Summary of β-oxidation€¦ · Glycerol O O O O CH 2OC-R 1 CHOC-R 2 CH 2OC-R 3 CHO 2C-R 2 CH...
Transcript of Summary of β-oxidation€¦ · Glycerol O O O O CH 2OC-R 1 CHOC-R 2 CH 2OC-R 3 CHO 2C-R 2 CH...
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