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9.

Lipid Metabolism
Introduction
Lipids constitute one of the four major classes of compounds that are found in
living systems. The lipids of metabolic significance include triacylglycerol,
phospholipids and the products of lipid metabolism such as free fatty acids and glycerol.

Lipolysis
Lipases
Triacylglycerols or triglycerides undergo hydrolysis by lipases to form glycerol
and fatty acids, which undergo further oxidation generating energy. Lipases have been
reported to be present in dry seeds of some species, e.g. castor bean, Scots pine and
Douglas fir but at a low level, or absent in others e.g. apple. In most cases of seeds,
following imbibitions, there appears to be a rise in lipase activity but whether this
increase is due to the de novo synthesis of the enyme or activation of existing lipases has
not been determined. ! decline in lipase activity is always associated with decline in
acylglycerol reserves. In castor bean, as in many other fat"storing seeds, free fatty acids
do not accumulate, but are rapidly degraded and converted to carbohydrate within the
endosperm. In other seeds such as germinating seeds of oil palm #Elaeis guineensis$, a
different pattern of fat mobiliation can be observed. The products of lipid catabolism
are transported via specialied structures called haustorium through its vascular system.
Lipases are generally non"specific and can hydrolyse a wide variety of triacylglycerols
#%igure &'.'$. They initiate digestion by hydrolying triacylglycerols to form free fatty
acids and &,'"diacylglycerols. (omplete hydrolysis of triacylglycerols produces glycerol
and fatty acids. Lipase hydrolyses easily the terminal fatty acids to produce '"monoacyl
glycerol as major end product and it can digest the secondary lin)age only with difficulty.
In plants, **+ of total lipase activity is associated with the acid lipase #p, -..$. The
precise location of the acid lipase is still undetermined but it could be associated with the
glyoxysomes. In castor bean, within two days of the start of imbibitions, the acid lipase of
p, /.0 is activated to the pea) level followed by decline in activity on the -th day by
which time the al)aline lipase of p, *.0 shows maximal activity. The acid lipase is
associated with oil bodies and capable of hydrolysing tri", di" and mono acylglycerols
whereas the al)aline lipase is specific only for monoacylglycerols.
Phospholipases
1hospholipases are the hydrolytic enymes acting on phospholipids and splitting
into different products. There are four types of phospholipases )nown as phospholipase
!
&
, phospholipase !
'
or 2
&
, phospholipase ( and phospholipase D.
Phospholipase A
1hospholipase ! is present in large amounts in sna)e venom and human pancreas.
It is also designated as phospholipase !
&
. It catalyses the hydrolysis of the fatty acids in
the ' or "position of the phospholipids. Though this enyme attac)s on
glycerophosphatides, it is fairly specific for phosphatidyl choline #lecithin$. The enyme
is relatively stable to heat #below p, 3.0$. The product of the hydrolysis, a lysolecithin,
#monoacylphosphoryl choline$ has a powerful hemolytic activity.
Phospholipase B (A
2
)
It is otherwise termed as lysophospholipase and widely distributed in nature often
in association with phospholipase !. 1hospholipase 2 is also designated as
phospholipase !
'
since it acts on the lysolecithin #the product obtained from
phospholipid by the action of phospholipase !
&
$. The action of this enyme following
that of phospholipase ! yields glycerophosphorylcholine as the final product.
Phospholipase C
1hospholipase ( is mostly found in the plant )ingdom but it may also be present
in some animal tissues and venoms. It catalyses the liberation of a &,'"diacylglycerol and
phosphorylcholine from phosphatidylcholine. 1hosphorylcholine is also liberated from
sphingomyelin by this enyme.
Phospholipase D
1hospholipase D, an enyme described mainly in plants catalyses the hydrolysis
of choline from phosphatidylcholine leaving phosphatidic acid.
Oxidation of fatty acids
%atty acids obtained by hydrolysis of fats undergo different oxidative pathways
designated as alpha #$, beta #$ and omega #$ pathways.

-oxidation
"4xidation of fatty acids has been found in certain tissues especially in brain
tissue of mammals and plant systems. It does not re5uire (o! intermediates and no
high"energy phosphates are generated. This type of oxidation results in the removal of
one carbon at a time from the carboxyl end of the fatty acid. The physiological role of
"oxidation in plants is not yet fully established but it has been suggested that it may be
involved in the degradation of long chain fatty acids as observed in many animal tissues.
"4xidation is clearly the main source of the odd"carbon fatty acids and their derivatives
that occur in some plant lipids. In this process, se5uential removal of one carbon at a
time from free fatty acids of chain length ranging from (
&6
to (
&7
occur.
-Oxidation
"4xidation is normally a very minor pathway brought about by hydroxylase
enymes involving cytochrome 1"-/0 in the endoplasmic reticulum. %atty acids with
oxygen function #alcoholic or carboxyl$ at the methyl terminal end #"end$ are formed by
"oxidation and fre5uently occur as constituents of cutin and suberin. The re5uirements
for the oxygenase"mediated conversion of a "methyl fatty acyl (o! into a
"hydroxymethyl fatty acyl (o! are molecular oxygen, reduced pyridine nucleotide and
a non"heme iron protein in higher plants.
-Oxidation of fatty acids
In &*0-, %ran 8noop made a critical contribution to the elucidation of the
mechanism of fatty acid oxidation and demonstrated that most of the fatty acids are
degraded by oxidation at the "carbon. "4xidation of fatty acids ta)es place in
mitochondria. %atty acids are activated before they enter into mitochondria for oxidation.
Activation of fatty acids
%atty acids are converted into active intermediate in a reaction with !T1 and
coenyme !. ! thioester lin)age between the carboxyl group of a fatty acid and the
sulfhydryl group of coenyme ! is formed with the hydrolysis of !T1. This activation
reaction ta)es place on the outer mitochondrial membrane catalyed by acyl (o!
synthetase. Several acyl (o! synthetases each specific for fatty acids of different chain
length are present in the membrane of mitochondria.
Penetration of long chain fatty acids into mitochondria
Long chain acyl"(o! molecules do not readily get into the inner mitochondrial
membrane and are carried across the inner membrane by conjugating with carnitine
#"hydroxy "trimethyl ammonium butyrate$, a witterionic compound formed from
lysine. !ctivation of lower fatty acids and their oxidation within the mitochondria occur
independently of carnitine, but long"chain acyl (o! will become oxidied unless they
form acylcarnitines. The acyl (o! combines with carnitine in the presence of carnitine
acyltransferase I, which is bound to the outer mitochondrial membrane. !cylcarnitine is
transported in, coupled with the transport out of one molecule of carnitine. The
acylcarnitine then reacts with coenyme ! catalyed by carnitine palmitoyl transferase II,
located on the inside of the inner membrane. !cyl (o! is reformed in the mitochondrial
matrix and carnitine is liberated.
Oidation
! saturated acyl (o! is oxidied by a recurring se5uence of four reactions9
oxidation in presence of %!D, hydration, oxidation in presence of :!D
;
, and thiolysis
by (o!S,. In "oxidation, ' carbons are cleaved at a time from acyl (o! molecules,
starting from the carboxyl end. The chain is bro)en between the "and "carbon atoms.
The two"carbon units formed are acetyl (o!.
i$ The first reaction in "oxidation of acyl (o! is the formation of trans
'
" enoyl
(o! or , "unsaturated acyl (o! in presence of acyl"(o! dehydrogenase and the
coenyme, %!D.
ii$ The next step is the hydration of the double bond between ("' and ("6 by
enoyl (o! hydratase with the formation of "hydroxy acyl (o!.
iii$ In the third step, the "hydroxy acyl (o! is dehydrogenated in the presence of
"hydroxy acyl (o! dehydrogenase and :!D
;
forming ")etoacyl (o!.
iv$ In the last step of "oxidation, ")etoacyl (o! reacts with coenyme ! in the
presence of the enyme, thiolase. The products of this reaction are acetyl (o! and an
acyl (o! containing two carbons less than the original acyl (o! molecule that
underwent oxidation.
2y the above steps of "oxidation fatty acids are completely degraded to acetyl
(o! units. The acetyl (o! formed from fatty acids can be oxidised to carbon dioxide
and water via citric acid cycle.
Energetics of oxidation
The energetics or the energy conserved in terms of !T1 by oxidation of a
molecule of palmitic acid is given below9
1almitic acid #&. carbons$ undergoes "oxidation forming eight molecules of
acetyl (o! by undergoing seven "oxidation spirals. <hen one cycle of "oxidation
ta)es place, one molecule of %!D,
'
, one molecule of :!D, and one molecule of acetyl
(o! are produced. =lectrons from these reducing e5uivalents #%!D,
'
and :!D,$ are
transported through the respiratory chain in mitochondria with simultaneous regeneration
of high"energy phosphate bonds. >itochondrial oxidation of %!D,
'
eventually results in
the net formation of about &./ !T1. Li)ewise, oxidation of electrons from :!D, yields
'./ molecules of !T1. ,ence, a total of four !T1 molecules are formed per cycle and
ten molecules of !T1 are formed through 8rebs?s cycle from each molecule of acetyl
(o!.

7 !cetyl (o! through T(! cycle yield #7x&0$ @ 70 !T1
3 "oxidation spiral reactions yield #3x-$ @ '7 !T1
""""""""""""""
Total9 &07 !T1
"""""""""""""

!T1 utilied in the initial step @ ' !T1
,ence, complete oxidation of palmitic acid yields &0. !T1.
Biosynthesis of fatty acids
%or years, it was thought that fatty acid biosynthesis occurred by reversal of the
"oxidation pathway. 4n the contrary, it occurs by a separate pathway that differs from
"oxidation in several ways.
i. Synthesis ta)es place in the cytosol, in contrast with degradation or oxidation,
which occurs in the mitochondrial matrix.
ii. Intermediates in fatty acid synthesis are covalently lin)ed to the sulfhydryl
group of an acyl carrier protein #!(1$ whereas intermediates in fatty acid brea)down are
bonded to coenyme !.
iii. The enymes of fatty acid synthesis in animals are joined in a single
polypeptide chain called fatty acid synthase. In contrast, the degradative enymes do not
seem to be associated. 1lants employ separate enymes to carry out the biosynthetic
reactions.
iv. The reductant in fatty acid synthesis is :!D1,, whereas the oxidants in fatty
acid oxidation are :!D
;
and %!D.
=longation by the fatty acid synthase complex stops upon formation of palmitate
#&. ($. %urther elongation and the formation of double bonds are carried out by other
enyme systems.
!he follo"ing seven steps are involved in fatty acid #iosynthesis.
i) $ormation of malonyl CoA
The synthesis of malonyl (o! from acetyl (o! is catalyed by acetyl
(o! carboxylase having biotin as prosthetic group. The production of malonyl (o! is
the initial and controlling step in fatty acid synthesis. In this reaction, bicarbonate serves
as a source of (4
'
. The reaction ta)es place in two steps, namely carboxylation of biotin
involving !T1 and transfer of the carboxyl group to acetyl (o! resulting in malonyl
(o!.
2iotin " enyme ; !T1 ; ,(4
"
6
"""""" (4
'
" biotin " enyme ; !D1 ; 1i
(4
'
" biotin " enyme ; acetyl (o! """""" malonyl (o! ; biotin " enyme
!cetyl (o! carboxylase plays a )ey role in regulating fatty acid metabolism and the
same is inactivated by phosphorylation.
ii) $ormation acetyl and malonyl ACP
!cetyl transacylase and malonyl transacylase catalye the formation of
acetyl !(1 and malonyl !(1 respectively. !cetyl transacylase can transfer acetyl as
well acyl groups whereas malonyl transacylase is highly specific.
!cetyl
transacylase
!cetyl (o! ; !(1 """""""""""""""" acetyl " !(1 ; (4!S,
>alonyl
transacylase
>alonyl (o! ; !(1 """"""""""""""" >alonyl " !(1 ; (4!S,
iii) $ormation of acetoacetyl % ACP (% &etoacyl ACP)
!cetyl !(1 condenses with malonyl !(1 to form acetoacetyl !(1.
(arbondioxide is eliminated from malonyl !(1.
iv) 'eduction of %&etoacyl ACP to %hydroyl acyl ACP
The " )eto group in acetoacetyl !(1 is reduced by :!D1," dependent "
)etoacyl reductase.
v) $ormation of unsaturated acyl ACP
The "hydroxyl group combines with the hydrogen atom attached to the "carbon
and a water molecule is removed to form , "unsaturated acyl !(1.

vi) $ormation of Acyl ACP
The unsaturated acyl !(1 is converted in the next step to a saturated acyl
!(1 by the enyme ,"unsaturated acyl !(1 reductase using :!D1, as the
coenyme. The resultant product contains two carbon atoms more than the starting
material. !ddition of subse5uent acetyl units through malonyl !(1 leads to the
formation of &."carbon palmitate.
Stoichiometry of fatty acid synthesis
The stoichiometry of the synthesis of palmitate is given below9
!cetyl (o! ; 3 malonyl (o! ; &- :!D1, ; '0 ,
; """"""""""""""
1almitate ; 3 (4
'
; &- :!D1
;
; 7 (o!S, ; . ,
'
4
The e5uation for the synthesis of the malonyl (o! used in the above reaction is
3 !cetyl (o! ; 3 (4
'
; 3 !T1 """""""" 3 malonyl (o! ; 3!D1
; 3 1i ; &- ,
;
The overall stoichiometry for the synthesis of palmitate is
7 !cetyl (o! ; 3 !T1 ; &- :!D1, ; .,
;
""""""" 1almitate ;
&- :!D1 ; 7 (o!S, ; . ,
'
4 ; 3 !D1 ; 3 1i
%atty acid synthesis and degradation are reciprocally regulated so that both are not
simultaneously active.
2iosynthesis of triacylglycerols
Triacylglycerols are not synthesised by reversal of lipolysis. They are synthesisd by
a different mechanism in which both glycerol and fatty acids are activated by !T1 before
they are incorporated into acylglycerols.
i) Activation of glycerol
Alycerol )inase catalyses the activation of glycerol to glycerol 6"phosphate. If
glycerol )inase is found in low 5uantity or absent, glycerol 6"phosphate will be formed
from dihydroxyacetone phosphate obtained from glycolysis and this reaction is catalysed
by the enyme glycerol 6"phosphate dehydrogenase.
ii) Activation of fatty acids
%atty acids are activated to acyl (o! by the enyme acyl (o! synthetase,
utiliing !T1 and (o!S,. Two molecules of acyl (o! combine with glycerol
6"phosphate to form &,'"diacylglycerol phosphate. %ormation of &,'"diacyl glycerol
phosphate ta)es place in two stages, catalysed by glycerol 6"phosphate acyl transferase
and then by &"acyl glycerol 6" phosphate acyl transferase. The phosphate group is
removed from &,'"diacyl glycerol phosphate by phosphatidate phosphatase to form
&,'"diacyl glycerol. Triacylglycerols are finally formed by esterification of one or more
molecule of acyl (o! with the diacylglycerol.
!lternative pathway for triacylglycerol biosynthesis
In this pathway, dihydroxyacetone phosphate from glycolysis is reduced by
:!D1,, acylated and converted to lysophosphatidate. This pathway accounts for less
than &0+ of total triacylglycerol synthesis.
Summary
Triacylglycerols are the highly concentrated form of energy stored in seeds. They
provide up to six times the metabolic energy of an e5ual weight of hydrated glycogen.
Triaylglycerols are hydrolysed by lipases to glycerol and fatty acids, which then undergo
further oxidation generating energy.
1hospholipases are the hydrolytic enymes acting on phospholipids and splitting
into different products. There are four types of phospholipases. 1hospholipase !
catalyses the hydrolysis of the ester bonds and releases the fatty acids in the ' or "
position of the phospholipids. This enyme is fairly specific to lecithin. 1hopholipase (
catalyses the liberation of a &,'"diacyl glycerol and phosphoryl choline from a
phosphatidyl choline. 1hopholipase D catalyses the removal of choline from phosphatidyl
choline.
%atty acids obtained by hydrolysis undergo different oxidative pathways called as
, and . >ost of the fatty acids are oxidised through oxidation pathway, which
ta)es place in mitochondria. 2efore fatty acids are oxidied, they are converted to the
acyl (o! derivatives by acyl (o! synthase in an !T1 re5uiring process, transported into
mitochondria as carnitine esters, reconverted inside the mitochondrial matrix to acyl
(o!. "4xidation of fatty acyl (o! occurs in '"carbon units so as to convert even"
chain fatty acyl (o!s completely to acetyl (o!. The pathway involves %!D"dependent
dehydrogenation of all al)yl group, hydration of the resulting double bond, oxidation of
this alcohol to )etone, and ("( bond cleavage to form acetyl (o! and a new fatty acyl
(o! with two carbon atoms less than the parent compound. (omplete oxidation of the
acyl (o! is achieved through the citric acid cycle.
4xidation does not re5uire (o! intermediates and no high"energy phosphates
are generated. This type of oxidation results in the removal of one carbon at a time from
the carboxyl end of the fatty acid.
"4xidation is a very minor pathway. %atty acids with oxygen function at the
methyl terminal end are formed by "oxidation. 4xidation of unsaturated fatty acids
follows many reactions of fatty acids but re5uire the participation of additional enymes,
an isomerase and a novel reductase.
%atty acid biosynthesis differs from fatty acid oxidation in several aspects.
Synthesis ta)es place in cytosol. The intermediates in fatty acid synthesis are covalently
lin)ed to acyl"carrier protein #!(1$. >alonyl (o! is the precursor in biosynthesis. The
pathway involves formation of acetyl and malonyl !(1. 1almitate is the primary product
of fatty acid biosynthesis. Longer chain fatty acids and unsaturated fatty acid
biosynthesis from palmitate occur by elongation and desaturation reaction. The
unsaturated fatty acid linoleate and "linolenate cannot be synthesised by mammals, but
plants can synthesise both.
Triacylglycerols are synthesied from both glycerol and fatty acid, which are
activated by !T1 before they are incorporated into acylglycerol. !n alternate pathway
for the synthesis of triacyl glycerol also exists but this pathway accounts for less than
&0+ of total triacylglycerol synthesis.

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