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21 | Lipid Biosynthesis. Lecture Connections. © 2009 W. H. Freeman and Company. CHAPTER 21 Lipid Biosynthesis . Biosynthesis of fatty acids and eicosanoids Biosynthesis of triacylglycerols Biosynthesis of fatty cholesterol.

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lecture connections

21 | Lipid Biosynthesis

Lecture Connections

© 2009 W. H. Freeman and Company

chapter 21 lipid biosynthesis
CHAPTER 21Lipid Biosynthesis
  • Biosynthesis of fatty acids and eicosanoids
  • Biosynthesis of triacylglycerols
  • Biosynthesis of fatty cholesterol

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
slide5

Subcellular localization of lipid metabolism. Yeast and vertebrate cells differ from higher plant cells in the compartmentation of lipid metabolism. Fatty acid synthesis takes place in the compartment in which NADPH is available for reductive synthesis (i.e., where the [NADPH]/[NADP+] ratio is high); this is the cytosol in animals and yeast, and the chloroplast in plants. Processes in red type are covered in this chapter.

overview of fatty acid synthesis
Overview of Fatty Acid Synthesis
  • Fatty acids are built in several passes processing one acetate unit at a time
  • The acetate is coming from activated malonate in the form of malonyl-CoA
  • In each pass involves reduction of a carbonyl carbon to a methylene carbon
slide8

The overall process of palmitate synthesis. The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO2 at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of four, then six, then eight carbons, and so on. The final product is palmitate (16:0).

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
slide10

The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction; and transcarboxylase, which transfers activated CO2 (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.

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
slide12

The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein; biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction; and transcarboxylase, which transfers activated CO2 from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.

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
what were the steps of fa degradation
What were the steps of FA degradation????
  • 1. Oxidation
  • 2. Hydration
  • 3. Oxidation
  • 4. Cleavage
  • Design a synthesis pathway for FAs.
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
slide20

Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system.

1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons.

The β-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of β oxidation, but in the reverse sequence:

2 the β-keto group is reduced to an alcohol,

slide21

Step 3 elimination of H2O creates a double bond

Step 4 the double bond is reduced to form the corresponding saturated fatty acyl group.

slide22

Fatty Acid Synthase in Animals and Fungi is a Large Multifunctional Polypeptide

KS :β-ketoacyl-ACP synthase

MAT: malonyl/acetyl-CoA—ACP transferase

DH: β-hydroxyacyl-ACP dehydratase

ER:enoyl-ACP reductase

KR:β-ketoacyl-ACP reductase

The seventh domain (TE) is a thioesterase that releases the palmitate product from ACP when the synthesis is completed. The ACP and TE domains are disordered in the crystal and are not shown in the structure.

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
synthesis of unsaturated fatty acids
Synthesis of Unsaturated 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
vertebrate fatty acyl desaturase is non heme iron containing mixed function oxidase
Vertebrate Fatty Acyl Desaturase is Non-Heme Iron-Containing 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
  • Dioxygenases incorporate both oxygen atoms into the organic product
dioxygenase reaction example
Dioxygenase Reaction: Example
  • Converted to starch in the chloroplast
  • Converted to sucrose for export
  • Recycled to ribulose 1,5-bisphosphate
iron cofactors in mono oxygenases
Iron Cofactors in Mono-oxygenases
  • Single iron in the heme ring
    • Found in the cytochrome P-450 family
    • Heme ring stabilizes radicals intermediates
  • Di-iron-oxo bridged clusters
    • Well-studies in methane monooxygenase
    • Not so well understood in fatty acid desaturases
    • Co-substrate Cyt b5 reduces di-iron Fe3+ to di-iron Fe2+
    • O2 acquires two electrons from di-iron Fe2+ and forms a Fe2(iV)O2 intermediate that oxidizes the fatty acid
synthesis of eicosanoids
Synthesis of Eicosanoids
  • Cyclooxygenase activity does not require metal cofactors
  • Cyclooxygenase is a target for many anti-inflammatory drugs
formation of mevalonate
Formation of Mevalonate
  • HMG-CoA reductase is a target for some cardiovascular drugs
formation of squalene
Formation of Squalene
  • Pyrophosphate is a good leaving group in these nucleophilic substitution reactions
regulation of cholesterol biosynthesis
Regulation of Cholesterol Biosynthesis
  • Insulin means “we have plenty of glucose”
  • Glucagon means “we are out of 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