hendra wijaya esa unggul university. transport of acetyl-coa into the cytosol
TRANSCRIPT
Hendra WijayaEsa 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
OVERVIEW OF FATTY ACID SYNTHESIS
SYNTHESIS OF FATTY ACID
MOVIE
SYNTHESIS OF FATTY ACID
Acetyl-CoA Carboxylase reaction
• 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
Intermediates in Fatty Acid Synthesis are Linked to Acyl Carrier Protein (ACP)
• 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
• 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
• 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
• 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
• 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
• 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
CONFORMATIONAL MODEL OF (A) PHOSPHOLIPID PHOSPHATIDYLCHOLINE AND (B) TRIACYLGLYCEROL
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
CTP: Citidene Tryphosphate
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
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
PHOSPHOLIPID SYNTHESIS
04/19/23 36Metabolisme Lipida
• 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
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
• 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
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
SPHINGOLIPIDS
• 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
SYNTHESIS OF CERAMIDA
• 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
• 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
β
FATTY ACID BIOSYNTHESIS VS β-OXIDATION