FA synthesis occurs primarily in the ______.
- Liver
- Also in brain, kidneys, and adipose tissue
- Components located in cytoplasm: Enzymes, acyl carrier proteins, co-factors, reducing power, energy (ATP)
Major source of carbon for fatty acid synthesis is ___________.
•Dietary carbohydrates
Major steps in synthesis of FA
- Formation of Acetyl CoA (2 carbon)
- Conversion of Acetyl CoA to Malonyl CoA (3 carbon)
- Elongation (addition of carbons)
- Desaturation (introduction of double bonds)
________ supplies carbons for FA synthesis.
- Citrate
- Citrate lyase important enzyme that converts citrate–>OAA
- Malic enzyme important to convert pyruvate–>malate
Conversion of Acetyl CoA to Malonyl CoA:
- Rate limiting step in FA biosynthesis**
- Catalyzed by Acetyl CoA Carboxylase (ACC)**
- Acetyl CoA converted to Malonyl CoA by carboxylation
- ACC adds a CO2 to acetyl CoA
Regulation of ACC
- Allosteric regulation: citrate (+), long chain FA (-)
- Phosphorylation (-)/Dephosphorylation (+): Insulin (+), Epinephrine (-), Glucagon (-)
- Induction/repression: Gene expression up-regulated by high carb/low fat diet, down-regulated by high fat/low carb diet
Two carbon units from malonyl CoA are sequentially added to growing fatty acyl chain to form _______.
•Palmitate
The reactions of fatty acid synthesis occur on the ________.
•Fatty Acid Synthase Complex
FA synthase
- large multi-enzyme complex
- Composed of 2 identical dimers (260 kDa each) HUGE
- Each has 7 catalytic activities and an acyl carrier protein (ACP)
- ACP segment has a phosphopantetheine (PP) residue
- Two dimers arragned head to tail conformation-PP of one is aligned with cysteinyl sulfhydryl group of another
Reactions of FA synthesis
•Condensation–>Reduction–>Dehydration–>Reduction
Regulation of FAS
- Allosteric effect (presence of phosphorylated sugars)
- Induction and repression at gene level
- High carb/low fat diet increases FAS synthesis
- High fat diet as well as starvation lowers FAS synthesis
TAG packaged with apoproteins to form _______ and secreted into blood.
•Very Low Density Lipoproteins (VLDL)
Eicosanoids
- Products generated by the oxidation of 20-carbon FA (arachidonic acid)
- Four families: prostaglandins, prostacyclins, thromoboxanes, and leukotrienes**
Synthesis of Phospholipids (PLs) Mechanism 1
- Phosphatidic acid cleaved by phosphatase to form diacyglycerol (DAG)
- DAG reacts with various headgroups to form different phospholipids
- Headgroups need to be ‘activated’ prior to this reaction
- Choline headgroup combines with CTP to form CDP-Choline (activated
- Phosphocholine (PC) transferred to DAG to form phosphatidylocholine and CMP is released
Synthesis of PLs Mechanism 2
- Phosphatidic acid reacts with CTP to form CDP-DAG
- CDP-DAG reacts with inositol to form PL and CMP
- CDP-DAG may react with glycerol to procuce phosphatidyl glycerol
- Forms diphosphatidyl glycerol (cardiolipin), a component of the inner mito matrix
Interconversion between PLs
- PS is formed by exchanging ethanolamine for serine
- PS can be reconverted to PE by decarboxylation
- PE can be methylated to form PC
Cholesterol
- Most abundant sterol
- Component of membranes and precursors of biologically active compounds: bile acids and salts, Vit D, steroid hormones
- Daily intake ~250 mg (30-60% absorbed in gut)
- Daily production ~1g, mostly in liver
- Daily excretion ~5% excreted, ~95% re-absorbed
- Biosynthesis regulated by dietary intake
What is the rate limiting step of cholesterol biosynthesis?
- HMG CoA reductase (target of statins)**
* Converts Acetyl CoA to Mevalonate
