SUBJECT: BIOCHEMISTRY

TOPIC: LIPID METABOLISM 1 (Chapter 22:

Oxidation of Fatty Acids: Ketogenesis & Chapter 23:
Biosynthesis of Fatty acids and Eicosanoids )

LECTURER: Dr. LAYGO

DATE: 11/23/2010

There is a relationship between intake of carbohydrates  If the cells need energy, pyruvate will be brought
and lipid synthesis. Predominating hormone during inside the mitochondrial matrix and be oxidatively
sembreak (eat, sleep, rest) is insulin. decarboxylated to form Acetyl CoA.

Glucose derived from carbohydrates undergoes glycolysis  β- oxidation

and is stimulated in the presence of insulin. There are o Process whereby cells try to degrade fatty
acids
enzymes that are induced* with the presence of insulin.
o Beta because beta carbon (or carbon
Insulin also stimulates fatty acid synthesis. That is the time number 3) is the one involved
when our cells have the luxury of synthesizing fatty acids  Beta carbon is transformed into a
and there by storing them as triacylglycerol. Triacylglycerol carbonyl carbon (carbon attached
is a molecule with glycerol backbones, and in the carbons to oxygen with a double bond)
of this glycerol are esterified fatty acids.  First 3 steps utilized by
the cells in order to
liberate 2 carbon
moieties from fatty acids
 For cells to degrade fatty
acids, 2 carbons should
be removed at a time
 General Types of pathways:
o Linear pathway
 Glycolysis
 Glucose  Pyruvate (or
lactate in a different case)
o Cyclic pathway
 Kreb’s cycle
 Every turn gives rise to
OAA
* Induced/ induction involves 2 processes: transcription and translation. o Spiral pathway
Wherein in enzymes that are critical for stimulation of glycolysis will be  Fatty acid synthesis
synthesized in more amounts such as Fructose 1,6-Bisphosphate and
 β- oxidation of fatty acid
Pyruvate kinase.

** Fatty acid #1 is usually palmitate, Fatty acid #2 is usually oleate, Fatty

acid #3 is oleate or a polyunsaturated fatty acyl group. Every time a cell removes 2 carbon at a time, the cell
utilizes 4 reactions.

 Synthesis of fatty acids is the exact opposite of

I. FATTY ACID SYNTHESIS: how the cells break them down.

 Needs activated intermediates that are bound to a
particular molecule, example of the molecule of
which activate intermediates are bound is:
o ACP – Acyl Carrier Protein
 Needs a source of electrons and protons
o NADPH + H coming from hexose
monophosphate (alternative carbohydrate
metabolic pathway) pathway and can also
come from citrate shuttle system (aka
Acetyl-CoA shuttle system)
 Found in the cytoplasm, enzymes that will carry the
different steps are coming from the cytosol.
 To carry on the elongation of carbons to make up
the fatty acid, specifically the palmitic acid, we
need an enzyme complex known as Fatty Acid
Synthase Enzyme Complex.
 After intake a lot of carbohydrates, this will go
through glycolysis producing the pyruvate.
Franz Knoop elucidated the different steps initially making
up the β- oxidation or the breakdown of fatty acids. And
since the breakdown of fatty acids is in spiral pathway, he
hypothesized that synthesis of these is exactly in the
opposite way. And later on he was proven right.
Requirements of Fatty Acid Synthesis:
 Acetyl CoA
o Carbohydrates in the form of glucose after
being transformed to pyruvate enters the
mitochondrial matrix to be oxidatively
decarboxylated to form Acetyl CoA
o The one initially utilized to synthesize fatty
acids
o Acted upon by an enzyme called Acetyl
CoA Carboxylase or ACC enzyme
 Catalyzes the carboxylation
reaction producing Malonyl CoA

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  Catalyzes the rate limiting step for
synthesis fatty acids
 Single, multifunctional enzyme
 Requires a biotin group which is
attached to a lysine residue of a
protein molecule
 Contains an allosteric regulatory
site
 Citrate – most important
regulatory factor
 Catalyzes the rate-limiting step for
fatty acid synthesis which forms
malonyl CoA
 Long chain fatty acyl CoAse
 Inhibits Acetyl CoA
Carboxylase
o Initial building block
o 2-carbon moiety
o 16th and 15th carbon of palmitic acid
(most common fatty acid synthesized by
the cell) came from Acetyl CoA and the
rest came from malonyl CoA
 CO2 in the form of bicarbonate
o Source of carbon
 ATP
o Source of energy to form a covalent bond
 Biotin from biocytin
o Being a carboxylation reaction wherein the
the source of carbon is CO2, it is the
coenzyme needed by Acetyl CoA
Carboxylase
 Malonyl CoA
o Utilized by the cell to lengthen the carbons
from Acetyl CoA
o As a result of carboxylation reaction, it is
3-carbon moiety
o It is the source of the 2 carbons used to
elongate Acetyl CoA
o In utilizing a 3-carbon moiety, remember
that the cells only need 2 carbons, so the
other one is liberated as CO2
Question: If the cells will be synthesizing a 16-carbon fatty
acid, how many spirals or cycles will the cells need in order
to form palmitic acid (most common fatty acid synthesized
by the cell)?
Structure of Palmitic acid
 Remember:
o Starting material is a 2-carbon moiety,
Acetyl CoA
 16th and 15th carbon of Palmitic
acid came from the initial Acetyl
CoA
 The rest came from Malonyl CoA
o Acetyl CoA Carboxylase (ACC) is only
initially needed to synthesize Malonyl CoA
 After the cells have acted upon
the initial Acetyl CoA by means of
Acetyl CoA Carboxylase, forming
Malonyl CoA. Then the fatty acid
synthase enzyme complex will
now take over the process of
elongation.
o Fatty acid synthesis is a spiral pathway.
o We start of Acetyl CoA and we elongate
that by utilizing 4 different reactions
utilized by the cell every cycle (every time
a cell adds 2 Carbon Moiety to Acetyl CoA):
 Condensation
 1st Reduction
 Dehydration
 2nd Reduction
 Answer:
o 7 cycles or spirals needed
 We have an original 2 carbon
moiety from Acetyl CoA and cells
try to elongate this by adding 2
carbons at a time (1 spiral/cycle).
So initially 2 carbon moiety plus 2
carbons added per cycle (7 cycles)
is equal to 16 carbons which is
the number of carbon of palmitic
acid. 2 + (2 x 7) = 16
Question: How many NADPH + H will the cells need to be
able to synthesize a 16-carbon saturated fatty acid?
 Answer: If the cell utilizes 7 cycles, and each of this
cycle involves 2 reduction reactions, it needs 14
NADPH + H because each reduction reaction
needs one NADPH + H.
 For every cycle, we need 2 NADPH+H because we
have 2 reduction reactions
Malonyl CoA
 Has 3 carbons
 Source of 2 carbons used to elongate Acetyl CoA
o We only need 2 carbons, and 1 carbon
should be eliminated in the form of
Carbon Dioxide.
 Is taken over by fatty acid synthase enzyme
complex, thereby elongating acetyl CoA to
eventually form palmitic acid.
 Signal for the cell to synthesize fatty acids
o It’s a negative allosteric effector for fatty
acid oxidation
 Cells are endowed with a lot of
energy and therefore can
synthesize a lot of fatty acids
Fatty acid Synthase complex
 A dimer
o Arranged in a head-to-tail manner
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  A large molecule 3-OHACYL dehydrase Alpha beta trans- Dehydration
 Multiple domain butenoyl ACP

Enoyl Reductase Butyryl ACP 2nd Reduction

STOICHIOMETRY OF PALMITATE SYNTHESIS:

8ACETYLCoA +7ATP + 14NADPH 

PALMITATE + 14NADP++ 8CoASH +6H2O +
7ADP + 7Pi

We need 8 Acetyl CoA molecules, and then from it, we

synthesize 7 Malonyl CoA), 7 ATP, 14 NADPH+H forming
palmitate, releasing 14 oxidized form of NADP, CoA, water,
and 7 ADP and 7 inogrganic phosphates.

It being a dimmer, they are arranged into a head to tail

manner. These subunits carry on the different 4 reactions
that are utilized by the cell every cycle of the pathway.
 Transacylation reaction
 Initial reaction that attaches and activates
intermediates for fatty acid synthesis to ACP
(Acyl Carrier Protein).
 Acetyl transacylase
o Enzyme that catalyzes the binding of
acetyl CoA to the ACP
 Malonyl transacylase
o Enzyme that catalyzes the binding of
malonyl CoA to the ACP
 Coenzyme A
o Counterpart of Fatty Acid Synthase in
Beta-oxidation
CITRATE
 During starvation (glucagon and epinephrine are
predominating hormones), if the cells need more
energy, Acetyl CoA will be shuttled to kreb’s cycle,
and will be condensed with OAA, catalyzed by
citrate synthase to form citrate.
 If the cells are endowed with a lot of energy after a
lot of carbohydrate intake, we will be bombarding
the citric acid cycle with a lot of citrate which
cannot be accommodated by the next step
(aconitase and isocitrate dehydrogenase step), so
excess of citrate will go out into the cytoplasm
(Citrate Shuttle System)
CITRATE SHUTTLE SYSTEM/ACETYL CoA SHUTTLE SYSTEM:

2 reductions and therefore require NADPH+

Needs 7 cycles, 7 malonyl therefore, 14 NADPH+H Inner mitochondrial membrane is highly selective. It would
not allow just the entry and exit of molecules. In the
Enzymes that catalyzes the 4 different reactions: cytoplasm, there will be occurrence of glycolysis to form a
lot of pyruvate. Pyruvate goes into the matrix through
Enzyme Product Reaction pyruvate translocase situated in the inner membrane.
catalyzed Pyruvate in the mitochondrial matrix will then be oxidatively
decarboxylated by pyruvate dehydrogenase (enzyme
3-Ketoacyl ACP Acetoacetyl ACP Condensation
synthase
complex) to become acetyl CoA. Acetyl CoA will condense
with oxaloacetate to form citrate with the help of citrate
3-Ketoacyl ACP 3-OH Butyryl ACP 1st Reduction synthase. If there is a lot of energy, excess of citrate will go
reductase out of the cytoplasm and will be converted back to acetyl-

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coA and oxaloacetate with the help of ATP dependent
citrate lyase enzyme. Acetyl CoA will be acted upon by
Acetyl CoA carboxylase to form malonyl-CoA and thereby
will be taken over by fatty acid synthase to form fatty acids
(such as palmitate). Oxaloacetate will be subsequently
reduced by malate dehydrogenase cytosolic with the help
of NADH to form malate. Malate can either go again inside
the mitochondrial matrix or it can be oxidatively
decarboxylated by malate enzyme (or NADP-dependent
malate dehydrogenase enzyme) with the help of NADP,
which after oxidizing malate back to pyruvate, the cells
generate NADPH+H (much needed reducing equivalent
needed for fatty acid synthesis).
Therefore, if we will try to count the number of citrate
molecules that goes out into the cytoplasm, creating acetyl
CoA molecules that the cells utilize for fatty acid synthesis,
How many of this will be generated, that will contribute to
the 14 NADPH+H to complete the synthesis of palmitic
acid ?
 NADPH+H = 14
 Acetyl CoA needed by the cell to synthesize
palmitic acid = 8
 Citrate = 8 (because from 8 citrates, 8 acetyl CoA
will be formed by citrate lyase enzyme)
 OAA= 8 converted to pyruvate  (8 NADPH+H is
generated)
***14 NADPH+H – 8 NADPH+H = remaining 6 NADPH+H
(which can be provided by HMP or Hexose Monophosphate
Pathway)
As long as we have citrate in the cytoplasm, Acetyl CoA
Carboxylase is stimulated.
Inactive form Acetyl CoA carboxylase is in the form of
monomers. If there are 40 monomers, they try to aggregate
to form the active form (protein-protein interaction).
There is insulin predominance during FA synthesis. The
confirmation of Acetyl CoA carboxylase is in the
dephosphorylated form (activated form). Insulin and
glucagon are peptide hormones, so they cannot just
traverse the plasma membrane due to the nature of the
structures. For them to be able to transmit their message
inside the cell, they must possess their receptors
expressed on the membrane. Epinephrine (amine hormone)
is derived from tyrosine. The receptor in the plasma
membrane, epinephrine and glucagon have to bind to the
receptor, forming a hormone-receptor complex to activate
the G-protein. Activated G-protein then activates AC
(Adenylyl cyclase), that tries to cyclycize ATP to form the 2nd
messenger, which is cAMP (Cyclic AMP). cAMP activates
the inactive protein kinase A. If there is an activated
protein kinase A, proteins and enzymes will receive
phosphate groups. Therefore, these enzymes and proteins
are inactivated due to their phosphorylation.
There is a predominance of epinephrine and glucagon
during starvation. Insulin is exerting the opposite effect of
glucagon. Insulin is also a peptide hormone, which has a
receptor on the membrane. The receptor of insulin is called
receptor tyrosine kinase. So from this moment, when it
binds, after forming a hormone-receptor complex, one of
the actions is to stimulate an enzyme called
phosphodiestarase (3’,5’-cyclic AMP phosphodiesterase) to
transform cAMP to 5’-AMP. Therefore, protein kinase is not
activated… Enzymes will be in the dephosphorylated form.
Activated form of Acetyl CoA carboxylase is in
dephosphorylated form, therefore can do its job to
transform Acetyl CoA into Malonyl CoA. But with the
predominance of glucagon and epinephrine, Acetyl CoA is
inhibited.
Remember: Enzymes catalyze a specific reactions and
therefore specific names:
Protein kinase A  activation is dependent on cAMP.
Protein kinase G  activation is dependent cGMP (a second messenger
that activates protein kinase G)
Protein kinase C  activation is dependent on calcium ions (C2+)
Covalent modification:
 Attachment of phosphate group to enzymes and
proteins
 One way of which the cells try to stimulate/ inhibit
2 opposing pathways
o Ex: Glycogenolysis & Glycogenesis
(Carbohydrate metabolism)
 By attaching a phosphate through glucagon
 Glucagon and epinephrine  1st messengers (they
can transmit messages inside the cells through
cAMP dependent protein kinase A cascade).
Through covalent modifications whereby activity of
most enzymes are activated, while some are
inhibited.
o So.. Depende sa enzymes.. Merong ibang
enzymes na pag naka-tanggap ng
phosphate group, ma-aactivate, meron
naman iba na ma-iinhibit.
 Sa ACC, gumagana lang siya
kapag dephosphorylated sila. So
dapat walang phosphate group.
o Our cells do not have the luxury to
synthesize molecules when there’s a need
for energy. When there is a need for
energy, cells mostly induce catabolism to
release a lot of electrons and protons to
be harnessed in ETC. After being carried
by coenzymes such as FAD and NADH+H.
If we transfer electrons and protons
through NADH+H, it will create a PO ratio
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 of 3:1 (3 moles of ATP per 1 mole of NADH
+ H) and ½ of oxygen molecule (O2) or 1
oxygen atom will be used as electron
acceptor to form metabolic H2O. If FADH2
(2:1), 2 moles of ATP as against 1 atom of
oxygen that serves as the final electron
acceptor to form metabolic water.
 The opposite is brought about by the
predominance of insulin  removal of phosphate
group
o Wherein it stimulates phosphodiesterase
not adenylyl cyclase
o Insulin also stimulates phosphatase
 Phosphatase removes phosphate
group.
and series 3 leukotrienes). Furthermore, through a
desaturase delta 5, there will be an introduction of double
bonds in between carbons 5 and 6 to form arachidonic acid
(precursor of series 2 prostaglandins and series 4
leukotrienes). This can also be elongated after elongation
desaturation to form another precursor for eicosanoid
synthesis called tinodonic acid or eicosapentaenoic acid
(precursor of series 3 prostaglandins or series 5
leukotrienes)
dihomo-gamma-linolenic acid 

Therefore, this will now effect attachment of a phosphate,

enzymes in the cytoplasm when interact with protein kinase
A, are activated while some are inhibited.

Introduce a double bond, and elongate the FA to form a

C18, C20, C22 FA.

For introduction of double bond in a saturated fatty acid, we

need a source of electrons and protons coming form
NADH+H with the help of cytochrome B5 reductase, in the Concept of elongation:
participation of FAD. NADH+H transfers electrons to FAD
become reduced to FADH2, that again will be oxidized. Introducing a double bond (action of desaturase) and
FADH2 will transfer electrons and protons to the ferric form adding a carbon atom (elongase) alternately. So initially
(Fe3+) that will be reduced to ferrous (Fe2+) forming a desaturation, elongation, desaturation, and so on.
double bond, with water molecule removal. After
introduction of double bond, elongation process is started.
SHORT TERM REGULATION OF FATTY ACID SYNTHESIS with
Example:
the predominance of INSULIN.
LINOLEIC ACID: 18 carbon with 2 double bonds situated in
carbon 9 and 10, and carbons 12 and 13. Initially, there
will be an introduction of another double bond between
carbons 6 and 7.

Remember: Polyunsaturated fatty acids have 2 or more double bonds, but

after desaturase activity, it will become 3, 6, 9, 12.

Then there will be an elongation process wherein there is

addition of 2 carbon moiety through elongase enzyme to
form a 20-carbon  dihomo-gamma-linolenic acid or
eicosatrienoic acid (precursor of series 1 prostaglandins

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 TRANSPORT OF FATTY ACIDS IN THE BLOODSTREAM:

1. PLASMA ALBUMIN

a. Major carrier of free fatty acids in blood

b. Binds ~6 molecules of fatty acids per 1

molecule of albumin

c. Also binds and transports bilirubin, other

organic anions, and a variety of xenobiotic
compounds (aspirin, barbiturates,
Coumadin, oral hypoglycaemic agents)

2. LIPOPROTEINS
In β- oxidation, Malonyl CoA inhibits carnitine acyl
transferase 1 (enzyme needed for beta oxidation) a. Carriers of esterified fatty acids, primarily
as triaglycerols
Insulin

 Induces glycolysis, therefore forms a lot of pyruvate,

a lot of Acetyl CoA, a lot of citrate which cannot be
accommodated by kreb’s cycle and goes out to the
cytoplasm and is cleaved into acetyl CoA and OAA.
Acetyl CoA will be acted upon by acetyl CoA
carboxylase. More citrate will further stimulate
allosterically your acetyl CoA carboxylase activity,
thereby forming palmitate. When it is activated,
and bound to molecule, forms palmitoyl CoA. From
malonyl to palmitate, we will see the action of fatty
acid synthase complex (FAS).

MOBILIZATION OF STORED TRIAGLYCEROL

Lipoproteins, specifically chylomicrons which carry dietary

triacylglycerol, while VLDL carries the endogenously
synthesized triacylglycerol into the circulation.

TRANSLOCATION OF FATTY ACIDS INTO MITOCHONDRION

Epinephrine, glucagon  deactive Protein Kinase A will be

formed and acetyl CoA carboxylase will be phosphorylated
then transforming it into its inactive form. In times of
starvation, we need a lot of energy, and there must be
mobilization of stored triacylglycerol. In the presence of
glucagon and epinephrine, through cAMP dependent
protein kinase cascade, there will be phosphorylation of
hormone-sensitive lipase (sensitive to glucagon and
epinephrine). So now, these hormone sensitive lipase being
Lingual lipase  initial digestion of lipids in the mouth
phosphorylated, thereby activated, will now try to hydrolyze
triacylglycerol into fatty acids and eventually into glycerol Chyme goes down into duodenum and stimulates the
backbone. Fatty acids will be carried into circulation. And in secretion of pancreatic juice. Chyme contains
the circulation, will be carried by albumin protein. 6 lipids/triacyglycerol, proteins, carbohydrates so there is a
molecules of fatty acids in 1 albumin, going back to the variety of enzymes that permits digestion. In this lecture,
liver and is subjected to Beta-oxidation.
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we will focus on the enzyme, PANCREATIC LIPASE since it is ii. Hydrolysis of
the one responsible for lipid digestion. pyrophosphate to 2
inorganic phosphates
Pancreatic lipase acts on dietary triacylglycerols which ensures the
permits the release 2 free fatty acids and a 2- completion of the
reaction.
monoacylglycerol (there is still a fatty acid esterified at 2nd
Acyl CoA Synthetase
carbon of glycerol backbone). Pancreatic lipase is stabilized
by colipase. Before the action of pancreatic lipase, there is  Also known as thiokinase
an initial step in which the cells have a way to decerase the  Catalyzes the activation of acyl groups, forming
lipid-water interphase so that the hydrophilic enzymes can acyl CoA
interact with hydrophobic triacyglycerols (lipid droplets),  Ex: Palmitic acid + Coenzyme A  Palmitoyl CoA
which we call emulsification. After that, pancreatic lipase o Can now be allowed to enter the matrix.
takes effect. o Acted upon by Carnitine-Palmitoyl
transferase 1
Upon the breakdown, the fates of short and medium chain
fatty acids will be immediately transported into the
circulation, and will undergo oxidation in the mitochondrion
of the liver cells. While long chain fatty acids together with
2-monoacylglycerols (after absorption by intestinal cells),
they will resynthesize triacylglycerol inside intestinal cell
and will be given a coat of apoliprotein B48 to form
chylomicrons and to which the chylomicrons transport them
to the lymphatic system and will eventually be emptied into
the thoracic duct and then to subclavian vein.
CARNITINE –PALMITOYL TRANSFERASE 1
Fransup  said that FA must be degraded by removal of 2 Allows the transfer of acyl group to carnitine to form acyl
carbons at a time, which occurs in mitochondrion (by carnitine, subsequently releasing coenzyme A. As acyl
Leninger). And 2 carbons released is not acetate, but carnitine, it can now be translocated inside the matrix
acetyl-CoA (FA synthesis is also called as Linen Cycle) through the help of a protein embedded in the inner
mitochondrial membrane, which is named as carnitine-acyl
BETA-OXIDATION OF FATTY ACIDS carnitine translocase. Inside the matrix, this acyl carnitine
will be subsequently acted upon by carnitine-palmitoyl
 Beta carbon is the one involved in the process of transferase 2, transferring acyl group back to Coenzyme A,
cleavage releasing carnitine. Carnitine will be translocated outside
i. By transforming this 3rd carbon into into the intermembranous space, by means of the
carbonyl/carboxyl carbon translocase, in time for the second load of palmitoyl-Coa
ii. Done by the 1st 3 steps exactly opposite of
the Fatty Acid synthesis (Condensation,
**Carnitine-Acyl Transferase 1 is just a general name, while Carnitine-
Reduction, Dehydration)
Palmitoyl Transferase 1 is a more specific one.
1. Oxidation
2. Hydration
PROTEINS FOR FATTY ACID TRANSPORT
3. 2nd Oxidation
4. Cleavage
 Cells liberate phenylacetate  true for even chain
fatty acids
 Cells liberate benzoic acid  true for odd chain
fatty acids
 Cell degrade fatty acids by removal of 2 carbons at
a time

 For fatty acid oxidation:

i. Molecule attached to intermediate is attached
by Coenzyme A (counterpart of transacylase in
fatty acid synthesis) which is carried out by
Acetyl CoA Synthetase
ii. 2-step reaction
1. ATP is hydrolyzed to AMP +
Pyrophosphate Site of action of malonyl CoA inhibits carnitine-palmitoyl
2. Pi is hydrolyzed by pyrophosphatase transferase 1. Carnitine-palmitoyl transferase 1. Malonyl
to liberate 2 Pi CoA is the rate limiting for beta-oxidation.
a. Energy liberated by 1 mole of
Pyrophosphate being Carnitine is a molecule is synthesized by liver and kidney
hydrolyzed to Pi = -6.6 kCal cells from Lysine and Methionine. In the biostatic pathway,
i. If this is the kind of there are 2 enzymes that need the coenzyme vitamin,
hydrolysis carried out, ascorbic acid.
it amounts to 2 moles
of ATP Different steps repeated every cycle in the pathway of B-
oxidation:
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 the mitochondrion, palmitate must be activated and
therefore must be attached to coenzyme A through acyl
CoA synthetase. And in the process, it utilizes 2 moles of
ATP. Therefore if we would like to know the net amount of
ATP produced, we have to subtract 2 moles of ATP to know
the net amount of ATP is 129 moles per 1 mole of palmitic
acid.

For additional information:

In the 1st step: OXIDATION:

 1.5~ 2 ATP is the original amount for FADH2

 2.5~ 3 ATP is the original amount for NADH+H

ODD CHAIN FATTY ACIDS

 Can also be utilized and can be subjected to

normal B-oxidation
 15-carbon FA  beta-oxidation removes up to the
12th carbon. The last 3 corresponds to carbon
Oxidation carried out by Acyl CoA dehydrogenase with the number 1, alpha carbon (2nd carbon), and beta
help of FAD (the one that will receive protons and electrons), carbon (3rd carbon). The resulting 3-carbon moiety
which is subsequently reduced to FADH2. FAD can easily in the form of Propionyl CoA can still be utilized by
the cell to generate energy.
transfer to ETC, creating a PO ration of 2:1. After the 1st
oxidation, the product is trans delta 2 Fatty enoyl CoA.
Through hydration, the double bond is hydrated and there
is formation of L-beta-Hydroxy acyl CoA with the help of
enoyl CoA hydratase and a water molecule. After hydration
reaction, comes the second oxidation with the help of NAD
with the help carried out by L-hydroxy acyl CoA
dehydrogenase, forming NADH+H which goes to electron
transport chain, creating a PO ratio of 3:1. Finally, the beta-
carbon becomes the carbonyl carbon. With the help of
Coenzyme A, the sulfur atom in it carries a lone pair of
electrons. Oxygen is more electron negative than carbon, so
it is a neutrophile that attracts electron to itself, which
makes carbon more positive. If we have there a nucleophile,
it can easily attack there through a nucleophilic attack,
cleaving the bond and releasing acetyl CoA, shortening
original FA by 2 carbons and the cycle will go on. If FA is
palmitic acid, there is 7 cycles, therefore yields 1 mole of
FADH2 and 1 mole of NADH+H per cycle, 5 ATP generated
per cycle (because this will create 2(from FADH2 +3 from
NADH + H). How many moles of acetyl CoA from B-
oxidation of palmitic acid? 8 moles of Acetyl CoA. How
many moles of ATP?
Propionyl CoA is carboxylated through propionyl CoA to form
How many FADH2? = 7 D-Methylmalonyl CoA and this will be isomerized by
epimerase to form L-Methyl Malonyl CoA and through
How many NADH+H = 7
methylmalonyl CoA mutase, forms succinyl CoA.
8 Acetyl CoA goes to the TCA cycle to synthesize more
Succinyl CoA is an intermediate of Kreb’s cycle. With this
energy during starvation. Remember that 1 mole of Acetyl
respect, form L-Methylmalonyl CoA to be catalyzed by
CoA, when enters the TCA cycle yields 12 ATPs.
mutase to form Succinyl CoA. Mutase is one of the 2
Gross amount of ATP generated out of complete beta- enzymes in which vitamin B12 (in the form of 5-
oxidation of palmitic acid is (12ATP x 8) + 14 ATP + 21 ATP deoxyadenosyl cobalamine) is needed. While the other
= 131 gross ATP per mole of palmitic acid enzyme that needs vitamin B12 is methionine synthase
enzyme which catalyzes the synthesis of methionine from
2 moles of ATP utilized in acyl CoA synthetase to activate FA homocystein. This methionine synthase needs vitamin B12
to form palmitoyl CoA. Palmitic acid that will be oxidized (in the form of Methyl Cobalamine).
through Beta-oxidation came from the deposited
triacylglycerol through the action of HSL (Hormone UNSATURATED FATTY ACIDS
Sensitive Lipase). Palmitate is carried by albumin in the
circulation to bring it back to the liver. Before it enters to  Cells can also utilize them for energy purposes.

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  2 kinds of unsaturated fatty acids:

1. Monounsaturated Fatty Acids

Carbon number 1, Carbon number 2 (alpha carbon), Carbon number 3

(beta carbon) has a methyl substituent; our cells do not have an enzyme
to act upon the beta carbon with a methyl substituent. The cells then
utilize alpha oxidation, wherein the alpha carbon will be the carbonyl
carbon, and the carbon number 1 is liberated as CO2. When carbon 1 is
removed, the former alpha carbon becomes the carbon number 1, and
the former beta carbon will not have branch. So therefore, this can be
subjected to the 4 steps that are repeated every cycle of the pathway.

If that is the case, the cleavage will be at the site wherein it releases
propionyl CoA (a 3-carbon moiety). Propionyl CoA is transformed to
Succinyl CoA and eventually enters Kreb’s cycle. Beta carbon can be
  subjected to a normal beta oxidation, releasing Acetyl CoA (2-carbon
moiety). After that, it releases propionyl CoA again.
Initially, there is a double bond situated in carbon 9 and 
10. Initially, oleoyl CoA is subjected to 3 cycles of normal 
B‐oxidation. After removing 6 carbons, the initial carbon  Refsun’s Disease refers to the accumulation of phytanic
7 becomes carbon 1, carbon 8 now becomes our alpha  acid especially in the brain, secondary to enzyme
carbon, and carbon 9 becomes the beta carbon. The beta 
deficiencies.
carbon as we can see is now involved in a double bond, 
which our cells will not be able to utilize the carbon with 
double bond. So the cells isomerizes  cis‐delta‐3‐ OMEGA OXIDATION
Dodecenoyl CoA forming trans‐delta‐2‐Dodecenoyl CoA, 
which can be subsequently hydrated with a mole of   Last carbon or the omega carbon is transformed
water to form L‐beta‐Hydroxy‐Decanoyl. After this we  into a carboxylic carbon.
can now utilize the normal B‐oxidation cycle to degrade 
this kind of fatty acid.
o If this happens, both sides can be
subjected to normal B-oxidation
2. Polyunsaturated Fatty Acids

2 double bonds are seen between carbons

9 and 10, 12 and 13 and they undergo 3
cycles of beta-oxidation. Afterwhich, the
beta carbon is again involved in a cis
confirmation of double bond. By means of
an isomerase, it can be transformed into a
trans-delta-2-enoyl CoA.

Cells use isomerase initially, then

dehydrogenase, and lastly reductase so
that normal B-oxidation of polyunsaturated
fatty acids may be take place. SHORT TERM REGULATION FOR FA METABOLISM:

PEROXISOMAL OXIDATION

 Flavin-dependent reaction
 Amount of energy in the form of ATP is less
because electrons are not transformed to ETC, but
instead transferred to a molecular oxygen, forming
hydrogen peroxide
 Hydrogen peroxide is a harmful compound that is
degraded to oxygen and water by the catalase
enzyme.

ALPHA OXIDATION

 Oxidizes branched chain fatty acids

 We derive metabolite intermediate coming from  Glucagon and Epinephrine phosphorylate the
chlorophyll (phytanic acid), a branched chain of acetyl CoA carboxylase, which forms cAMP which
fatty acid. then activates protein kinase A and therefore
 May also be a source of energy. phosphorylates, ACC, inhibiting its activity.

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 o So instead of FA synthesis, the
predominant pathway is beta-oxidation,
forming a lot of acetyl Coa. Acetyl CoA
goes to kreb’s cycle.
After oxidation, cells form a lot of ketone bodies. And if cell
is in starvation, the source of energy is from Acetyl CoA
then the cell forms a lot of ketone bodies. Condensation of
2 moles of Acetyl CoA catalyzed by thiolase, with the
release of coenzyme A forming acetoacetyl CoA. By means
by synthetase and with another mole of Acetyl CoA, we will
form 3-hydroxy-3-methylbutaryl CoA, with the release of
acetyl CoA, we form the 1st ketone body—acetoacetate.
Acetoacetate forms acetone.
Acetone
 A volatile ketone body which is released through
respiration.
 Its accumulation may also result to type 1 diabetes
mellitus which has the propensity to develop
ketoacidosis due to the absence of insulin
synthesis.
3-hydroxy Butarate
 Another ketone body
 Acetone + dehydrogenase
Liver is the site of ketogenesis. But with respect to energy
utilization, the liver cannot utlize them as source of energy
due to the absence of succinyl CoA -aceto-acetate CoA
transferase (thiophorase). “Ako ang nag saing, iba ang kumain.
Awww Emo much:(”
EICOSANOIDS
 Autocrine (the same cell that secretes the
hormone will be the one affected) and paracrine
hormones (adjacent cells will be the ones that will
be affected).
 Example: Prostaglandins, leukotrienes,
thromboxanes, lipoxins
 Synthesized from
o 20-carbon FA (AKA eicosanoic acids)
 Arachindonic (4 double bonds) 
series 2 prostaglandins (through
cycleoxygenase pathway)
 Timnodonate (5 double bonds)
 Eicosapentaenoic acids  series
3 prostaglandins
 Eicosatrienoate
Exert their effects through formation of cAMP.
 They have to bind to the receptor in the plasma
membrane which stimulates the G-protein which
activates Adenylyl Cyclase, which forms cAMP out
of ATP (cAMP protein dependent kinase cascade).
Physiological responses:
 Negates inflammatory responses
 Produce pain and fever
 Regulate blood clotting
 Induce labor (for specific kinds)
 Have an effect on regulation of split weight cycle
 Inhibits gastric secretions
 Stimulate contraction of intestinal smooth muscles
PROSTAGLANDIN
 Identified in human semen and other cells
 Prostaglandin E and Prostaglandin F are initially
discovered
 Derived from hypothetical prostanoic acid
 There are 3 major classes (depending on the
structure):
o Prostaglandin A – α,β- unsaturated
ketones
o Prostaglandin E- β- hydroxy ketones
o Prostaglandin F- 1,3 dioles (2 hydroxy
groups)
Series 1 prostagalinds– there is 1 double bond outside the
cyclicized region from eicosatrienoic acid or dihomo-
gamma-linolenic acid
Series 2 prostaglandins – there are 2 double bonds outside
the cyclicized region from eicosatetraenoic acid or
arachidonic acid
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Series 3 prostaglandins – there are 3 double bonds outside o Cyclooxygenase activity is inhibited by
the cyclicized region from eicosapentaenoic acid or aspirin (acetylsalicylic acid) and ibuprofen
timnodonic acid (Non-steroidal anti-inflammatory drugs)
 2 isoforms of cyclooxygenase
Among the unsaturated fatty acids, there are 2 essential  COX1 – a constitutive
polyunsaturated acids: enzyme (it’s always
present whether or not
1. linoleic acid (true essential) there are substrates)
a. From this, we can synthesize dihomo- o When blocked,
gamm-linolenic through a GI bleeding and
dehydrogenation reaction gastritis
2. linolenic acid o Needed for the
maintenance of
integrity of the
membranes of
intestinal cells

 COX2 – an inducible
enzyme
o Made only in
response
through
inflammatory
initiators such as
cytokines
o The one that is
blocked
o Celecoxib are
LEUKOTRIENES specific
inhibitors
o Catalysis through lipooxygenase o Cyclooxygenase activity is inhibited by
o Series 3 from eicosatrienoate aspirin and ibuprofen (Nonsteroidal anti-
o Series 4 from arachidonic acid inflammatory drugs)
o Series 5 from eicosapentaenoate

Pathway for Cyclooxygenase:

Arachidonic acid is the most important precursor.
o Prostaglandin H2 synthase enzyme complex:
o Generation of Arachidonic acid through: o Possesses:
o Reaction of phospholipase A2 which acts  Cyclooxygenase activity
on carbon 2 of glycerol backbone.  Aspirin inhibits this
o Phospholipase A1 acts on carbon 1 of activity
glycerol backbone  Peroxidase activity
o Phospholipase C acts on carbon 3
o Phospholipase D removes the base.
 Ex: Enositol portion of Structure of cyclooxygenase domain has 3 important amino
phosphatidyl enositol is removed acid residues
through this phospholipase D.
o Diacylglycerol lipase 1. Tyrosine 3,8,5
o Diacylglycerol kinase a. Forms a radical in the process of forming
prostaglandins
b. If we give NSH, it will affect the tyrosine
Phosphatidyl enositol through phospholipase A2  residue that prevents the formation of
arachidonic acid + lysophospholipid radical
2. Serine 5,30
Diacylglycerol kinase + phospholipase C  phosphatidic a. Aspirin acetylates this, producing acetyl
acid (+ phospholipase A2 arachidonic acid) moiety which blocks the whole entry of
arachidonic acid
Diacylglycerol lipase from 1,2 diacyl glycerol  arachidonic 3. Arginine 1,20
acid a. Forms an ion pair with substrate
b. If arachidonic acid cannot enter, arginine
2 major pathways of arachidonic acid metabolism: cannot forms an ion pair with substrate

1. Cyclooxygenase (Cyclic pathway)

2. Lipooxygenase (Linear pathway) Phospholipase A2 generates arachidonic acid

o Hormones that stimulate angiotensin 2:

Shows us how Arachidonic Acid  Prostaglandin o Bradykinin
o Epinephrine
o Thrombin
o 2 activities:
o Cortisol (principle corticosteroid) inhibits the
activity of phospholipase A2
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 o WBC, Muscles, Lungs, Brain
o Actions:
Prostaglandin dehydrogenase  Induces release of lysosomal enzymes
 Promotes adhesion of WBC
o Carbon attached to hydroxyl group is subsequently
oxidized, and therefore inhibits prostaglandin
o Message is transmited by the formation of 2nd
messenger of cAMP

LIPOXINS

 Family of congregated tetraenes

 Vasoactive and immunoregulatory effects

-----------------------END OF TRANSCRIPTION-------------------------------

Kung hindi clear yung image, please refer to the uploaded

pdf file if it is available
LIPOOXYGENASE PATHWAY

o Peptidoleukotriene – mediates anaphylaxis

o Leukotriene C4
o Leukotriene D4
o Leukotriene E4

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