FATTY ACID METABOLISM I

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FATTY ACID METABOLISM - I
PA BIOCHEMISTRY (Lec. 36) BAHS 501, FALL 2001
Dr. Jack Kinkade 4135 Rollins Research
Center jkinkad_at_emory.edu 404-727-5965
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CATHY
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CATHY
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OVERVIEW OF FATTY ACID AND TRIACYLGLYCEROL
METABOLISM
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Metabolism of Fatty Acids and Triacylglycerols
and Relationship to Carbohydrate Metabolism
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OBJECTIVES

• To learn how the body carries out the de novo
  (from scratch) synthesis of palmitic acid
  (palmitate), a C-16, saturated fatty acid
  (C160).
• To understand the relationship between glucose
  metabolism and palmitate synthesis.
• To understand why certain fatty acids are
  essential.
• To learn how fatty acids are stored as
  triacylglycerols.

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Overview
Cells convert carbons from carbohydrates, amino
acids, and other lipids to fatty acids as long as
they can be first metabolized to
acetyl-CoA. Fatty acid synthesis occurs
primarily in the liver and lactating mammary
gland, and to a lesser extent in adipose tissue
and kidney. The major intracellular site of
synthesis of acetyl-CoA is the mitochondrion,
whereas fatty acid synthesis takes place in the
cytosol therefore, a pathway for efflux of the
acetyl-CoA is needed. This is achieved via the
citrate shuttle Cytosol Mitochondrion Glyc
olysis ---gt Pyruvate ---Transport---gt Pyruvate
---gt Acetyl-CoA Acetyl-CoA ---gt
Citrate Citrate lt---Transport--- Citrate Citr
ate ---gt Acetyl-CoA
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Mechanism for transfer of acetyl CoA from
mitochondria to cytosol for fatty acid
biosynthesis
ÅÅ_at_Ä-f91Ü!
CoA
Figure 9.10
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Acetyl CoA Carboxylase Catalyzes the Committed
and Rate Limiting Step of Fatty Acid Biosynthesis
Cytosolic Reaction
(Biotin)

• HIGHLY REGULATED
• Allosteric Effectors citrate () palmitoyl
  CoA (-)
• Phosphorylation/Dephosphorylation Enzyme-P is
  inactive
• Transcription e.g., high carbohydrate diets
  stimulate

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Fatty Acid Synthase Catalyzes the Biosynthesis of
Palmitate
In humans, this enzyme is a dimer that has seven
(7) different activities ACP acyl carrier
protein(in bacteria), in mammals it is a domain
of the fatty acid synthase (PhP domain)
OVERVIEW

• Fatty acid synthesis involves the condensation
  of a priming molecule of acetyl-CoA plus
  malonyl-CoA.
• The iterative cycling of the enzyme to
  synthesize a fatty acid involves reactions
  similar to the reversal of fatty acid oxidation,
  to grow the chain in 2-carbon units
• Acetyl-CoA (C20) malonyl-CoA ---gt
• Butyryl-CoA (C40) malonyl-CoA ---gt
• Hexanoyl-CoA (C60) malonyl-CoA ---gt etc.

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Reactions of Fatty Acid Biosynthesis
Reactions 1 and 2 are Priming
Dehydration
ReductionNADPH
6 additional cycles
Condensation and loss of CO2
(3)
ReductionNADPH
ENZYME STOPS AT C160
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Reactions Taking Place on Mammalian Fatty Acid
Synthase
Thioesterase
Recall ACP PhP
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Palmitic Acid is Further Modified to Meet the
Bodys Needs

• Palmitate is ELONGATED in the mitochondrion and
  in the endoplasmic reticulum (ER).
• Palmitate (and other fatty acids) are DESATURATED.

• Desaturase enzymes introduce double bonds up to
  CARBON 9,
• but not further along the chain. This is why
  linoleic (C189,12)
• and linolenic (C189,12,15) are essential fatty
  acids.

• A major desaturase is stearoyl-CoA desaturase,
  which makes oleic
• acid (C189). The enzyme is induced by diets
  low in unsaturated
• fatty acids.

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REGULATION OF FATTY ACID BIOSYNTHESIS
Regulatory Agent
Effect
PALMITATE BIOSYNTHESIS Citrate C16-C18 acyl
CoAs Insulin Glucagon cAMP-mediated
phosphorylation Dephosphorylation High
carbohydrate diet Fat-free diet High-fat
diet Fasting Glucagon
Allosteric activation Allosteric
inhibition Stimulation Inhibition Inhibition Stimu
lation Stimulation by increased enzyme
synthesis Stimulation by increased enzyme
synthesis Inhibition by decreased enzyme
synthesis Inhibition by decreased enzyme
synthesis Inhibition by decreased enzyme synthesis
ÅÅ_at_Ä-f91Ü!
Short Term
Long Term
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Fatty Acids are Stored as Triacylglycerols

• Liver and adipose tissue are the primary sites
  of triacylglycerol
• synthesis.

• Fatty acids must be activated before they can be
  utilized for the synthesis of triacylglycerols.

(thiokinase)
in vivo
2 Pi
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Glycerol - 3 - Phosphate can be formed via two
Pathways
Glycerolipid synthesis begins with EITHER
dihydroxyacetone phosphate or glycerol
3-phosphate, which provides mechanisms for
linking lipid and carbohydrate synthesis (DHAP)
as well as for recycling glycerol derived from
previous lipid turnover
Glycolysis
NADH/ NAD
ATP
Glucose
DHAP
Glycerol 3-P
Glycerol
Glycerol kinase
OH
OH
OH
O
HO
HO
OPO3H2
OPO3H2
OH
Glycerol kinase is NOT found in adipose cells,
which explains why they do not become trapped in
a futile cycle of triacylglycerol turnover /
resynthesis but rather, require insulin for TG
synthesis since this induces uptake of glucose
while suppressing lipolysis.
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(Lysophosphatidic Acid)