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Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

Dec 26, 2015

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Page 1: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

Hendra WijayaEsa unggul University

Page 2: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

TRANSPORT OF ACETYL-COA INTO THE CYTOSOL

Page 3: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

Acetyl-CoA generated in the mitochondrion Mitochondrial membrane is impermeable to acetyl-CoA Acetyl-CoA enters the cytosol in the form of citrate Processing of malate to pyruvate generates NADPH for fatty

acid biosynthesis

TRANSPORT OF ACETYL-COA INTO THE CYTOSOL

Page 4: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

OVERVIEW OF FATTY ACID SYNTHESIS

Page 5: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

SYNTHESIS OF FATTY ACID

MOVIE

SYNTHESIS OF FATTY ACID

Page 6: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

Acetyl-CoA Carboxylase reaction

Page 7: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.
Page 8: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Irreversible reaction that is the committed step in fatty acid synthesis

• Biotin-dependent

• Mechanism similar to that of pyruvate carboxylase

• Subject to allosteric and hormonal control

– Stimulated by citrate, inhibited by long-chain fatty acids

– Phosphorylation, which inhibits enzyme activity, is promoted by glucagon and reversed by insulin

Acetyl-CoA Carboxylase reaction

Page 9: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

Intermediates in Fatty Acid Synthesis are Linked to Acyl Carrier Protein (ACP)

Page 10: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Intermediates attached to the sulfhydryl terminus of a phosphopantetheine group

• Phosphopantetheine linked to Ser hydroxyl of ACP, while attached to AMP in CoA

• ACP can be considered a big CoA molecule

• Individual enzymes in bacteria, enzyme complex in eukaryotes

• Condensation of malonyl-CoA and acetyl-CoA driven by decarboxylation

• Stereochemistry and reducing agent are different between synthesis and degradation

• In subsequent round of elongation, butyryl thioester condenses with malonyl-ACP after transfer to condensing enzyme

• Elongation cycles continue until palmitoyl(C16)-ACP is formed, which is hydrolyzed to give palmitate and ACP

REACTION SEQUENCE FOR FATTY ACID BIOSYNTHESIS

Page 11: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Stoichiometry of palmitate synthesis:

Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+ palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O

• Malonyl-CoA synthesis:

7 Acetyl-CoA + 7CO2 + 7ATP

7 malonyl-CoA + 7ADP + 7Pi + 7H+

• Overall stoichiometry of palmitate synthesis:

8 Acetyl-CoA + 14 NADPH + 7ATP + 7H+

palmitate + 14NADP+ + 8CoA + 6H2O + 7ADP + 7Pi

STOICHIOMETRY OF FATTY ACID BIOSYNTHESIS

Page 12: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.
Page 13: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• In eukaryotes, elongation occurs in both mitochondria and the endoplasmic reticulum (ER), but the ER system has much higher activity

• Reactions occur on separate enzymes rather than in a complex

• Fatty acid is elongated as its CoA derivative

• Two carbon units are added sequentially the carboxyl end of both saturated and unsaturated fatty acids

• Malonyl-CoA is again the two-carbon donor

FATTY ACID ELONGATION

Page 14: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Double bonds are introduced into long-chain acyl-CoAs through an electron-transfer process coupled to the reduction of molecular oxygen

• Reaction catalyzed by a complex of membrane-bound enzymes• Double bonds inserted such that the new double bond is three

carbons closer to the CoA group, and never beyond the C9 position

Fe2+

Fe3+ Fe2+

Fe3+

O

-O

O

-O

E-FAD

E-FADH2

NADH + H+

NAD+

NADH-cytochrome b5 reductase

cytochrome b5 desaturase

Oleoyl-CoA + 2H2O

Stearoyl-CoA + O2

stearate

oleate

FATTY ACID DESATURATION

Page 15: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• The formation of D12 and D15 double bonds is not possible in animals

• Animals cannot synthesize linoleic acid (18:2D9,12), linolenic acid (18:3D9,12,15), or arachidonic acid (20:4 D5,8,11,14), which are used in the synthesis of eicosanoid hormones– Prostaglandins– Leukotrienes

• These are called essential fatty acids because they are essential lipid components that must be provided in the diet

ESSENTIAL FATTY ACID

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• Generally synthesized from glycerol 3-phosphate, which is produced by the reduction of dihydroxyacetone phosphate (DHAP)

• Acylations performed with acyl-CoA and acyltransferases• Fatty acyl chain at C1 is usually saturated, fatty acyl chain at C2

is usually unsaturated• TG and phospholipid pathways generally diverge at

phosphatidic acid and diacylglycerol– Diacylglycerol formed by phosphatase– Acyltransferase forms TG

TRIACYLGLYCEROL (TG) SYNTHESIS

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Page 23: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

CONFORMATIONAL MODEL OF (A) PHOSPHOLIPID PHOSPHATIDYLCHOLINE AND (B) TRIACYLGLYCEROL

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HO

O

O P

O

O-

O

NH3

O

O-

O

R2

O

R1

HO

O

O P

O

O-

ON(CH3)3

O

R2

O

R1

HO

O

O P

O

O-

ONH3

O

R2

O

R1

HO

O

O P

O

O-

O

O

R2

O

R1

OH

OH

OHOH

HO

HO

O

O P

O

O-

O

O

R2

O

R1

CHOH

CH2OH

HO

O

O P

O

O-

OCH2CHCH2O

O

R2

O

R1

OH

P

O

O-

O

O

O

R2

O

O

R1

+

phosphatidylserine (PS)

++

phosphatidylcholine (PC)phosphatidylethanolamine (PE)

phosphatidyl-inositol (PI)

phosphatidyl-glycerol (PG)

cardiolipin (CL)

• C1 substituents mostly saturated fatty acids, C2 substituents mostly unsaturated fatty acids

• PE, PG, and CL found in bacteria, eukaryotes contain all six• Phospholipases serve as digestive enzymes and as generators

of signal molecules

GLYCEROPHOSPHOLIPIDS: Membrane

Lesitin

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Page 28: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

CTP: Citidene Tryphosphate

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HO

O

O P

O

O-

O P

O

O-

OO

HOH

HHHH

N

N

NH2

O

O

R2

O

R1

HO

O

O P

O

O-

O

NH3

O

O-

O

R2

O

R1

HO

O

OPO3

O

R2

O

R1

CTP PPi2-

phosphatidic acid CDP-diacylglycerol

serine

CMP

+

phosphatidyl-serine (PS)

CTP: Citidene Tryphosphate

Sytosin

Biosynthesis Of PhospatidylserineI: CDP-Diacylglycerol Pathway

Page 31: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

O P

O

O-

O P

O

O-

OO

HOH

HH

HH

N

N

NH2

O

(H3C)3N

HO

O

O P

O

O-

O

O

R2

O

R1

N(CH3)3

CTP PPi

P

O

-O O

O-N(CH3)3

HON(CH3)3

phosphocholine

ATP ADP

choline

+++

CDP-choline

1,2 diacylglycerol

CMP

+

phosphatidlycholine (PC, lecithin)

Biosynthesis Of Phospatidylcholine: CDP-Choline & CDP-ethanolamine

Page 32: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

PHOSPHOLIPID SYNTHESIS

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Page 36: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

04/19/23 36Metabolisme Lipida

Page 37: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Acetyl-CoA from fatty acid oxidation enters the citric acid cycle when fat and carbohydrate breakdown are balanced – Entry depends on oxaloacetate – Oxaloacetate consumed to form glucose

by gluconeogenesis in fasting, diabetes, and starvation

• In the absence of oxaloacetate, acetyl-CoA is converted to acetoacetate or D--hydroxybutyrate through ketogenesis

• Acetone is formed by the non-enzymatic decarboxylation of acetoacetate

• Ketone bodies are important fuel molecules

O O

O-

O

O

O-

OH

acetoacetate

acetone

D--hydroxybutyrate

OVERVIEW

KETONE BODIES

Page 38: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

1. Initial condensation

2. Ester condensation to form HMG-CoA (also precursor in cholesterol biosynthesis)

3. Acetoacetate and acetyl-CoA formed in a mechanism similar to the reverse of the citrate synthase reaction

Formation of keton bodies from acytil-CoA

Page 39: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Acetoacetate reduced to hydroxybutyrate in an NADH-dependent reaction

• Acetoacetyl-CoA can be cleaved by thiolase to give 2 acyl-CoA

• The liver can supply acetoacetate to other tissues

Metabolic Conversion of Ketone Bodies to Acetyl-CoA S

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HNH

O

O

R2

X

OH (CH2)12CH3

HNH

O

O

R2

P

OH (CH2)12CH3

O

O

O-N(CH3)3

sphingolipid

X = H ceramideX = carbohydrate glycosphingolipidX = phosphate ester sphingophospholipid

+

sphingomyelin

SPHINGOLIPIDS

Page 52: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

SPHINGOLIPIDS

Page 53: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Backbone is ceramide rather than glycerol• Most sphingolipids contain carbohydrates as their head

group• Sphingolipids play important roles in nervous tissue

– Sphingomyelin is an important component of the myelin sheath

– Gangliosides constitute 6% of the lipids in gray matter

SPHINGOLIPIDS

Page 54: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

SYNTHESIS OF CERAMIDA

Page 55: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Gangliosides are degraded inside lysosomes by the sequential removal of terminal sugars

• In Tay-Sachs disease, ganglioside GM2 accumulates because hexosaminidase activity is absent

• This ganglioside interferes with neuronal function

• Genetic recessive disease

GalGalNAcNAN

Glc

ceramide

ganglioside GM2

ganglioside GM3

N-acetylgalactosamine

Gal

NAN

Glc

ceramide

+

Toy-Sachs Disease: A Disorder of Ganglioside Breakdown

Page 56: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

• Have a hydrophilic and hydrophobic component

– 1,2-diacylglycerol or N-acetylsphingosine (ceramide) linked to a polar head group

– Hydrophobic acyl chains

• Form bilayered membranes in aqueous media

• Membranes are noncovalent, fluid assemblies

• Membrane lipids synthesized predominantly on the cytoplasmic face of the ER, then transported in vesicles to their destinations

MEMBRANE LIPIDS

Page 57: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

β

Page 58: Hendra Wijaya Esa unggul University. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL.

FATTY ACID BIOSYNTHESIS VS β-OXIDATION

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