if fatty acid synthesis occurs in the cytosol, where does the acetyl-coa come from? acetyl-coa (not...
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If fatty acid synthesis occurs in the cytosol, where does the acetyl-CoA
come from?• Acetyl-CoA (not from fatty acid oxidation) is
generated in the mitochondria – hence needs transport mechanism
• The shuttle involved is interesting as it provides a control mechanism and produces NADPH needed for the process
• The shuttle involves citrate, which is also produced in the mitochondria, as you should recall from acetyl-CoA and OAA
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Involvement of citrate in fatty acid synthesis makes sense
• Accumulation of citrate indicates too much for citric acid cycle to handle, so what happens?
• Shut down PFK-1 and glycolysis
• Divert citrate to fatty acid synthesis since the energy generating pathway is saturated
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Palmitate is a precursor for other fatty acids
• Requires enzymes for
elongation and desaturation
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Desaturating fatty acids
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Regulation of fatty acid biosynthesis
• When too much food, acetyl CoA diverted to fatty acid biosynthesis instead of citric acid cycle
• The first committed step is catalyzed by acetyl-CoA carboxylase – the rate limiting step in fatty acid biosynthesis, and the regulatory point
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Inhibition and activation
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Hormones also regulate this
pathway• In animal cells:
• Phosphorylation
• Respond to NADPH
levels also
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In eukaryotic cells, elongation occurs in the mitochondria and ER
• Reactions are analogous to the fatty acid synthase, but use CoA rather than ACP as carrier
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Desaturation of fatty acids
• Involves desaturase, cytochrome b5, and cytochrome b5 reductase
• Most common unsaturated fatty acids are oleic acid (18:19) and palmitoleic acid (16:19) – use a desaturase specific for this bond – other desaturases specific for other bond positions in fatty acids
• However, mammals lack certain desaturases, thus require essential fatty acids from diet
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Linoleate and linolenate are essential as
precursors for other fatty acids • Arachidonic acid is precursor
for eicosanoids (cell signaling
molecules)
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Arachidonic acid is a precursor for prostaglandins
• Arachidonic acid
liberated from
phospholipid bilayer in
Response to a stimulus,
which is either bradykinin,
epinephrine, or proteases
such as thrombin
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Arachidonate is cyclized to PGs
Notice use of molecular oxygen here and elsewhere
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Arachidonate is also a precursor of leukotrienes
• Leukotrienes, prostaglandins, and thromboxanes are called eicosanoids, because they share a common origin (arachidonic acid)
• Biologically active eicosanoids are short-lived, locally acting hormones
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Many of these reactions involve molecular oxygen
• Oxygenases catalyze reactions where oxygen atoms are directly incorporated into substrate– Dioxygenase both oxygen atoms are added to
substrate– Monooxygenase – only one oxygen is
incorporated, the other is reduced to water
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Cytochrome P-450 is an interesting monooxygenase family
• Heme containing protein that binds oxygen and carbon monoxide (when CO bound, absorbs light at 450 nm)
• Most vertebrates genomes contain more than 40 genes encoding variants of this protein
• These proteins act upon thousands of xenobiotics – hydroxylation usually increases their solubility and helps in detox, metabolism and excretion
• Expressed in liver, brain
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Fatty acids Triacylglycerol and membrane lipids
• Need glycerol 3-phosphate, which is generated from DHAP (from glycolysis) or by ATP-dependent phosphorylation by glycerol kinase (adipocytes lack glycerol kinase)
• Regardless, glycerol 3-phosphate undergoes two successive enzymatic esterifications with fatty acyl-CoAs to yield diacylglycerol 3-phosphate (phosphatidic acid)
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To form a triacylglyerol:
• Phosphatidic acid phosphatase
cleaves off the phosphate group
and another transesterification
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Pathways in glycerophospholipid biosynthesis
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Divergence between triacylglycerol and glycerolphospholipid
• Note first steps are shared, however, need attachment of head group
• Note on previous slide this attachment is mediated by nucleotide activation (CTP)
• The nucleotide activation can occur either through activation of head group or diacylglycerol
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CTP activation of diacylglycerol occurs in prokaryotes
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This pathway yields cardiolipin and…
• Cardiolipin accounts for 5-15%
of E. coli membrane
Not observed in hepatocyte
plasma membrane, but a
prominent component of
mitochondrial inner membrane
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phosphatidylethanolamine
• Phosphatidylethanolamine is
about 75-85% of E. coli
membrane and prominent in
all animal cell membrane
layers
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CTP activation of diacylglycerol also is
important for eukaryotic plasma membrane
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Eukaryotes have a distinct mechanism for other membrane phospholipids
• Swap head groups between serine and ethanolamine
• Phosphatidylcholine is generated by three methylation reactions using phosphatidylethanolamine as a substrate OR
• By activation of headgroup with CTP
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CDP activation can generate phosphatidylcholine and
phosphatidylethanolamine
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Alternative path for phosphatidylserine
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Can also go back
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Ether-linked lipids
• Built on DHAP, where ester-linked fatty acyl group is displaced by a long chain alcohol, reduced, then head group attached
• Still contain ester-linked acyl group at C2
• Comprise 50% of choline phospholipids in heart tissue, but virtually undetectable in other tissues
• Synthesis carried out in peroxisomes
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Archaeal membrane phospholipids
• Ether linkages at both C1 and C2
• Lack fatty acids, instead have repeating units of isoprenes
• Major lipids in membranes are glycerol diethers and tetraethers
• Tetraethers yield a monolayer, instead of bilayer, which are quite resistant to peeling apart – facilitates growth under hyperthermophilic conditions