Summary of β-oxidation

Energy yieldThe ATP yield for every oxidation cycle is 14 ATP, broken down as follows:

1 FADH2 x 1.5 ATP = 1.5 ATP 1 NADH x 2.5 ATP = 2.5 ATP

1 acetyl CoA x 10 ATP = 10 ATP

For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary and the final process yields an additional acetyl CoA.

In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as: (n - 1) * 14 + 10 - 2.Therefore, the total ATP yield can be stated as: (n - 1) * 14 + 10 - 2.

For instance, the ATP yield of palmitate (C16, n = 8) is:(8 - 1) * 14 + 10 - 2

106 ATPor

7 FADH2 x 1.5 ATP = 10.5 ATP 7 NADH x 2.5 ATP = 17.5 ATP

8 acetyl CoA x 10 ATP = 80 ATP ATP equivalent used during activation = -2

Total: 106 ATP

What Are Ketone Bodies?

• They aren’t “bodies”, and• Only two are ketones• Same origin : acetyl-coA

Synthèse à partir de l’acétylCoA (beta oxidation –catabolisme des AA)= cétogénèse

Catabolisme en acétylcoA = cétolyse

Enzymes sont mitochondriaux

Besoins énergétiques couverts par glucose et lipides

Si glucose manque il y a les acides gras

Tous les tissus n’y ont pas accès : cerveau

On fait appel aux corps cétonique

Cétogénèse : exclusivement dans le foie. Normalement faible (importante en période de Jeune, diabète sucré non équilibré)

Cétolyse : myocarde, muscles , cerveau et cortex rénal

Where Do These “Bodies” Come

From?• These 3 perfectly soluble small

molecules are• Produced in side reactions from

acetoacetyl-CoA at the penultimate step in β-oxidation,

• When there is excess acetyl-CoA for

β-ox

idat

ion

of F

As

condensation

• When there is excess acetyl-CoA for the TCA cycle

• This also produces free CoA• Thus allowing continued oxidation of

fatty acids in the liver• Acetone, the most volatile, is exhaled• Note reduction by β-HBdH and the

regeneration of S-CoA…

β-HBdH

Passent dans le sang et ….tissus extrahépatique

Ketone Bodies from Liver Can Be Used as Fuel Elsewhere

• The ketone bodies are then exported to other tissues

• Renal cortex, skeletal and heart muscle, and brain (though it prefers glucose)

β-HBdH

(though it prefers glucose) can oxidize ketone bodies for use in their TCA cycles

• Apport glucidique insuffisant, les corps cétonique prennent le relais, glucose est réservé aux tissus glucodépendants

From TCA

To TCA

• Cétogénèse est dépendante de la disponibilité mitochondriale de :

• Acétyl CoA. Défaut d’insuline (diabète, privation de glucide) accèlère lipolyse dans les tissus adipeux et on libère des acides gras captés comme substrats énergétique ou par le foie en tant que précurseurs des corps cétoniques

• En oxaloacétate• En oxaloacétate

Apport de glucide insuffisant, le taux d’oxaloacétate issu du pyruvate issue du glucose baisse et donc freine l’entrée de l’acétyl CoA dans le cycle de l’acide citrique

L’oxaloacétate issu du pyruvate provenant de lactate d’alanine, entièrement dirigé vers la néoglucogénèse

Acétyl coA issu de la beta oxydation s’engouffre dans la cétogénèse ce qui en plus libère du CoA permettant une beta oxidation continue

Ketogenesis (Ketosis): Formation of Ketone Bodies

2 CH3COSCoA CH 3COCH2COSCoAThiolase

CH3COSCoA

Acetoacetyl CoA

HMG CoA

HO2C-CH2-C-CH2COSCoA

OH

CH3

ββββ-Hydroxy- ββββ-methylglutaryl CoA(HMG CoA)

HMG CoASynthase

Cholesterol(in cytosol)

Severalsteps

Ketogenesis(in liver: mitochon-

drial matrix)

Ketogenesis: Formation of Ketone Bodies (Cont’d.)

HO2C-CH2-C-CH2COSCoA

OH

CH3

CH3COCH2CO2H

Acetoacetic Acid

HMG CoAlyase

- CH3COSCoA

HMG CoA- CO2

CH3COCH3

Acetone(volatile)

CH3CHCH2CO2H

OH

ββββ-Hydroxybutyrate

NADH + H+

NAD+Dehydrogenase

Ketone bodies are important sources of energy, especially in starvation

Ketone Bodies As Energy Sources

ββββ-Hydroxybutyrate Acetoacetate Succinyl CoA

ββββ-Ketoacyl CoAtransferase

Succinic acidAcetoacetyl CoA

transferase

2 Acetyl CoAThiolase

TCA Cycle

Rôle des acides gras

• Structural

• Fonctionnel

• énergétique

Exogènes : apport alimentaire couvre les besoins de l’organismeFoie , tissu adipeux et la glande mammaire en péride de lactation synthèse À partir de l’acetylcoA. Acide gras pouvant être remanier par élongation, désaturation

Fatty Acid Synthesis vs. Degradation

Intermediates

Synthesis Degradation

Linked to SH in Linked to CoASHProteins

Site

Enzymes

RedoxCoenzymes

Proteins (Acyl Carrier Proteins)

Cytosol Mitochondr ia

Components of Separate PolypeptidesSingle Peptide

NADP+ / NADPH NAD + / NADH

Fatty Acid Biosynthesis

• Occurs in cytosol• Starts with acetyl CoA• Starts with acetyl CoA

• Problem:» Most acetyl CoA produced in mitochondria» Acetyl CoA unable to traverse mitochondrial

membrane

Cytosol Mitochondria

Glucose Pyruvate Pyruvate Acetyl CoA

Fatty AcidsPyruvate

Dehydrogenase

BetaOxidation

Fatty Acids

Mitochondrial membrane

Oxalo-acetateCitrate

CitrateAcetyl CoA

ATP-CitrateLyase

Amino acids

Fatty Acids

Végétaux: chloroplastes

Mitochondria

Cytosol

Acetyl CoA

TCA CycleCitrate

Citrate

Oxaloacetate

(2C) Acetyl CoAAcetyl CoA

HCO3

ATP(3C) Malonyl CoA

COAcetyl CoA Carboxylase(biotin)

CO2

NADPH

4C Butyryl CoA

2C Acetyl CoA 3C Malonyl CoA

6C Caprayl CoA

CO2

NADPH

Fatty Acid Synthase

Complexe Enzymatique7 activités enzymatiques+ acyl protéine

propionylcoA

Source NADPHDécarboxylation malate –pyruvate (adipeux)Voie des pentoses phosphates

Fatty Acid Biosynthesis: Formation of Malonyl CoA

CH3COSCoA + ATP + HCO 3- -O2CCH2COSCoA

Acetyl CoACarboxylase Malonyl CoA

+ ADP + P i + H+

• Committed step in fatty acid synthesis• Reaction is irreversible• Regulation of acetyl CoA carboxylase activity:

by palmitoyl CoAby citrate

• Malonyl CoA inhibits carnitine acyl transferase I • Blocks beta oxidation

Fatty Acid Biosynthesis:Role of Acyl Carrier Proteins

CH3COSCoA CH3CO-S-ACP

AcetylTransferase

Malonyl

Acetyl ACP

-O2CCH2COSCoA -O2CCH2CO-S-ACP

MalonylTransferase

Malonyl ACP

ACP = Acyl carrier protein

Fatty Acid Biosynthesis:Formation of Acetoacetyl ACP

CH3CO-S-ACP + -O2CCH2CO-S-ACPββββ-Ketoacyl ACP

CH3COCH2CO-S-ACP + CO2Acetoacetyl ACP

ββββ-Ketoacyl ACPSynthetase

Fatty Acid Biosynthesis:Formation of Butyryl ACP

CH3COCH2CO-S-ACP CH3CCH2CO-S-ACP

OH

HAcetoacetyl ACP

ββββ-Ketoacyl ACPreductase

NADPH NADP+ HAcetoacetyl ACPββββ-D-Hydroxybutyryl ACP

NADPH+ H+

NADP+

CH3C=C-CO-S-ACP

H

H

ββββ-Hydroxyacyl ACPdehydratase- H2O

Crotonyl ACP

CH3CH2CH2CO-S-ACP

Butyryl ACP2,3-trans-Enoyl ACPreductase

NADPH+ H+

NADP+

Fatty Acid Biosynthesis:Sources of NADPH

Pentose Phosphate Pathway:

CHO

OHHO

CO2-

OHHO

NADP+NADPH+ H+ NADP+

NADPH+ H+ OH

OHO

OHOHOP

HOOHOHOP

HO

CO2

OHOHOP

Ribulose-5-phosphate6-Phospho-

gluconateGlucose-6-phosphate

Malic Enzyme:

HO-CH-CO2-

CH2CO2-Malate

CO2

NADP+

NADPH+ H+

Malic Enzyme

CH3CCO2-

O

Pyruvate

Mitochondria

Cytosol

Acetyl CoA

TCA CycleCitrate

Citrate

Oxaloacetate

(2C) Acetyl CoAAcetyl CoA

HCO3

ATP(3C) Malonyl CoA

COAcetyl CoA Carboxylase(biotin)

CO2

NADPH

4C Butyryl CoA

2C Acetyl CoA 3C Malonyl CoA

6C Caprayl CoA

CO2

NADPH

Fatty Acid Synthase

Complexe Enzymatique7 activités enzymatiques+ acyl protéine

Bactéries et végetaux : Poly indépendantesAnimaux: dimère

propionylcoA

Source NADPHDécarboxylation malate –pyruvate (adipeux)Voie des pentoses phosphates

Fatty Acid Biosynthesis:Chain Elongation

CH3CH2CH2CO-S-ACP -O2CCH2CO-S-ACP+

CH3CH2CH2COCH2CO-S-ACP

CH2CH2CH2CHCH2CO-S-ACP CH3CH2CH2C=CCO-S-ACP

H

H

OH

Fatty Acid Biosynthesis:Chain Elongation (Cont’d)

CH3(CH2)3CH2CO-S-ACPCH3CH2CH2C=CCO-S-ACP

H NADPH+ H+

NADP+

H

CH3(CH2)13CH2CO-S-ACP

5 Cycles

Palmitoyl ACPCH3(CH2)13CH2CO2

-

Palmitate

Further Processing of Fatty Acids: Elongation

CH3(CH2)13CH2CO2-

Palmitate

Thiolase

CH3COSCoA

In mitochondria andat surface of endoplasmic reticulum

Navette carnitinepalmitoylcoA

CH3(CH2)13CH2COCH2COSCoA

CH3(CH2)13CH2CCH2COSCoA

OH

H

NADH + H+

NAD+

Thiolase

Dehydrogenase

L-ββββ Configuration

palmitoylcoA

Further Processing of Fatty Acids: Elongation (Cont’d)

CH3(CH2)13CH2CCH2COSCoA

OH

H- H2O

CH3(CH2)13CH2C=CCOSCoA

H

H

- H2OHydratase

CH3(CH2)13CH2CH2CH2COSCoA

Stearoyl CoA

NADPH + H+

NADP+

Dehydrogenase

Further Processing of Fatty Acids: Unsaturation

CH3(CH2)13CH2CH2CH2COSCoAStearoyl CoA

Stearoyl CoADesaturase

O2

CH3(CH2)7C=C(CH2)7COSCoA + H2O

H HOleoyl CoA

This reaction occurs in eukaryotesEndoplasmic reticulum membrane

Desaturase

Further Processing of Fatty Acids: Polyunsaturation

CH3(CH2)7C=C(CH2)7CO2H

H HOleic acid

Plants: Further unsaturationoccurs primarily in this region

Animals: Further unsaturationoccurs primarily in this region

(18:1∆∆∆∆9)

9

occurs primarily in this region occurs primarily in this region

CO2H

Linoleic acid (18:2 ∆∆∆∆9, 12)

12 9

Linolenic acid (18:3 ∆∆∆∆9, 9, 9, 9, 12, 15)

15 12 9

Essential dietaryfatty acids in mammals

CO2H

Formation of Arachidonate in Mammals

Linoleic acid As CoA ester:1) Elongation

CO2H

CO2H14 11 8 5

Arachidonic acid (20:4 ∆∆∆∆5, 5, 5, 5, 8, 11, 14)(Eicosa-5,-8,11,14-tetraenoic acid)

1) Elongation2) Desaturation x 2

Prostaglandins

Omega-3 Fatty AcidsCO2H

CO2H

ωωωω-3 double bond Eicosapentaenoic acid (20:5 ∆∆∆∆5, 5, 5, 5, 8, 11, 14, 17)

CO2H

Docahexaenoic acid (22:6 ∆∆∆∆4, 4, 4, 4, 7, 10, 13, 16, 19)

• Found in fish oils, esp. cold water fish• Important in:

Growth regulationModulation of inflammationPlatelet activationLipoprotein metabolism

Metabolite Regulation of Fatty Acid Synthesis and Breakdown

Pyruvate Acetyl CoA Malonyl CoA

Citrate

Stimulates

BetaBlocks

Glucose

Pyruvate Acetyl CoA Malonyl CoA

Palmitoyl CoA

Inhibits

BetaOxidation

Hormonal Regulation of Fatty Acid Synthesis and Breakdown

ATP cAMP AMPAdenylyl cyclase Phosphodiesterase

Stimulates

Glucagon

Stimulates

Insulin

Stimulates

Activates Protein Kinase

Inactivates ACC byphosphorylation

Inhibition offatty acidsynthesis

Activates triacyl-glycerollipase

Inactivateslipase

Synthesis of Phosphatidic Acid

O-

O

-

O

CH2O-P-O-

CH2O2C-R1

CHO2C-R2C=O

CH2OH

CH2O-P-O-CH2OH

CHOH

CH2OH

Dihydroxyacetone Phosphate

(from glycolysis)

Glycerol

O- O-

O

O

O

CH2OC-R1

CHOC-R2

CH2OC-R3

CHO2C-R2

CH2O2C-R1

CH2OH

CH2O-P-O2 CH2OH

Phosphatidic acid

Diacylglycerol(important incell signaling)

R3COSCoA

Diacylglycerolacyltransferase

Triacylglycerol

Triglyceride synthase(membrane du réticulum lisse)

Synthesis of Glycerophospholipids

CH2OH

CH2O2C-R1

CHO2C-R2

N

N

NH2

O

O

OHOH

R3NCH2CH2OPOPO+

R=H; CDP ethanolamine

+ Transferase

O

CHO2C-R2

CH2O2C-R1

CH2O-P-O-CH2CH2R3CH2OHR=H; CDP ethanolamineR=CH3; CDP cholineCDP = cytidine diphosphate

DiacylglycerolR3=NH3; Phosphatidylethanolamine

R3=N(CH3)3; Phosphatidylcholine

O-

O

CO2-

CH2O-P-O-CH2CHNH 3

CH2O2C-R1

CHO2C-R2

+

+

CO 2-

HOCH 2CHNH3

HOCH 2CH2NH3

+ Serine

Ethanolamine

O-CH2O-P-O-CH2CH2R3

+

+

Phosphatidylserine

Synthesis of Glycero -phospholipids (Cont’d)

O

CHO2C-R2

CH2O2C-R1

CH2O-P-O-CH2O-CDP

CH2O2C-R1

CHO2C-R2 Phosphatidyl-inositol

O-

O

OH OH

CH2O-P-O

CH2O2C-R1

CHO2C-R2

O-CH2O-P-O CH2O-CDP

Phosphatidic acid Cytidine diphosphate (CDP) diacylglycerol OH

OHHO

OH

OH

OPO3H2H2O3PO

OH OH

OPO3H2

CH2OH

CH2O2C-R1

CHO2C-R2+

Diacylglycerol (DAG)

Phospholipase C

Both IP 3 and DAG are important second messengersin cell signaling pathways

Inositol-1,4,5-triphosphate (IP 3)

Synthesis of Glycero -phospholipids (Cont’d)

CHO C-R

CH2O2C-R4CH2O2C-R1

CHO2C-R2

CH2O2C-R1

CHO2C-R2

O-

O O

O-OH

CHO2C-R3

CH2O-P-O-CH2CHCH2-O-P-O-CH2

CHO2C-R2

CH2O-CDP

CHO2C-R2

Cytidine diphosphate (CDP) diacylglycerol Cardiolipin

Quite a VarietyNote trends:

MP vs lengthMP vs saturation

Solubility vs length

Uns

at’d

Sat

’d

Table 10-1

Uns

at’d

Sat

’d

Do Classes of Lipids Make Sense?

Glycerol backbone Sphingosine backbone

Sphingolipids

Sphingosine,Is a fatty amine,A feature that’sOutlined in green!

Some rhymes…

Outlined in green!

No glycerolAt all!

Sterols: Structural Lipids, Hormone Precursors, and Detergents

• Have a structural role in most eukaryotic membranes (we’ll see why later)

Fig. 10-16

• Hormone derivatives regulate gene expression

• Bile acids are polar derivatives that help emulsify dietary fats

Turnover of Membrane Phospholipids Exploits Specific Enzymes

Glycerophospholipid synthesis starts with phosphatidic acid or diacylglycerol

Phosphatidylserine is formed from phosphatidylethanolamine byan exchange of the polar head group

Figure 25-79 Phosphatidylserine synthesis .Page 971

Ceramide comes from Palmitoyl~CoA, serine, and an acyl~CoA

Cholesterol is synthesized from acetyl~CoA in three stages

1. Synthesis of isopentenyl pyrophosphate, an activated isoprene unit.

2. Condensation of 6 molecule of IPP to form squalene.

3. Squalene cyclizes and the tetracyclic product is converted to cholesterol.

Cholesterol is a component of membranes and a precursor to steroids and bile salts.

Sphingolipid biosynthesis

Stage 2: the condensation of isoprenoid units

mechanism of IPP isomeraseHMG-CoA reductase catalyzes an irreversible reactionthat is the committed step. It is highly regulated.

Likely mechanism for the prenyl transferase reaction

Page 947

Formation of squalene

Figure 25-47 Formation of squalene from isopenteny l pyrophosphate and dimethylallyl

pyrophosphate.

Page 946

Stage three: Lanosterol is produced by squalene cyclization

Figure 25-42 Squalene. ( a) Extended conformation. Each box contains one isop rene unit. (b) Folded in preparation for cyclization as predicte d by Bloch and Woodward.

The cyclization reaction occurs in two steps: Squalene epioxidase forms 2,3 oxidosqualene,lanosterol synthase brings about cyclization by protonation of the epioxide, the cyclizationinvolves a series of hydride and methyl shifts.

The squalene epioixidase reaction

The lanosterol synthase reaction

enzyme protonates the epioxide, forminga cation.

a series of methyl and hydride migrationsa series of methyl and hydride migrationsprobably yeilds carbocation at position C8

elimination of a proton gives C8-C9double bond

Pentose Phosphate Pathway

• Produces reducing power• Produces ribose and other pentoses

Glucose 6-phosphate ----------> ----------> C5 -----------> ribose 5P

Overview• Important products of PPP

– Production of NADPH – the pyridine nucleotide used for reductive biosynthesis• Fatty acids• Cholesterol• Nucleic acids• Nucleic acids

– Formation of ribose 5-phosphate for ribonucleotides• RNA, DNA, certain coenzymes

• Mammary glands, liver, adrenal glands, adipose– Not in brain and muscle

• Enzymes of pathway are cytosolic

NADPH

• Enzymes that have a high affinity for NADPH have a 1000-fold lower 1000-fold lower affinity for NADH.

Phase oxidative(irréversible)

D’isomérisation

Pentose Phosphate Pathway

Non-oxidative

Pentose Phosphate Pathway: Oxidative Phase

Production of 2 NADPH and ribulose-5-phosphate from glucose-6-phosphate

Étape limitante dépendanteDu ratio NADP/NADPH

glucose-6-phosphate

Pentose Phosphate Pathway: Nonoxidative Phase

Si besoin que de NADHP, ribose 5 phosphate retourne à la glycolyse.

Comment passer C5 à un C6 sans fixation de Comment passer C5 à un C6 sans fixation de carbone

6C5 donneront 5C6

+xyulose-5-P � G-3-P + F-6-P