Lipid Synthesis
Overview of Fatty Acid Synthesis
Fatty Acid Synthesis
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acetyl CoA cannot travel across inner membrane of mito
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when acetyl CoA accumulates, citrate level is elevated as well
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acetyl CoA + OAA --> citrate + CoA​
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citrate translocated to cytosol, serving as the intermediate for the transfer of acetyl CoA from mito to cytosol
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citrate activates acetyl CoA carboxylase
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when ATP needs are low, [citrate] increases and has two functions
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travels to cytosol and inhibits PFK (slows glycolysis)​
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gets cleaved in cytoplasm
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fatty acid synthesis costs 1 ATP each time one citrate splits
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acetyl CoA carries a 2-carbon building block
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what came off in FA oxidation​
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resulting OAA in cytosol is available to shuttle H+ and e- to recycle NAD in cytosol for glycolysis
2 part process
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designate acetyl CoA as
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1. anchored to enzyme (via biotin) so chain can grow
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2. prepare to add 2C units to the anchored starting chain
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need to make a compound called malonyl CoA first
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condensation of two acetyl groups is energetically unfavorable, therefore need to make malonyl CoA first​
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carboxylases needs biotin (vitamin B7) to help add single carbons
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bicarb ion is the donor of the new carbon (costs another ATP)
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reminder we already used 1 ATP to split citrate​
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acetyl CoA carboxylase (ACC)
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rate limiting enzyme​
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stimulated by citrate
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inhibited by long chain acyl-CoA
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so far, we have made a 2C unit into a 4C unit
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now ready for reduction
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"reductive synthesis"​
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add H to newly added carbons (for later fuel value)
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4 step process
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now have a 4C FA
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start over and add 2 more C and reduce
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use more NADPH + H to reduce these new carbons of C6 unit
SUMMARY
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process of adding 2C via malonyl CoA followed by reduction using NADPH + H continues until you reach desired chain length
ENERGY COST
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Fatty Acid Synthesis: Desaturation
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Desaturation if FA occurs in the ER
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first double bond is Δ9
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Δ9 desaturase or stearoyl CoA desaturase (SCD) complex
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SCD 1 in liver and adipose tissues​
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mammalian cells involve 4 broad specificity fatty acyl-CoA desaturases
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these enzymes introduce double bond at C4, C5, C6 or C9​​​
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Fatty Acid Synthesis vs β-Oxidation
Fatty Acid Synthesis (FAS) Complex
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A single polypeptide in mammals and birds
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contains all the activities in separate domains
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easier channeling of substrates in a sequence of reactions
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end product: C16:0
ACC and FAS​
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adaptable enzymes
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increase when fed (insulin)
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decrease
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starvation​
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feeding of fat
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diabetes
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TAG synthesis
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FAs are stored for future use as TAGs in all cells, but primarily adipocytes
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the FAs present in TAGs are mostly saturated
TAG synthesis in the liver
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liver has glycerol kinase
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FA needs to be activated to fatty acyl CoA
TAG synthesis in adipose tissue
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adipocytes lack glycerol kinase
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DHAP is the precursor for TAG synthesis in adipose tissue​
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adipocytes must have glucose to oxidize in order to store fatty acids in the form of TAGs
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DHAP can also serve as a backbone precursor for TAG synthesis in tissues other than adipose, but to a much lesser extent than glycerol kinase
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How does CHO --> Fat?
Excess dietary CHO can end up in adipose tissue as fat
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what is needed for adipose tissue to synthesize and store TAG
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TAG: glycerol and FA​
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glycerol from DHAP
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FA from glc (acetyl CoA) and lipoproteins
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role of insulin
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increase in glc uptake (GLUT4)​
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glc--> DHAP --> G3P​
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increase in FA uptake
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