13: Fatty Acid Synthesis Flashcards
Fatty Acid synthesis occurs primarily in the _____ with dietary _______ serving as the carbon source. The _______ is converted by glycolysis to pyruvate which enters the mitochondria where it is converted to acetyl CoA and oxaloacetate which then form citrate which is transported into the cytosol.
Fatty Acid synthesis occurs primarily in the liver with dietary glucose serving as the carbon source. The glucose is converted by glycolysis to pyruvate which enters the mitochondria where it is converted to acetyl CoA and oxaloacetate which then form citrate which is transported into the cytosol.
Once in the cytosol citrate is converted to _______ which is the source of carbons for fatty acid synthesis.
_______ (key regulatory enzyme) and _______ convert acetyl CoA to palmitic acid (16 carbon saturated fatty acid). Once activated to palmityl CoA this fatty acid can be elongated or desaturated by enzymes which are located in the _______.
Once in the cytosol citrate is converted to acetyl CoA which is the source of carbons for fatty acid synthesis.
Acetyl CoA carboxylase (key regulatory enzyme) and fatty acid synthase convert acetyl CoA to palmitic acid (16 carbon saturated fatty acid). Once activated to palmityl CoA this fatty acid can be elongated or desaturated by enzymes which are located in the ER.
The eicosanoids which include the _______, _______, and _______ are synthesized primarily from arachadonic acid (20 carbons, polyunsaturated fatty acid).
They are produced by _______ cells and have functions in the inflammatory response, smooth muscle contraction, blood pressure regulation, bronchoconstriction and bronchodilation.
The eicosanoids which include the prostaglandins, thromboxanes, and leukotrienes are synthesized primarily from arachadonic acid (20 carbons, polyunsaturated fatty acid).
They are produced by all cells and have functions in the inflammatory response, smooth muscle contraction, blood pressure regulation, bronchoconstriction and bronchodilation.
Understand how glucose from our food intake is converted to fats (lipogenesis).
Know the key enzymes, substrates, coenzymes and hormonal regulation involved in the
synthesis of saturated and unsaturated fatty acids.
Fatty acid are synthesized primarily in the liver. Dietary carbs are converted to glucose which serves as the substrate for glycolysis which produces pyruvate. Pyruvate enters the mitochondria where it is converted to citrate. Citrate, unlike acetyl CoA, can exit the mitochondria into the cytosol. Once in the cytosol the citrate is converted to acetyl CoA, which is then converted to malonyl CoA, the two carbon donor for fatty acid synthesis. The product of fatty acid synthesis is palmitic acid, a sixteen carbon saturated fatty acid.
STEPS
Pyruvate enters the mitochondria & is concerted to Acetyl CoA by pyruvate dehydrogenase & to OAA by pyruvate carboxylase. When Acetyl CoA condenses with OAA it forms Citrate. In the cytosol, Citrate is cleaved to Acetyl CoA & OAA by Citrate Lyase.
NADPH is required for the synthesis of fatty acids. One source of NADPH i the recycling of OAA which is formed as a product of Citrate lyase. A second source of NADPH is the pentose phosphate pathway.
The 2 enzymes in FA synthesis are Acetyl CoA Carboxylase & FA synthase. ACC is the rate limiting step.
ACC is the Regulatory Enzyme which converts Acetyl CoA to Malonyl CoA. CO2 binds to the cofactor Biotin which is linked to ACC. The attachment of CO2 to Biotin requires ATP hydrolysis.
Regulation of ACC:
POSITIVE REGULATORS:
Citrate causes ACC to polymerize
Insulin stimulates phosphatase which activates ACC (phosphorylated = inactive)
ACC transcription occurs when you have high caloric intake
NEGATIVE REGULATORS:
Glucagon/ Epi stimulates kinase that phosphorylates ACC & inactivates it
Palmitoyl CoA (feedback inhibition by product)
High AMP = low ATP
FA synthase catalyzes everything else.
FA synthase adds 2 Carbons from Malonyl CoA to the growing fatty acyl chain with the final product being palmitate. The cofactor for FA synthase is phosphopantethenyl residue–it is attatched to ACP segment.
After the previous steps, Acetyl CoA condenses with Malonyl CoA. Acetyl CoA & Malonyl CoA both associate with the phosphopantethenyl sulfhydryl group to condense.
In the following steps there is a reduction of a B-Keto group to an alcohol followed by a dehydration to a double bond & then another reduction step reduces the double bond. NADPH provides all of the reducing equivalents for all of these steps.
In order to keep adding carbons, must repeat steps 2-5 (start @ Malonyl CoA), until get palmitate (C16).
Desaturation is the oxidation of fatty acids resulting in CIS double bonds–this occurs in the ER by enzymes called desaturases. There are 3 desatureases: Δ9, Δ6, Δ5. Δ9 desaturase is the most common.
Appreciate the general mechanisms by which key eicosinoids are produced and their
physiologic functions.
Polyunsaturated fatty acids with double bonds 3 or 6 carbons away from the methyl end are required for Eicosinoid synthesis. (ω3 or ω6). These come from essential fatty acids linolenic & linoleic.
Arachidonic acid, a 20-carbon polyunsaturated FA, is an important component of certain membrane lipids, prostoglandins, and precursor of several classes of the signaling molecules known as eicosanoids. The biosynthesis of arachidonic acid comes from linoleic acid. Arachadonic acid (ω6) is not essential as long as linoleic acid is around!
Arachidonic acid is the precursor for the Eicosanoids known as Leukotrienes, Thromboxanes, & Prostaglandins.
Eicosanoids are unstable & have a short half-life. They are generated in situ (synthesized close to where they are utilized) & are local mediators involved in the inflammatory response, smooth muscle contraction, & bronchoconstriction or bronchodilation.
Arachadonic acid can have one of three fates depending on the enzyme acting upon it:
- Cyclic pathway by enzyme Cyclooxygenase makes the prostoglandins thromboxane & prostacyclin
- Linear pathway by enzyme lipoxygenase forms leukotrienes & lipxins
- Cytochrome P450 enzyme pathway forms epoxides.
Most cells only have the enzymes for 1 pathway & make only 1 type of eicosanoid. However, there are exceptions like platelets which use the cyclic & linear pathway.
NSAIDS + asprin act on cyclooxygenase 1 & 2 which prevents synthesis of PGH2. COX 1 = all cells, COX 2 = inflammation. All NSAIDS act on COX 1 & 2, it would be better to only target COX2 = only inflamation & would avoid effects of blocking COX1. Asprin acetylates COX1,2 = irreversible inhibitor since covalent bond. All other inhibitors are reversible inhibitors = not covalent bond.
Test question: what is the rate limiting enzyme in FA synthesis?
ACC = Acetyl CoA Carboxylase
