Lipid Metabolism

Lipid Metabolism

Fatty Acids

CH3(CH2)nCH2CO2H

OO

O

CH3(CH2)nCH2C-O-R

CH3(CH2)nCH2C-OH H-O-R

O

O

CH3(CH2)nCH2C-OH H-S-R

CH3(CH2)nCH2C-S-R

Ester Thioester

Release of Fatty Acids from Triacylglycerols

O

O LipasesCHOH

CH2OHCH2OC-R1

CHOC-R2

O

O O O

+

HOC-R3 HOC-R2 HOC-R1

Triacylglycerol Glycerol

CH2OH

CHOHCHOC-R2

CH2OC-R3

Hormone(Adrenalin, Glucagon, ACTH)

Receptor

ATP c-AMP

AdenylylCyclase

Activates

Lipolysis

Adipose Cell

Activates lipase

Triacylglycerols Glycerol +Fatty acids Blood

Insulinblocks thisstep

ATP c -AMP AMP

Inactive Kinase Activated Kinase

Inactive Lipase Activated Lipase

P

Adenylyl cyclase Phosphodiesterase

Enhanced by insulinEnhanced by glucagon

Inactive Lipase Activated Lipase

Triacyl-glycerol

Glycerol +Fatty Acids

Phosphatase(Hormone-sensitiveLipase)

Insulin favors formationof the inactive lipase

Acylglycerol Lipases

TriacylglycerolLipase

DiacylglycerolLipase

OH

Triacylglycerol (TAG)

Diacylglycerol (DAG)

Lipase

OH

OH

MonoacylglycerolLipase

OH

OH

OH

Monoacylglycerol(MAG)

Glycerol

Beta Oxidation

• Cleavage of fatty acids to acetate in tissues

• Occurs in mitochondria

9 CH3COSCoACO2H

[O] [O] [O] [O] [O][O] [O] [O]

N atomes de carbone N/2 molécules acétylCoA

Steps in Beta Oxidation

• Fatty Acid Activation by Esterification with CoASH

• Membrane Transport of Fatty Acyl CoA EstersEsters

• Carbon Backbone Reaction Sequence• Dehydrogenation• Hydration• Dehydrogenation• Carbon-Carbon Cleavage (Thiolase Reaction)

Fatty Acid Activation by Esterification with CoASH

CoASH + RCO 2H + ATP RCOSCoA + AMP + PP i

AcylCoA

Synthetase Pyrophos-phatase

Synthetase

2 Pi

phatase

Occurs in outer mitochondrialmembrane for long chain fatty acids

ATP AMP + PP i -32.3CoASH + RCO 2H RCOSCoA +31.5PPi 2 Pi -33.6

∆∆∆∆G0’(KJ/mole)

-34.4

Lipid Metabolism

Membrane Transport of Fatty Acyl CoA Esters

(CH3)3NO

O -OH

Carnitineacyltransferase II(matrix side of inner mitochondrial

Carnitineacyltransferase I(outer part of mitochondrial

Carnitine

+RCOSCoA +

Transported across inner mitochondrial

membrane by translocase

(CH3)3NO

O -O2CR

inner mitochondrialmembrane)

(outer part of mitochondrial inner membrane)

O-Acylcarnitine

+

Beta Oxidation Reaction SequenceH H

H H

H

H

Enoyl CoA Hydratase

R-CH2-C-C-COSCoA R-CH2-C=C-COSCoA

Acyl CoADehydrogenase

FAD FADH2trans-∆2-enoyl CoA

H2O

L-β-Hydroxyacyl β-Ketoacyl CoA

Occurs in Mitochondria

Repeat Sequence

H H

HO HO

H

O

H

O

R-CH2-C-C-COSCoAR-CH2-C-C-COSCoA

R-CH2-C-SCoA CH3-C-SCoA

L-β-Hydroxyacyl CoA

L-β-Hydroxyacyl CoADehydrogenase

NAD+NADH + H+

CoASH

+

Thiolase

β-Ketoacyl CoA

Complete Beta Oxidation of Palmitoyl CoA

CH3CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA

7 Cycles7 Cycles

8 CH3COSCoA + 7 FADH 2 + 7 NADH + 7 H+

Energetics of Complete Oxidation of Fatty Acids

Palmitic Acid Palmitoyl CoA -1

CH COSCoA CO + H O 131

High Energy PhosphateBonds Generated

TCA CycleCH3COSCoA CO 2 + H2O 131

Net 130

TCA Cycle

130 High Energy Phosphate Bonds ∆∆∆∆G0’ = 3965 KJ/Mole

For Palmitic Acid CO 2:∆∆∆∆G0’ = - 9790 KJ/Mole

Efficiencyof ββββ-Oxidation = 25%

ATP = -30.5 KJ/mol

Beta Oxidation

Beta Oxidation

Beta Oxidation of Odd Carbon Fatty Acids (veg)

CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA

5 Cycles

5 CH3COSCoA + CH 3CH2COSCoA

Propionyl CoA

CO2H

COSCoA

H-C-CH3

CO2H

COSCoA

CH3-C-HHO2CCH2CH2COSCoA

D-MethylmalonylCoA

L-MethylmalonylCoA

Succinyl CoA

TCA Cycle

Propionyl CoA CarboxylaseATP/CO2

EpimeraseMutase

Vit. B 12

Beta Oxidation of Unsaturated Fatty Acids

H H

CH3(CH2)7-C=C-CH2(CH2)6COSCoA

Oleoyl CoABeta Oxidation

H H

CH3(CH2)7-C=C-CH2COSCoA

H

H

CH3(CH2)7-CH2-C=C-COSCoA

Beta Oxidation(3 Cycles)

cis-∆∆∆∆3

Isomerase

trans-∆∆∆∆2

Continuation of Beta Oxidation

Beta Oxidation of Branched Chain Fatty Acids

CH3 CH3

CH3(CHCH2CH2CH2)3CHCH2CO 2H

Phytanic Acid (from breakdown of chlorophyll)(from breakdown of chlorophyll)

CH3 CH3

OH

CH3(CHCH2CH2CH2)3CHCHCO 2HCH3 CH3

CH3(CHCH2CH2CH2)3CHCO 2H

αααα-Hydroxylase

αααα-Oxidation

(in peroxisomes)

CO2

Pristanic Acid

Beta Oxidation of Branched Chain Fatty Acids (Cont’d)

CH3 CH3

CH3(CHCH2CH2CH2)3CHCO 2H

Pristanic Acid

CH3 CH3

CH3(CHCH2CH2CH2)3CHCOSCoA

Pristanoyl CoA

Beta Oxidation(6 cycles)

CH3CHCOSCoA + 3 CH 3CH2COSCoA + 3 CH 3COSCoA

CH3

iso-Butyryl CoA Propionyl CoA Acetyl CoA

HO2CCH2CH2COSCoASuccinyl CoA

TCA Cycle