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CHAPTER 21 Lipid Biosynthesis . Biosynthesis of fatty acids and eicosanoids Biosynthesis of isoprenes and cholesterol Cholesterol regulation Biosynthesis of triacylglycerols, and membrane lipids. Key topics : . Lipids Fulfill a Variety of Biological Functions. Storage of energy

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chapter 21 lipid biosynthesis
CHAPTER 21Lipid Biosynthesis
  • Biosynthesis of fatty acids and eicosanoids
  • Biosynthesis of isoprenes and cholesterol
  • Cholesterol regulation
  • Biosynthesis of triacylglycerols, and membrane lipids

Key topics:

lipids fulfill a variety of biological functions
Lipids Fulfill a Variety of Biological Functions
  • Storage of energy
  • Constituents of cellular membranes
  • Anchors for membrane proteins
  • Cofactors for enzymes
  • Signaling molecules
  • Pigments
  • Detergents
  • Transporters
  • Antioxidants
catabolism and anabolic of fatty acids proceed via different pathways
Catabolism and Anabolic of Fatty Acids Proceed via Different Pathways
  • Catabolism of fatty acids
    • produced acetyl-CoA
    • reducing power to NADH
    • location: mitochondria
  • Anabolism of fatty acids
    • requires malonyl-CoA and acetyl-CoA
    • reducing power from NADPH
    • location: cytosol in animals, chloroplast in plants
overview of fatty acid synthesis
Overview of Fatty Acid Synthesis
  • Fatty acids are built in several passes processing one acetate unit at a time
  • Acetate from activated malonate in the form of malonyl-CoA
  • In each pass involves reduction of a carbonyl carbon to a methylene carbon
synthesis of malonyl coa 1
Synthesis of Malonyl-CoA (1)
  • The three-carbon precursor for fatty acid synthesis is made from acetyl-CoA and CO2
  • The reaction is catalyzed by acetyl-CoA carboxylase (ACC)
  • ACC is a bifunctional enzyme
    • Biotin carboxylase
    • Transcarboxylase
  • ACC contains biotin, nature’s carrier of CO2
    • Biotin shuttles between the two active sites
synthesis of malonyl coa 2
Synthesis of Malonyl-CoA (2)
  • Bicarbonate reacts with the terminal phosphate of ATP to give carbamoyl phosphate
  • Biotin carries out a nucleophilic attack to carbamoyl phosphate
  • The product is a good donor of a carboxylate group
synthesis of malonyl coa 3
Synthesis of Malonyl-CoA (3)
  • The arm swing moves carboxybiotin to the transcarboxylase site
  • Terminal methyl of acetyl-CoA probably deprotonates to give a resonance-stabilized carbanion
  • The carbanion picks up the carboxylate moiety from biotin
fatty acid synthesis
Fatty Acid Synthesis
  • Overall goal is to attach a two-carbon acetate unit from malonyl-CoA to a growing chain and then reduce it
  • Reaction involves cycles of four enzyme-catalyzed steps
    • Condensation of the growing chain with activated acetate
    • Reduction of carbonyl to hydroxyl
    • Dehydration of alcohol to trans-alkene
    • Reduction of alkene to alkane
  • The growing chain is initially attached to the enzyme via a thioester linkage
  • During condensation, the growing chain is transferred to the acyl carrier protein
  • After the second reduction step, the elongated chain is transferred back to fatty acid synthase
acyl carrier protein
Acyl Carrier Protein
  • Contains a covalently attached prothetic group 4’-phospho-pantethiene
  • The acyl carrier protein delivers acetate (in the first step) or malonate (in all the next steps) to the fatty acid synthase
  • The acyl carrier protein shuttles the growing chain from one active site to another during the four-step reaction
charging the acyl carrier protein and fatty acid synthase
Charging the Acyl Carrier Protein and Fatty Acid Synthase
  • Two thiols participate in the fatty acid synthesis
    • Thiol from 4-phosphopantethine in acyl carrier protein
    • Thiol from cysteine in fatty acid synthase
  • Both thiols must be charged for the condensation reaction to occur
    • In the first step, acetyl from acetyl-CoA is transferred to acyl carrier protein
    • Acyl carrier protein passes this acetate to fatty acid synthase
    • Acyl carrier protein is then re-charged with malonyl from malonyl-CoA
assimilation of two carbon units condensation and first reduction
Assimilation of Two-Carbon UnitsCondensation and First Reduction
  • 1 Condensation of an activated acyl group
  • 2 the β-keto group is reduced to an alcohol
assimilation of two carbon units dehydration and second reduction
Assimilation of Two-Carbon UnitsDehydration and Second Reduction
  • 3 elimination of H2O creates a double bond, and
  • 4 the double bond is reduced
enzymatic activities in fatty acid synthase
Enzymatic Activities in Fatty Acid Synthase
  • Condensation with acetate
    • -ketoacyl-ACP synthase (KS)
  • Reduction of carbonyl to hydroxyl
    • -ketoacyl-ACP reductase (KR)
  • Dehydration of alcohol to alkene
    • -hydroxyacyl-ACP dehydratase (DH)
  • Reduction of alkene to alkane
    • enoyl-ACP reductase (ER)
  • Chain transfer
    • Malonyl/acetyl-CoA ACP transferase
c16 c18 and of un saturated fatty acids
C16, C18 and of Un-saturated Fatty Acids
  • Animals can readily introduce one double bond to palmitate and stearate
  • Vertebrates cannot introduce additional double bonds between C10 and methyl-terminal
  • We must obtain linoleate and -linolenate with diet; these are essential fatty acids
  • Plants, algae, and some insects synthesize linoleate from oleate
pc oleate acts as a substrate for plant desaturases
PC-Oleate Acts as A Substrate for Plant Desaturases
  • Oleic and Linoleic Acids are essential Fatty acids
vertebrate fatty acyl desaturase
Vertebrate Fatty Acyl Desaturase
  • Non-Heme Iron -- Mixed Function Oxidase
  • O2 accepts four electrons from two substrates
  • Two electrons come from saturated fatty acid
  • Two electrons come from ferrous state of Cytochrome b5
oxidases monooxygenase dioxygenase
Oxidases, Monooxygenase, Dioxygenase
  • Molecular oxygen can serve as an electron acceptor
  • Oxidases do not incorporate oxygen atoms into the organic product
    • Oxygen atoms usually end up in hydrogen peroxide
    • Often use flavin as redox cofactors
  • Monooxygenases incorporate one of the oxygen atoms into the product
    • The other oxygen ends up in water
    • Often use iron as redox cofactor
    • Cytochrome P450
  • Dioxygenases incorporate both oxygen atoms into the organic product
eicosanoids signalling functions
Eicosanoids - Signalling functions
  • Prostaglandins
    • Gastric Mucin (Cox-1)
    • Inflammation, Pain Fever (Cox-2)
  • Thromboxanes
    • Blood Clotting
  • Leukotrienes
    • Signal through G-protein Coupled receptors
    • Asthma and Bronchodilation
synthesis of eicosanoids
Synthesis of Eicosanoids
  • Cyclooxygenase is a target for many anti-inflammatory drugs
biosynthesis of cholesterol
Biosynthesis of Cholesterol
  • Summary

1. Acetyl CoA => Mevalonate

2. Mevalonate => Isoprenes

3. 6 isoprenes => squalene

4. Squalene to lanosterol

1 formation of mevalonate
1. Formation of Mevalonate
  • HMG-CoA reductase is a target for some cardiovascular drugs
formation of activated isoprene
Formation of Activated Isoprene
  • Pyrophosphate is a good leaving group in these nucleophilic substitution reactions
cholesteryl esters
Cholesteryl esters.

Esters more hydrophobic

for storage and transport

sterol regulatory element binding proteins srebps released in response to membrane sterol content
Sterol regulatory element-binding proteins (SREBPs) released in response to membrane sterol content
regulation of cholesterol biosynthesis
Regulation of Cholesterol Biosynthesis
  • Insulin “high glucose”
  • Glucagon “low glucose”
chapter 21 summary
Chapter 21: Summary

In this chapter, we learned that:

  • Malonyl-CoA is an important precursor for biosynthesis of fatty acids
  • Fatty acid synthesis is carried out by a large enzyme that contains multiple catalytic activities needed for the condensation, and subsequent reduction of acetate units
  • Not all organisms can synthesize polyunsaturated fatty acids; these that can utilize mixed function oxidases as desaturase
  • Cholesterol biosynthesis starts with synthesis of mevalonate from acetate; mevalonate yields two activated isoprenes; series of isoprene condensation steps gives squalene; oxidation and ring closure of squalene gives cholesterol