Fatty Acid Synthesis Flashcards
Anabolism of fatty acids requires
acetyl coA and malonyl coA (3C intermediate)
NADPH electron donor
to be in the cytosol in animals
Catabolism of FA takes place in
mitochondria
Phase 1 Biosynthesis of Fatty Acids
Acetyl-coA –> Malonyl coA
Enzyme: acetyl coA carboxylase (ACC)
Cofactors: biotin, HCO3- + ATP transferred to biotin
Location: cytosol
acetyl coA carboxylase catalytic units
1) biotin carboxylase: adds carboxyl from HCO3- to biotin using ATP
2) biotin carrier protein: carries in biotin and rotates 180°
3) transcarboxylase transfer carboxyl from biotin to acetyl coA forming malonyl coA
Types of fatty acid synthase
Structure of fatty acid synthase
Types I: in vertebrates and fungi, Type II: in bacteria and plants
Subunit Structure: A Killer Executive Does Much Kicking (of) Teeth
ACP (acyl carrier protein)
KR - K reductase
ER - E reductase
DH - dehydratase
MAT - malonyl-acetyl ACP transferase
KS - K synthase
TE (thioesterase)
Phase 2 Biosynthesis of Fatty Acids
Enzyme: fatty acid synthase
1) Condensation of acetyl and malonyl: acetyl added to KS, malonyl added to ACP (coA dissociate), then acetyl added to malonyl producing a CO2
2) Reduction by KR of carbonyl producing NADP+
3) Dehydration of C2/C3 by DH producing water and forming double bond
4) Reduction of double bond by ER producing NADP+
5) Translocation of fatty acid chain back to KS
Repeat until full fatty acid palmitate chain has been formed
thioesterase does what
frees palmitate from ACP through hydrolytic activity, 1 water used
role of malonyl
acts as the donor of 2 carbons to extend fatty acid chain in phase 2 fatty acid synthesis
every time bound to ACP and added onto growing chain bound to KS
Malonyl-coA is the inhibitor of acyl-carnitine transferase I in FA catabolism pathway
Overall equation of palmitate synthesis
8 acetyl coA + 7 ATP + 14 NADPH +14 H+ –>
Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6H2O
role of palmitate in FA synthesis
Palmitate is principle FA of FA synthesis
Acts as precursor for long chain FA synthesis
stearate can be desaturated to form
Palmitoleate is formed by
longer chain fatty acids in the smooth ER and mitochondria
desaturation of palmitate at Δ9 carbon by fatty acyl-coA desaturase enzyme
Synthesis of alpha-linolenate
Last 2 desaturations only in plants, must be consumed in humans (essential nutrient)
Palmitate (16:0) –> Stearate (18:0) –> Oleate (18:1Δ9) –> Linoleate (18:2 Δ9,12) –> alpha-linolenate (18:3 Δ9,12,15)
Enzymes: elongation and fatty acyl-coA desaturase
How is arachidonate formed?
Structure nomenclature
From linoleate via different (omega-6) desaturation pathway
Arachidonate (20:4 Δ5,8,11,14)
Sources of NADPH regeneration
Malic enzyme pathways and significance
Half from pentose phosphate pathway and half from malate/malic enzyme pathway
Malic enzyme pathway:
1) malate in cytosol converted to pyruvate by malic enzyme and reduces NADP+ –> NADPH
2) Pyruvate crosses back to mitochondrial matrix via pyruvate transporter
3) Pyruvate converted to oxaloacetate by pyruvate carboxylase and ATP
OR
1) malate crosses from cytosol to mitochondrial matrix via malate-alpha ketoglutarate transporter
2) Malate is converted to oxaloacetate by malate dehydrogenase reducing NADH in process
Significance: acetyl coA cannot cross mitochondrial membrane
Sources of acetyl-coA
pyruvate decarboxylation and amino acid catabolism in mitochondria
Role of citrate in fatty acid metabolism regulation
acts as activator of fatty acid synthesis in mitochondria
Acetyl-coA + oxaloacetate –> citrate via citrate synthase in mitochondria
Citrate –> acetyl-coA + oxaloacetate via citrate lyase in cytosol
Regulation of intermediates to feed into different pathways and regeneration of NADPH and NADH
What is the rate limiting enzyme of FA biosynthesis?
acetyl-coA carboxylase
citrate stimulates, palmitoyl-CoA inhibits
epinephrine and glucagon trigger inactivation phosphorylation
Insulin regulation of fatty acid synthesis
Promotes phosphatase activation of acetyl-coA carboxylase (ACC), leading to acetyl-coA –> malonyl-coA
Malonyl-coA negative feedback on carnitine acyl transferase-1 in FA catabolism pathway for transport into mitochondria
Glucagon regulation of fatty acid synthesis
Inactivation phosphorylation of ACC via PKA AMPK (AMP-activated protein kinase)
No malonyl-coA formed, fatty acid mobilization continues
Biosynthesis of TAGs from glycerol-3-phosphate
Insulin promoted
1) Dihydroxyacetone phosphate (source glycolysis/glycerol) –> glycerol-3-phosphate
Enzyme: glycerol-3-phosphate dehydrogenase
OR
glycerol –> glycerol-3-phosphate
Enzyme: glycerol kinase
2) Formation of 2 acyl coA and addition to glycerol 3-phosphate –> phosphatidic acid
Enzyme: acyl-coA synthase + ATP and acyl transferase x2
3) formation of glycerophospholipid OR formation of TAG
Enzyme: phosphatidic acid phosphatase + acyl transferase
Biosynthesis pathway of cholesterol
4 stages: condensation, phosphorylation, polymerization, and cyclization
1) Condensation: Acetate –> HMG-CoA –> Mevalonate
Enzyme: HMG-coA reductase and HMG-coA synthase
2) Phosphorylation: Mevalonate –> isoprene
3) Polymerization: Isoprene –> squalene
4) Cyclization: Squalene –> cholesterol
HMG-coA stands for
β-hydroxy-β-methylglutaryl-CoA
Inhibition of cholesterol synthesis (4)
High [AMP] leads to AMPK phosphorylation INactivation of HMG-coA reductase (decreased activity and cholesterol prod)
Glucagon and epinephrine also lead to AMPK inactivation pathway
Insig (insulin-induced gene protein) senses high cholesterol and triggers ubiquitination of HMG-coA reductase
Statins inhibit HMG-coA reductase to lower cholesterol prod
Stimulation of cholesterol synthesis (2)
Insulin leads to DEphosphorylation of HMG-coA reductase –> increased activity and cholesterol production
SREBPs (Sterol Regulatory Element Binding Proteins) activate HMG-coA Reductase
