR reduces it and so on
Cycles executes 7 times overall resulting in formation of palmitate
Thioesterase activity of fatty acid synthase then releases palmitoyl reside as free palmitate

10.5.6 Mitochondrial Export of Acetyl-CoA via Citrate

Since acetyl-CoA formed in mito by PDH it needs to leave and get into cytosol
Expect carnitine carries system to help for this problem
Also, if transport of acyl-CoA went both ways this could facilitate futile cycle of fatty acid
synthesis & degradation
Acetyl-CoA indeed transported by other means:
o Here citrate exported by the tricarboxylate carrier system
o Cleavage by ATP-citrate lyase reverts citrate synthase rxn producing acetyl-CoA
and oxaloacetate
o Oxaloacetate reduced by malate DH and malate exchanged for citrate
This process also transports one NADH equivalent to mito - usually
accomplished by dedicated shuttle systems
10.5.7 Mitochondrial Export of Acetyl-CoA via Acetoacetate
A transport mechanism consists in export of acetoacetate thats generated in mito. By
ketogenesis pathway
Cytosolic acetoacetyl-CoA Synthetase uses ATP to convert acetoacetate back to
acetyl-CoA and then cleaved to two molecules of acetyl-CoA by thiolase
Pathway demonstrated in rat livers and high activity found in adipose tissue
Large amount of NADP in sytosol required fatty acid synth.; which can be supplied by
hexose monophosphate shunt, but shuttles that export NADPH from mito also
10.5.8 Elongation and desaturation of fatty acids
Elongases reside in mito and ER
Chemistry of elongation similar to beta-oxid in mito, similar to fatty acid sunthase in ER
Desaturases occur in ER, introduce double bonds at various positions
Double bonds created approx. 9 carbons away from the w end w-3 fatty acids cannot
be formed and are therefore essential
o Palmitate end product released by fatty acid synthase
o Inside mitochondria, pathway of elongation mostly a reversal of oxidation,
except NADPH used instead of FADH2 in the nal reduction of enoyl-CoA.
o In ER, chemistry resembles fatty acid synthase, except substrate bound to coA
rather than to enzyme itself.
o Desaturases contain iron and cooperate with several other redox-active proteins
in ER membrane;
the hydrogen abstracted from the fatty acid is transferred to molecular
o Since we require -3 and -6 fatty acids as synthetic precursors of membrane
lipids and of prostaglandins, such fatty acids are essential they must be
obtained from the diet.
10.5.9 Cerulenin an antibiotic that irreversibly inhibits fatty acid synthase
A fungal antibiotic binds and irreversibly inactivated fatty acid synthase
Structure resembles beta-ketoacyl intermediated of fatty acid synthesis and indeed cerulenin
binds to KS site of enzyme
Cysteine in this site then reacts with epoxide ring in erulenin and is alkylated
Epoxide derivatives not popular as drug as they are very reactive and toxic presently there is
interest in development of fatty acid synthase inhibitors for treatment of obesity

10.5.10 slows tumor growth in mouse experiments

Most non-cancerous cell rely on fatty acids supplied by liver and fat tissue as they do not
express fatty acid synthase
Fatty acid synthase expression has been observed in cancer cells; cells probably use fatty acids
to supply their synthesis of membrane glycol- and phoshpholipids, which they require for
Inhibiton of fatty acid synthase in tumor cells can drive them into apoptosis