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Biosynthesis of fatty acidsBiosynthesis of fatty acids
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Biosynthesis of fatty acids (Palmitic acid)Biosynthesis of fatty acids (Palmitic acid)Saturated FAsSaturated FAs
Fatty acid synthesis does not occurnot occur by a reversalreversal of the degradative pathway, it consists of a new set of reactions.
The steps of synthesisThe steps of synthesis of fatty acid (Palmitic (Palmitic acid )acid ) start from acetyl-CoA & malonyl-CoA.
1)- Acetyl-CoAAcetyl-CoA is formed from glucose via pyruvic acidpyruvic acid & malonyl-CoAmalonyl-CoA is produced by carboxylation of acetyl-CoAacetyl-CoA by the enzyme acetyl-CoA carboxylaseacetyl-CoA carboxylase.
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COOH CH3CO-S – CoA + CO2 CH2CO-S – CoA +AMP+PPi Acetyl-CoA Malonyl-CoA
2)- Conversion of acetyl-CoA to acetyl-ACPacetyl-ACP (acyl carrier protein). It is catalyzed by acetyl acetyl transacylasetransacylase.
CH3-CO-SCoA +ACP-SH CH3-CO-S-ACP + CoASH Acety-CoA Acety-ACP
ATP Mn++
Acetyl-CoA carboxylase
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3)- Conversion of malonyl-CoAmalonyl-CoA to malonyl-ACPmalonyl-ACP in the presence of malonyl transacylasemalonyl transacylase.
HOOC-CH2-CO-SCoA + ACP-SH malonyl-CoA HOOC-CH2-CO-S-ACP + CoASH malonyl-ACP
4)- Formation of acetoacetyl-ACPacetoacetyl-ACP by condensation of acetyl-ACPacetyl-ACP with malonyl-ACPmalonyl-ACP. Catalyzed by ββ-ketoacyl-ACP synthase-ketoacyl-ACP synthase.
CH3-CO-S-ACP + HOOC-CH2-CO-S-ACP Acetyl-ACP Malonyl-ACP CH3-CO-CH2-CO-S-ACP+ CO2 Acetoacetyl-ACP
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5)- Reduction of acetyoacetyl-ACPacetyoacetyl-ACP to ββ--hydroxybutyryl-ACPhydroxybutyryl-ACP. By the enzyme ββ-ketoacyl--ketoacyl-ACPACP reductase reductase & NADPH+H as conenzyme.
CH3-CO-CH2-CO-S-ACP CH3-CHOH-CH2-CO-S-ACP β-hydroxy-butyryl-ACP
6)- Dehydration of ββ-hydroxybutyryl-ACP-hydroxybutyryl-ACP to crotonyl-ACPcrotonyl-ACP. Catalyzed by ββ-hydroxyacyl--hydroxyacyl-ACP dehydrogenaseACP dehydrogenase.
CH3-CHOH-CH2-CO-S-ACP CH3-CH=CH-CO-S-ACP Crotonyl-ACP
NADPH+H NADP+
+
H2O
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7)- Reduction of crotonyl-ACPcrotonyl-ACP to butyryl-butyryl-ACPACP, by enoyl-ACP reductase & NADPH+H is coenzyme.
CH3-CH=CH-CO-S-ACP CH3-CH2-CH2-CO-S-ACP
All the steps are repeatedrepeated to elongateelongate the carbon chaincarbon chain by 2 C2 C atoms in each operationeach operation.
The The acyl groupsacyl groups are finally are finally set freeset free from the from the acyl carrier protein either by acyl carrier protein either by hydrolysishydrolysis or by or by reactionreaction with with CoASHCoASH. .
NADPH+H NADP++
+
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O O CHCH33 – (CH – (CH22)n – C – S – ACP + CoASH)n – C – S – ACP + CoASH
OOCHCH33 – (CH – (CH22)n – C – SCoA + ACPSH )n – C – SCoA + ACPSH
CoASH
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Biosynthesis of fatty acid stepwise reactions
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A A general overall reactiongeneral overall reaction for the for the synthesissynthesis of of palmitic acidpalmitic acid as the principal product of as the principal product of synthetase system is:synthetase system is:
CHCH33-CO-S-ACP + 7HOOC-CH-CO-S-ACP + 7HOOC-CH22-CO-S-ACP + 14NADPH+14H-CO-S-ACP + 14NADPH+14H CHCH33-(CH-(CH22)14-COOH + 7CO)14-COOH + 7CO22 + 8ACP-SH + + 8ACP-SH + Palmitic acidPalmitic acid 14NADP + 6H 14NADP + 6H22OO
+
+
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Biosynthesis of Unsaturated fatty acids
Synthesis of monounsaturated fatty acids: The palmitoleic acidpalmitoleic acid (16-carbon) & oleic acidoleic acid
(18-carbon) are the two major monounsaturated FAsmonounsaturated FAs in the body.
Both having double bonddouble bond at C 9C 9 position. These are first produced as their coenzyme coenzyme
derivativesderivatives -- by the oxidationoxidation (loss of H) - palmitoyleoly-CoApalmitoyleoly-CoA & stearoyl-CoAstearoyl-CoA respectively in the presence of molecular O2.
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CH3(CH2)14CO – SCoA Palmitoyl-CoA
CH3(CH2)16COSCoA Stearyl-CoA CH3(CH2)5-CH=CH-(CH2)7-CO-SCoA Pamitoleoyl-CoA
CH3(CH2)7CH=CH(CH2)7CO-SCoA Oleoyl-CoA
NADP + ½ O2- H2
Acetyl-CoA+NADPH+NADH
(mitochondrial system
- H2 NADP + ½ O2+
+
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Palmitoleoyl-CoAPalmitoleoyl-CoA & oleoyl-CoAoleoyl-CoA then give rise to their respective fatty acidsfatty acids by the splitting up splitting up of coenzyme A coenzyme A portion of their molecules:e.g:
Palmitoleoyl-CoA + H2O Palmitoleic acid + CoA
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Biosynthesis of Cholesterol Cholesterol is synthesizedsynthesized by the body starting starting
fromfrom CH3CO-SCoA (acetyl-CoAacetyl-CoA). Synthesis has also been carried out in vitro
preparation of tissues. The main sitesmain sites of cholesterol biosynthesis are:
liverliver, small intestinesmall intestine, aortaaorta, skinskin, adrenal adrenal glandsglands & gonadsgonads etc.
Many reaction mechanismsreaction mechanisms have been proposed but the most acceptablemost acceptable by POPJACKPOPJACK.
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Synthesis of cholesterol involves 3 stages3 stages. (i) –(i) – ThreeThree units of acetateacetate condense to form 6- 6-
C C intermediate – mevalonatemevalonate. (ii) –(ii) – Mevalonate is convertedconverted to activated
isopreneisoprene units, which polymerizepolymerize to form 30-C30-C linearlinear structure of squalenesqualene.
(iii) –(iii) – Squalene is cyclizedcyclized to form lanosterollanosterol – converted to cholesterolcholesterol in few steps that removeremove 3 methyl3 methyl groups & rearrangerearrange double bonds.
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Structure
A B
C D
3 56
10
1317
18
19
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273 cyclohexane ringes
(phenanthrene arrangement
Cyclopentane ring
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Various reactionsVarious reactions involved in Biosynthesis of Biosynthesis of cholesterolcholesterol.
CH3CO-SCoA + CH3CO-SCoA Acetyl-CoA
CH3COCH2CO-SCoA Acetoacetyl-CoA
CH3
HOOC-CH2-C-CH2-CO-SCoA β-Hydroxy- β-methyl-glutaryl-CoA
OH
CondensationThiolase
- CoASH
+ (CH3CO-SCoA+H2O)- CoASH
HMG-CoA synthase
+ 2(NADPH + H- 2(NADP + CoASH)
(1)
(2)
(3)
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CH3 HOOC-CH2-C-CH2-CH2OH Mevalonic acid OH
CH3 O OHOOC-CH2-C-CH2-CH2O-P-O-P-OH Diphospho-mevalonic acid OH OH OH
CH3 O O C=CH-CH2-O-P-O-P-OH 3,3-Dimethyl allyl pyrophosphate CH3 OH OH
+ 2ATP- 2ADP
- (CO2 + H2O) ATP
Isomerization
(4)
(5)
(6)
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CH3 O O C-CH2-CH2-O-P-O-P-OH Isopentenyl-pyrophosphate (C5) CH2 OH OH
Geranyl-PP (C10) Farnesyl-PP (C15)
Squalene (C30) Lanosterol (C30)
Polymerizaion + IPP
Squalene synthetase
+Isopentenyl-PP
+ Farnesyl-PP
(7)
(8)
(9)
(10)
(11)
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Zymosterol
Desmosterol
CHOLESTEROL (C27)
The production of 1 molecule1 molecule of cholesterolcholesterol requires 18 molecule18 molecule of acetyl CoAacetyl CoA, 36 ATP36 ATP, 16 NADPH16 NADPH.
-
(12)
(13)
2020
Biomedical significance of cholesterol
The levellevel of cholesterolcholesterol in blood is directly directly relatedrelated to the development of atherosclerosisatherosclerosis.
Cholesterol is a componentcomponent of membranesmembranes & has a modulating effectmodulating effect on the fluid statefluid state of the membrane.
7-dehydrocholesterol7-dehydrocholesterol in skin is the precursorprecursor of Vitamin DVitamin D.
2121
Saponification number: HydrolysisHydrolysis of triacylglycerols by alkalialkali is
known as saponificationsaponification because one of the products is soap.
The number of mgs of KOHmgs of KOH used to saponify saponify fatty acids per gramper gram of a given fatfat is called saponification number.
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Iodine number: HalogensHalogens can be addedadded to the double bondsdouble bonds of
unsaturatedunsaturated acyl group of triacylglycerols. The amount of halognesamount of halognes absorbed is
proportionalproportional to the total number of double number of double bondsbonds present.
OneOne double bond absorbs 2 halogenabsorbs 2 halogen atoms. The # of gms# of gms of iodineiodine absorbed by
unsaturated fatty acidsunsaturated fatty acids present in 100 gms100 gms of fatfat or oiloil called iodine number.
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Biosynthesis of Triglycerides – Triacylglycereols (neutral lipids)(neutral lipids)
Recommended BooksRecommended Books
“HARPER’S Illustrated Biochemistry”, 28th Edition
&
“Essentials of Medical Biochemistry” Vol.1 by Mushtaq Ahmed
2424
Biosynthesis of Triacylglycerols (Neutral Fats)
These are triesterstriesters of different fatty acidsfatty acids with glycerolsglycerols.
The fatty cid partfatty cid part (RCOO, R'COO, RʺCOO) in triacylglycerols is known as acyl groupacyl group.
Acylglycerols differdiffer in number of OHnumber of OH groups of glycerol esterified with different fatty acids.
Simple triacylglycerolsSimple triacylglycerols, in which all OH groups esterified with similar ff,similar ff, are rarerare in humans but with different ff are called mixed mixed triacylglycerolstriacylglycerols & are very commonvery common.
2525
Structures O O O H2C – O – C – R H2C – O – C – R H2C – O – C – R
O O HC – O – C – R' HC – O – C – R' HC – OH
O H2C – O – C – Rʺ H2C – OH H2C – OH
Triacylglycerol Triacylglycerol 1,2-diacylglycerol1,2-diacylglycerol 1-monoacylglycerol1-monoacylglycerol
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Biosynthesis of TAGBiosynthesis of TAG Glycerol phosphateGlycerol phosphate is the initial acceptoracceptor of
fatty acids during TAG synthesisTAG synthesis. Two pathwaysTwo pathways for glycerol-P production. FirstFirst; In liverliver & adiposeadipose tissue, glycerol phosphate
can be produced from glucosefrom glucose, by glycolysisglycolysis to produce dihydroxyacetone-Pdihydroxyacetone-P.
Next, DHAP is reducedreduced to glycerol-P by glycerol phosphate dehydrogenaseglycerol phosphate dehydrogenase.
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Second pathwaySecond pathway found in liverliver, where by glycerol kinaseglycerol kinase convert free glycerolglycerol to glycerol phosphateglycerol phosphate.
Then there are four reactionsfour reactions, such as; Sequential additionaddition of two fatty acidstwo fatty acids from
fatty acyl CoA, the removal of phosphateremoval of phosphate, and the additionaddition of the third fatty acidthird fatty acid.
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H2C – OH H2C – OH H2C – OH HO – C – H HO – C – H C = O
GlycolysisGlycolysis H2C – OH H2C – O – P H2C – O – P
O H2C – O – C – R1 HO – CH H2C – O – P
Glycerol Glycerol 3-P Hydroxy acetone P
1-Acylglycerol 3-P(Lysophosphatidic acid)
Glycerol kinase Glycerol-3-Phosphate
dehydrogenas
ATP ADPNADH+HNAD
Acyltransferase Acyl-CoA (mainly saturated)
CoA
Acyl-CoA (mainly saturated)
Acyltransferase CoA
(1)
(2)
2929
O O H2C – O – C – R1 H2C – O – C – R1
R2 – C – O – C – H R2 – C – O – C – H O H2C – O – P O H2C – OH
O H2C – O – C – R1
R2 – C – O – C – H O O H2C – O – C – R3
1,2-DAG-P (Phosphatidic acid)
1,2-Diacylglycerol
Triacylglycerol
H2O Pi
Phosphatidate phosphohydrolase
Acyl-CoA
CoA
Acyltransferase
(3)
(4)
3030
Triacylglycerol producedproduced in the liverliver transportedtransported to;
Adipose tissueAdipose tissue & stores Blood VLDLVLDL During fastingfasting, insulin decreasesinsulin decreases while
glucagon increasesglucagon increases causing riserise in cAMPcAMP in adipose cells.
This stimulatesstimulates lipolysislipolysis, the process of breakdown of TAGs.
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Peroxisome = oxidizer of toxic substances: a tiny part within a cell containing enzymes that oxidize toxic substances such as alcohol and prevent them from doing any harm.
Porphyrin = compound in plants and animals: a metal-containing pigment in animal and plant tissue, consisting of four pyrrole rings linked by methylene groups, e.g. hemoglobin.
ACP = Acyl Carrier Protein HMG –CoA = Hydroxy Methyl Glutaryl Co A. Mushtaq Ahmad volume I. Lippincott’s
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