Transcript LIPID METABOLISM - Orange Coast College

LIPID METABOLISM
I.

Lipid Digestion,
Absorption, and Transport
Triglycerides
 ~ 90% of dietary lipids
 Metabolic NRG storage
 Oxidized to CO2 and H2O
Triglyerides, cont…
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oxidation state than glucose
 metabolism of fats yields
~9 kcal/gram
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vs ~4 kcal/gm
Carbohydrates, proteins
Triglyceride Storage, cont…
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Stored in anhydrous state
Non-polar
 Provide ~ 6 times energy of
hydrated glycogen
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Triglyceride storage, cont…
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Stored in large quantities in cells
Non-reactive with other cell components
 Segregated into lipid droplets
 Do not affect osmolarity of cytosol
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Triglycerides, cont…
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To be used as fuel:
insoluble in H2O
 Must emulsify before lipid digestion in
intestine
 Must be “carried” in blood (proteins)
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Triglycerides, cont…
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Sources of fat
 Three cellular sources
Fat in diet
 Fat stored in cells
 Fat synthesized in one organ and
transported to another
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Triglycerides, cont…
Fats obtained vary by organism
 Vertebrates
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Fat in diet
 Fat in adipose tissue
 Convert excess carbohydrate to fat
 in liver
 for export
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Triglycerides, cont…
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Humans
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Industrialized countries:
 ~ 40% of daily calorie
consumption is fat
 Should be < 30%!
 Atkins kills…
Humans, Triglycerides, cont…
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Used for > half the energy in:
 Liver
 Heart
 Resting skeletal muscle
Humans, Triglycerides, cont…
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Hibernating animals and migrating
birds
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sole source of NRG
Higher plants:
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Do not depend on fats for energy
 Germinating seeds
Lipid digestion, cont…
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Digestion
 Triglyceride digestion
takes place at lipid-water interfaces
 Rate is based on surface area at
interfaces
 Peristalsis
 Emulsification by bile
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Lipid digestion, cont…
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Bile
Synthesized from cholesterol,
biliverdin
 By liver
 Stored in gallbladder
 Released after ingestion of fat
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Lipid digestion, Bile, cont…
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Acts as digestive detergent
Converts dietary fats into mixed
micelles
 Micelles contain bile salts and
triglycerides
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Lipid digestion, cont…
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Role of lipase
 Pancreatic lipase:
catalyzes hydrolysis of triglycerides
 At 1 and 3 positions sequentially
 Forms 1,2-diglycerol
2-glycerol
 Soap
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Role of lipase, Lipid digestion, cont…
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Phospholipase A:
Pancreatic enzyme
 Degrades phospholipids
 Hydrolysis at C(2)
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Absorption of Lipids
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Absorption
 Molecules diffuse into cells of
intestine
 Facilitated by bile salts
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Micelles transport non-polar lipids
across aqueous boundary layer
Absorption, cont…
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Bile salts essential
Fatty Acids
 Fat soluble vitamins
 A,D,E & K
 Biliary disease interferes
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Lipid Uptake in Vertebrates
Role of Lipase, cont…
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Reconversion: in mucosa cells
 Lipid digestive products 
triglycerides
 Packaged into Chylomicrons
Lipoprotein aggregates
 Triglycerides, cholesterol, protein
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Chylomicron
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Aggregate of
triglycerides,
cholesterol, and
proteins
Reconversion, Role of Lipase, cont…
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Released into bloodstream:
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Via lymphatic system
Lacteals
Triglycerides synthesized in liver
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Packaged in VLDL
Directly released into blood
Role of lipase, cont…
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Transport
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APOLIPOPROTEINS: lipid-binding
blood proteins
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Transport between organs
Form classes based on density
Role of lipase, cont…
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Proteins on outside of Chylomicron
 Are apoproteins
 Act as cell surface receptors for
recognition (apo C-II)
Lipid Uptake in Vertebrates
Transport, Role Chylomicrons, cont…
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Chylomicrons and VLDL:
Move triglycerides, cholesterol
 To Skeletal muscle & adipose
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LIPOPROTEIN LIPASE
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an extracellular enzyme
Activated by apo C II
Hydrolyzes triglycerides
Chylomicron
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Carry
triglycerides,
cholesterol to
tissues via
lymphatic system
(lacteals)
Transport, Role of lipase, cont…
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Deletes lipoprotein from triglyceride
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LDL: (130-159 mg/dl)
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Forms IDL
Then LDL
removed from plasma
at liver, adrenals, adipose
HDL: (above 35 mg/dl)
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moves cholesterol from tissues
Sends to liver for excretion in bile salts
Ratio LDL:HDL = 2:1
Lipid Metabolism, cont…
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Uptake by cells
 FA taken in by:
muscle: oxidized for NRG
 adipose: stored as triglyceride
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Lipid Uptake in Vertebrates
Transport, Role of lipase, cont…
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Glycerol
Transported to liver or kidney
 Converted to dihydroxyacetone
phosphate
 And then???
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Pathway to Glycolosis
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Conversion of
glycerol to
dihydroxyacetone
phosphate
Transport, Role of lipase, cont…
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Remnants of Chylomicrons
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triglycerides;
cholesterol and
apoproteins (apo E, apo B-48)
 To liver
Uptake by endocytosis
 Triggered by apolipoproteins
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Uptake in Liver via Endocytosis
Chylomicron Remnants, cont…
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Triglycerides
Oxidized for energy or
 Converted to ketone bodies
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Excess fatty acid
Convert to triglycerides
 Pack into VLDL
 To adipose for storage
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Lipid Uptake in Vertebrates
Mobilization of Stored Fats
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Mobilization of stored triglycerides
 Triggered by hormones
 Stimulus is
in blood glucose
 Hormones:
Epinephrine
 Glucagon
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Mobilization of Stored Fats, Hormone Action, cont…
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Activate adenylate cyclase in
adipocyte plasma membrane
Increases cAMP
 Activates protein kinase
 Activates triglycerol lipase
 Catalyzes hydrolysis of ester bonds in
triglycerides
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Mobilization of Stored Fats
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Action of second
messenger
hormones triggers
mobilization of
stored triglycerides
Role of lipase, cont…
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Free fatty acid released into
bloodstream
Binds to serum albumin
 Carried to tissues
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Released to diffuse into cells
Role of lipase, cont…
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NOTE:
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Glycerol 
glycerol-3-phosphate
dihydroxyacetone phosphate 
glycolysis
II. Fatty Acid Oxidation
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FA activation:
 Free FA cannot enter Mitochondria
 Occurs in cytosol
 Acyl-CoA synthetases (thiokinases)
 3 isozymes
 mitochondrial membrane
FA activation, cont...
FA + CoA + ATP  fatty acyl-CoA +
AMP + PPi
 different acyl-CoA’s work on
different
FA
 Fatty acyl-CoA: high energy
compound
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Fatty acid oxidation, cont…
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Transport across mitochondrial
membrane:
 Formation of fatty acyl-carnitine
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Carnitine acyl transferase I
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Outer face of inner membrane
Fatty acyl from CoA  carnitine
CoA released  cytoplasm
Transport across mitochondrial membrane, cont…
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Acyl-carnitine/carnitine transporter
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Carrier
Fatty acyl-carnitine  matrix
carnitine  to inter-membrane space
Facilitated diffusion
F.A. Entry into Mitochondria
Fatty acid oxidation, cont…
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Transfer of acyl from Carnitine to
intra-mitochondrial membrane
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Carnitine acyltransferase II
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Inner face of inner membrane
Regenerates fatty acyl-CoA
Frees carnitine  returns to cytosol
Carnitine Acyltransferase II, cont…
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Two separate pools of CoA
(ATP, NAD+)
Cytoplasm: makes FA
 Mitochondria: oxidative degradation
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Pyruvate
FA
AA
ß-oxidation
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ß-oxidation: FA dismembered to fatty
acyl-CoA
 Mitochondrial oxidation of FA
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Stage One: ß-oxidation
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Remove 2-C chunks as acetyl-CoA
Begins at carboxyl end of fatty acid chain
ß-Oxidation
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Fatty acids are
dismembered
into Acetyl-CoA
subunits
Each acetyl
Co-A sends 4 H
to NAD, FAD
Mitochondrial oxidation, cont…
 For example, 16C palmitic acid 
8 acetyl CoA
 Stage Two:
oxidation of acetyl-CoA  CO2
Stage Three:
oxidative phosphorylation
 ATP (+H2O)
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ß oxidation, cont…
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ß oxidation: 4 reactions
 Formation of a trans – a, ß double
bond
Between C-2 (a) and C-3 (ß)
2
 Yields: Trans-∆ -enoyl-CoA
 Acyl-CoA dehydrogenase
 FAD  2 ATP
 Similar to succinate dehydration
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ß-Oxidation
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First: formation of
double bond
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Second: hydration
of double bond
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Third:
dehydrogenation
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Fourth: cleavage to
Acetyl Co-A
ß-oxidation, cont…
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Hydration of the double bond
By enoyl-CoA hydrase
 Forms 3-L-hydroxyacyl-CoA
 Similar to fumarase reaction
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ß-oxidation, cont…
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Dehydrogenation
By ß-hydroxyacyl-CoA
dehydrogenase
 To ß-ketoacyl-CoA
 NAD  3 ATP
 Similar to malate dehydrogenase
reaction
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ß-oxidation, cont…
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Ca -Cß cleavage (thiolysis)
Catalyzed by ß-ketoacyl-CoA thiolase
(thiolase)
 Produces:
 acetyl-CoA
 fatty acyl-CoA (2 carbons short)
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ß oxidation: Enzymes in Mitochondrial membranes
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3 kinds of acyl-CoA dehydrogenase
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Specify short, medium, long chain fatty
acid
Medium-chain acyl-CoA dehydrogenase
(MCAD)
 Deficient in ~10% of SIDS babies
 More common than PKU
Sites of Mitochondrial Enzymes
ß-oxidation, cont…
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Fatty acid oxidation is highly exergonic
 Each round of ß-oxidation
 1 NADH
 1 FADH2
 1 acetyl-CoA
ß-oxidation, Energy Payoff
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Acetyl-CoA  citric acid cycle
Example: PALMITOYL-CoA (16C)
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7 rounds of ß -oxidation  7 NADH
7 FADH2
8 acetyl CoA
So, 7 + 24 NADH = 31 x 3 = 93 ATP
7 + 8 FADH2 = 15 x 2 = 30 ATP
+ 8 GTP
131 hi-energy molecules
for fatty acyl CoA - 2 ATP
129 total
ß-oxidation, cont…
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READ IN TEXT:
Oxidation of unsaturated fatty acid:
2 additional reactions
 Oxidation of odd-chain fatty acid:
3 additional reactions
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III. Ketone Bodies
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Acetyl-CoA from ß-oxidation
 Enters citric acid cycle
 Converted to KETONE BODIES
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Water-soluble “equivalent” of FA
Ketone bodies, cont…
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Ketogenesis
 Occurs in liver:
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acetyl CoA  ketone bodies
Primary ketone bodies
Acetoacetate - out of liver
 D-ß-hydroxybutyrate - out of liver
 Acetone - exhaled
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Ketone Body Formation
Ketone bodies, cont…
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Function: fuel for peripheral tissues
 Heart, skeletal muscle
 Brain
Normal fuel is glucose
 In starvation: ketone bodies
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Enzyme production adapts over time
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>40 days, provide 70% energy
Ketone bodies, cont…
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Production and transportation
 Determined by availability of
oxaloacetate
Combine with acetyl group
 enter TCA cycle
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Ketone bodies, cont…
 In starvation
 Oxaloacetate pulled from citric
acid cycle
 Used in gluconeogenesis
 [oxaloacetate] decreases
 therefore little  kreb’s cycle
 Production of ketone bodies is
favored
Production and transportation, cont…
Overproduction: starvation, diabetes
 Moved from liver to other tissues
 Allows fatty acid oxidation in liver
 In tissues:
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ketone bodies converted back to
acetyl-CoA
Production and transportation, cont…
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Formation of ketone bodies from acetyl-CoA
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occurs in the mitochondrial matrix
thiolase
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2 Acetyl-CoA
acetoacetyl-CoA
Acetoacetyl-CoA + acetyl-CoA 
ß -hydroxy- ß -methylglutaryl-CoA
HMG-CoA  free acetoacetate + acetyl-CoA
Production and transportation, cont…
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Acetoacetate 
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D- ß -hydroxybutyrate dehydrogenase
D-ß-hydroxybutyrate
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Acetoacetate decarboxylase
Acetone
 High in uncontrolled diabetes
Production and transportation, cont…
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Ketosis
 Pathological
 Acetoacetate produced too fast
for elimination
 Breath smells like acetone
 Blood pH decreases  acidosis
Lipid Biosynthesis
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“Reverse” of lipid catabolism
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Know differences
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Where in the cell does each occur?
What are the e- transport molecules?
What are the acyl group carriers?
Where does acetyl Co-A “fit into” each set
of reactions?
Pathway Differences
Fatty Acid Biosynthesis
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Read in Text
 For major
steps, know
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Type of
reaction
Enzyme
Product
Cholesterol Biosynthesis
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Read in Text
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Know
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Draw steps
Intermediates