Fatty Acid Synthesis
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FA + GLYCEROL •
•
•
GLYCEROL o
Gluconeogenesis
o
FA synthesis
CARNITINE ACYLTRANSFERASE II – located in the INNER MITOCHONDRIAL MEMBRANE BETA OXIDATION •
FA -> Acetyl CoA
•
4 steps:
FA
o o
Oxidation
o
Storage
o
Free w/ albumin
OXIDATION (1ST)
Oxidation of FA by Acyl CoA Dehydrogenase
Forms a double bond between C2 & C3
Produces FADH2 from FAD
LIPOPROTEIN LIPASE – enzyme
FREE FATTY ACIDS – virtually all cells can use Fatty Energy except Brain, RBC & Medulla BETA OXIDATION •
Major pathway for catabolism of FA
•
2 carbon fragments are cleaved producing Acetyl CoA (enters Kreb’s Cycle)
o
HYDRATION
o
OXIDATION (2ND)
STEPS:
Hydroxyacyl CoA oxidized by NAD+
Became 3-Ketoacyl CoA
Forms NADH
1. TRANSPORT OF FA INTO MITOCHONDRIA •
After FA are taken up by a cell, it is converted to a CoA derivative (fatty acylCoA) o
•
Fatty aclyCoA synthetase/thiokinase
•
Transport to mitochondria
THIOLYTIC CLEAVAGE (THIOLYSIS)
*Mitochondrial membrane is impermeable
Cleavage of 3-Ketoacyl CoA by thiol group of another CoA
Produces shorter Acyl CoA and Acetyl CoA
CARNITINE SHUTTLE •
Acyl group must first be transferred Cytosolic CoA to Carnitine
•
Catalyzed by Carnitine Acyltransferase I
•
Forming Fatty Acyl Carnitine I & II
•
Inhibited by: MALONYL CoA
CARNITINE ACYLTRANSFERASE I – located in the OUTER MITOCHONDRIAL MEMBRANE
Add H2O
ENERGY YIELD FROM BETA OXIDATION •
•
Each time an acetyl group (2 carbons) is cleaved from acyl chain, it produces: o
1 NADH
o
1 Acetyl CoA
o
1 FADH2
Therefore:
*Carnitine is not needed inside the mitochondria because it is only a shuttle
o
PALMITATE (16:0) 16/2 = 8 – 1 = 7cycles
* Fats yield high energy •
O.H.O.T. FORMULA = (n/2) – 1
PALMITATE – 7 CYCLES
o 7 NADH
x3ATP
= 21
7 FADH2
x2ATP
= 14
RELEASE OF FA FROM TAG
8Acetyl CoA x 12ATP = 96 131 Energy investment FAcyl CoA synthase _-2 Total ATP
129
•
Mobilization of STORED FAT
•
HORMONE – SENSITIVE LIPASE o
Breaks stored fat
o
Present in ADIPOSE TISSUES
18 carbon = 8cycles
o 8 NADH
x3ATP
=
24
8 FADH2
x2ATP
=
16
TAG FA + GLYCEROL
9 Acetyl CoA x12ATP = 108
HORMONE – SENSITIVE LIPASE
148 – 2 = 146
•
OXIDATION OF ODD NUMBERED FA •
Same process until last 3 is reached
•
PROPIONYL CoA instead of Acetyl CoA
•
Propionyl CoA -> Methyl Malonyl CoA by enzyme Propionyl CoA Carboxylase
•
Methylmalonyl CoA -> Succinyl CoA by enzyme Methylmalonyl CoA Mutase
•
Activators: o
Epinephrine
o
Low level glucose
Reactivators: o
Insulin
o
High level glucose
FATE OF GLYCEROL
•
Succinyl CoA – can enter Kreb’s Cycle
•
Glycerol cannot be metabolized by adipocytes
•
COMPUTATION:
•
Lacks GLYCEROL KINASE transport to liver
•
Phosphorylated or converted to DHAP
•
Can participate in glycolysis/gluconeogenesis
o
17 carbons – 3= 14/2= 7-1 = 6cycles 6 NADH
x3ATP
= 18
6 FADH2
x2ATP
=
7 Acetyl CoA
x12ATP = 84
12
114
FA SYNTHESIS – can be created from Carbohydrates & proteins •
Location: primarily in the LIVER; kidney, lactating mammary glands, adipose tissues
•
Required energy:
-2 112 Kreb’s Cycle (Succinyl CoA) 118 •
o
+6
6 from Kreb’s cycle is constant for ODD
•
NADPH, Acetyl CoA, ATP
MAJOR SOURCES OF NADPH o
HMP shunt
o
•
NADP dependent MALATE HYDROGENASE
Byproduct: NADPH
Convert Malate to Pyruvate
o
Occurs in cytosol: FA synthesis
o
Acetyl CoA inside mitochondria
o
CITRATE SHUTTLE OAA + Acetyl CoA to produce CITRATE Enzyme: ATP CITRATE LYASE – removes citrate
2. CARBOXYLATION OF ACETYL CoA TO MALONYL CoA o
Outside the cytosol
o
Acetyl CoA Carboxylase
o
Requires ATP
o
Coenzyme = BIOTIN
o
Regulated step / IRREVERSIBLE
2 WAYS OF REGULATION OF ENZYME •
•
REDUCTION
DEHYDRATION
REDUCTION
o
Fatty acid synthase enzyme (7 activity) 2 domains
o
TOTAL RESULT OF 7 STEPS – production of 4 Carbon compound
STEPS: 1. PRODUCTION OF CYSTOLIC ACETYL CoA
FURTHER ELONGATION AND DESATURATION OF FA CHAINS •
Palmitate can be further elongated or desaturated
•
In humans, up to 9C double bonds
ESSENTIAL FA – have double bonds beyond C9 •
LINOLEIC ACID 18:2 (9,12)
•
LINOLENIC ACID 18:3 (9,12,15)
RELATIONSHIP OF GLUCOSE METABOLISM & PAMITATE SYNTHESIS:
FA = Acetyl CoA + ATP + NADPH
1. Glycolysis produce pyruvate 2. OAA is produced by gluconeogenesis
SHORT TERM o
Undergoes activation by Citrate
3. Acetyl CoA – mitochondria
o
Inactivated by Malonyl CoA
4. Citrate 5. Carbons of Cytosolic Acetyl CoA
LONG TERM o
o
Prolonged consumption of high carb or fat free diets increases enzyme synth (PRO) High fat diet/fasting reduces FA synth (ANTI)
3. FA SYNTHASE Opposite of oxidation
o
CONDENSATION
STORAGE:
TAG= 3FA + GLYCEROL
FA FATTY ACYL CoA
TAG (Storage Fat) = glycerol phosphate + 3Fattyacyl CoA
INSULIN – storage/anabolic GLUCAGON – degradation/catabolic
- Rosette Go 100208
•
•
GLYCEROL o
Gluconeogenesis
o
FA synthesis
CARNITINE ACYLTRANSFERASE II – located in the INNER MITOCHONDRIAL MEMBRANE BETA OXIDATION •
FA -> Acetyl CoA
•
4 steps:
FA
o o
Oxidation
o
Storage
o
Free w/ albumin
OXIDATION (1ST)
Oxidation of FA by Acyl CoA Dehydrogenase
Forms a double bond between C2 & C3
Produces FADH2 from FAD
LIPOPROTEIN LIPASE – enzyme
FREE FATTY ACIDS – virtually all cells can use Fatty Energy except Brain, RBC & Medulla BETA OXIDATION •
Major pathway for catabolism of FA
•
2 carbon fragments are cleaved producing Acetyl CoA (enters Kreb’s Cycle)
o
HYDRATION
o
OXIDATION (2ND)
STEPS:
Hydroxyacyl CoA oxidized by NAD+
Became 3-Ketoacyl CoA
Forms NADH
1. TRANSPORT OF FA INTO MITOCHONDRIA •
After FA are taken up by a cell, it is converted to a CoA derivative (fatty acylCoA) o
•
Fatty aclyCoA synthetase/thiokinase
•
Transport to mitochondria
THIOLYTIC CLEAVAGE (THIOLYSIS)
*Mitochondrial membrane is impermeable
Cleavage of 3-Ketoacyl CoA by thiol group of another CoA
Produces shorter Acyl CoA and Acetyl CoA
CARNITINE SHUTTLE •
Acyl group must first be transferred Cytosolic CoA to Carnitine
•
Catalyzed by Carnitine Acyltransferase I
•
Forming Fatty Acyl Carnitine I & II
•
Inhibited by: MALONYL CoA
CARNITINE ACYLTRANSFERASE I – located in the OUTER MITOCHONDRIAL MEMBRANE
Add H2O
ENERGY YIELD FROM BETA OXIDATION •
•
Each time an acetyl group (2 carbons) is cleaved from acyl chain, it produces: o
1 NADH
o
1 Acetyl CoA
o
1 FADH2
Therefore:
*Carnitine is not needed inside the mitochondria because it is only a shuttle
o
PALMITATE (16:0) 16/2 = 8 – 1 = 7cycles
* Fats yield high energy •
O.H.O.T. FORMULA = (n/2) – 1
PALMITATE – 7 CYCLES
o 7 NADH
x3ATP
= 21
7 FADH2
x2ATP
= 14
RELEASE OF FA FROM TAG
8Acetyl CoA x 12ATP = 96 131 Energy investment FAcyl CoA synthase _-2 Total ATP
129
•
Mobilization of STORED FAT
•
HORMONE – SENSITIVE LIPASE o
Breaks stored fat
o
Present in ADIPOSE TISSUES
18 carbon = 8cycles
o 8 NADH
x3ATP
=
24
8 FADH2
x2ATP
=
16
TAG FA + GLYCEROL
9 Acetyl CoA x12ATP = 108
HORMONE – SENSITIVE LIPASE
148 – 2 = 146
•
OXIDATION OF ODD NUMBERED FA •
Same process until last 3 is reached
•
PROPIONYL CoA instead of Acetyl CoA
•
Propionyl CoA -> Methyl Malonyl CoA by enzyme Propionyl CoA Carboxylase
•
Methylmalonyl CoA -> Succinyl CoA by enzyme Methylmalonyl CoA Mutase
•
Activators: o
Epinephrine
o
Low level glucose
Reactivators: o
Insulin
o
High level glucose
FATE OF GLYCEROL
•
Succinyl CoA – can enter Kreb’s Cycle
•
Glycerol cannot be metabolized by adipocytes
•
COMPUTATION:
•
Lacks GLYCEROL KINASE transport to liver
•
Phosphorylated or converted to DHAP
•
Can participate in glycolysis/gluconeogenesis
o
17 carbons – 3= 14/2= 7-1 = 6cycles 6 NADH
x3ATP
= 18
6 FADH2
x2ATP
=
7 Acetyl CoA
x12ATP = 84
12
114
FA SYNTHESIS – can be created from Carbohydrates & proteins •
Location: primarily in the LIVER; kidney, lactating mammary glands, adipose tissues
•
Required energy:
-2 112 Kreb’s Cycle (Succinyl CoA) 118 •
o
+6
6 from Kreb’s cycle is constant for ODD
•
NADPH, Acetyl CoA, ATP
MAJOR SOURCES OF NADPH o
HMP shunt
o
•
NADP dependent MALATE HYDROGENASE
Byproduct: NADPH
Convert Malate to Pyruvate
o
Occurs in cytosol: FA synthesis
o
Acetyl CoA inside mitochondria
o
CITRATE SHUTTLE OAA + Acetyl CoA to produce CITRATE Enzyme: ATP CITRATE LYASE – removes citrate
2. CARBOXYLATION OF ACETYL CoA TO MALONYL CoA o
Outside the cytosol
o
Acetyl CoA Carboxylase
o
Requires ATP
o
Coenzyme = BIOTIN
o
Regulated step / IRREVERSIBLE
2 WAYS OF REGULATION OF ENZYME •
•
REDUCTION
DEHYDRATION
REDUCTION
o
Fatty acid synthase enzyme (7 activity) 2 domains
o
TOTAL RESULT OF 7 STEPS – production of 4 Carbon compound
STEPS: 1. PRODUCTION OF CYSTOLIC ACETYL CoA
FURTHER ELONGATION AND DESATURATION OF FA CHAINS •
Palmitate can be further elongated or desaturated
•
In humans, up to 9C double bonds
ESSENTIAL FA – have double bonds beyond C9 •
LINOLEIC ACID 18:2 (9,12)
•
LINOLENIC ACID 18:3 (9,12,15)
RELATIONSHIP OF GLUCOSE METABOLISM & PAMITATE SYNTHESIS:
FA = Acetyl CoA + ATP + NADPH
1. Glycolysis produce pyruvate 2. OAA is produced by gluconeogenesis
SHORT TERM o
Undergoes activation by Citrate
3. Acetyl CoA – mitochondria
o
Inactivated by Malonyl CoA
4. Citrate 5. Carbons of Cytosolic Acetyl CoA
LONG TERM o
o
Prolonged consumption of high carb or fat free diets increases enzyme synth (PRO) High fat diet/fasting reduces FA synth (ANTI)
3. FA SYNTHASE Opposite of oxidation
o
CONDENSATION
STORAGE:
TAG= 3FA + GLYCEROL
FA FATTY ACYL CoA
TAG (Storage Fat) = glycerol phosphate + 3Fattyacyl CoA
INSULIN – storage/anabolic GLUCAGON – degradation/catabolic
- Rosette Go 100208
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