Fatty Acid and Lipid Biosynthesis Quiz

Fatty Acid and Lipid Biosynthesis

• Fatty acid and lipid biosynthesis occurs in several passes, processing one acetate unit at a time
• The acetate is activated into malonyl-CoA
• Acetyl-CoA + CO2 + ATP → malonyl-CoA + ADP + P
• Biotin is necessary for this reaction
• Insulin stimulates the conversion of dietary carbohydrates and proteins to fats
• Insulin promotes the process of Acetyl-CoA production

Catabolism and Anabolism of Fatty Acids

• Fatty acid catabolism produces acetyl-CoA and reducing power (NADH, FADH2)
• Fatty acid catabolism takes place in the mitochondria
• Fatty acid anabolism requires acetyl-CoA and malonyl-CoA
• Fatty acid anabolism needs reducing power from NADPH for fatty acid synthesis
• The anabolism of fatty acids takes place in the cytosol in animals and chloroplast in plants

Overview of Fatty Acid Synthesis

• Fatty acids are built in several passes, processing one acetate unit at a time.
• The acetate is derived from activated malonate in the form of malonyl CoA
• The process of making malonyl CoA uses acetyl CoA carboxylase (ACC)

Fatty Acid Synthase Makes Palmitate

• Fatty acid synthase functions in a repeating 4-step sequence
• The chain elongates by two atoms each time
• Vertebrates have a single polypeptide chain with several catalytic domains
• The product of fatty acid synthase is palmitate 16:0

Acyl Carrier Protein (ACP)

• ACP contains a covalently attached prosthetic group, 4'-phosphopantetheine
• ACP has a flexible arm that tethers acyl chains
• ACP carries intermediates between enzyme subunits
• ACP delivers acetate or malonate to the fatty acid synthase
• ACP shuttles the growing chain between active sites during the four-step reaction

Stoichiometry of Palmitate (16:0) Synthesis

• 7 acetyl-CoA molecules are carboxylated to 7 malonyl-CoA molecules
• Seven cycles of condensation, reduction, dehydration, and reduction, use NADPH
• The final product is palmitate (16 carbons), formed from 8 acetyl-CoA, 7 ATP, 14 NADPH and 14 H+
• The byproducts are 7 CO2, 8 CoA, 14 NADP+, 7 ADP, 7 Pi, and 6 H2O.

Pathways for NADPH Production

• NADPH is produced in the cytosol for fatty acid synthesis.
• NADPH is obtained from the malic enzyme and pentose phosphate pathway
• Malic enzyme, takes pyruvate, converts it into malate, producing CO2 and NADPH
• Pentose phosphate pathway produces NADPH during the conversion of glucose-6-phosphate to ribose- 5-phosphate

Acetyl-CoA Is Transported into the Cytosol

• Acetyl-CoA made in the mitochondria is transported to the cytosol as citrate
• Acetyl-CoA combines with oxaloacetate to form citrate
• Citrate is transported into the cytosol where it is oxidized to acetyl-CoA and oxaloacetate

FAS Anabolism/Synthesis & Catabolism/ß-oxidation

• Insulin stimulates fatty acid synthesis and promotes fatty acid catabolism.
• Factors that affect the flux through pathways are the hormonal state and major tissue site
• Subcellular location varies between these two processes
• Oxidation and reduction factors (cofactors) and type of "two-carbon donors/products"

Routes of Synthesis of Unsaturated Fatty Acids

• The ratio of -6 fatty acids to -3 fatty acids in diet is important, and excess can lead to cardiovascular disease.
• Essential fatty acids, such as Omega-6 and Omega-3 fatty acids, must be obtained from the diet

Synthesis of Backbone of TAGS (Fats) and Phospholipids

• Glycerol 3-phosphate is derived from dihydroxyacetone phosphate (DHAP) from glycolysis
• Glycerol 3-phosphate dehydrogenase converts DHAP into glycerol 3-phosphate
• Some glycerol 3-phosphate is synthesized from glycerol via glycerol kinase (minor pathway)

Synthesis of Phosphophatidic Acid

• Phosphatidic acid is a precursor for TAGs and phospholipids
• Fatty acids are attached to phosphatidic acid by acyl transferases
• Phosphatidic acid is important in the biosynthesis of TAGs and phospholipids
• The advantage is that phosphatidic acid then can be made into triacylglycerol or phospholipid.

Phosphatidic Acid Modification

• Phosphatidic acid phosphatase (lipin) removes the 3-phosphate group from phosphatidic acid, which yields 1,2-diacylglycerol
• The third carbon on the 1,2-diacylglycerol is acylated with a third fatty acid to produce triacylglycerol

Insulin Stimulates Conversion of Dietary Carbohydrates and Proteins to Fats

• Insulin promotes the conversion of dietary carbohydrates and amino acids into acetyl-CoA
• This acetyl-CoA is then utilized in the synthesis of fats and triacylglycerols.

Triacylglycerol Cycle

• The Triacylglycerol cycle is important in starvation
• The process involves the breakdown of triacylglycerols in adipose tissue to release fatty acids and glycerol.
• Glycerol is converted to glycerol 3-phosphate, supplying precursors for gluconeogenesis and fatty acid synthesis
• Fatty acids are transported to other tissues for energy production

Glyceroneogenesis

• Glyceroneogenesis is similar to gluconeogenesis
• It is active in adipose cells
• During lipolysis (stimulated by glucagon or epinephrine), glycolysis is inhibited
• DHAP is not readily available to make glycerol 3-phosphate
• Adipose cells do not have glycerol kinase, so they make DHAP via glyceroneogenesis.

Thiazolidinediones

• Thiazolidinediones ("insulin sensitizers") decrease insulin resistance, a phenomenon associated with high blood levels of free fatty acids and obesity-related type 2 diabetes.
• They are stimulators of PPAR (peroxisome proliferation activated receptor), a nuclear receptor that regulates the expression of genes involved in fat metabolism.

Biosynthesis of Isoprenoids and Cholesterol

• Isoprenoids and cholesterol are synthesized from acetyl-CoA via mevalonate and squalene
• The process involves a series of enzymatic reactions starting with acetyl-CoA
• Mevalonate is a key intermediate in the synthesis of isoprenoids and cholesterol.
• Squalene is an intermediate molecule in the production of cholesterol

Formation of Mevalonate from Acetyl-CoA

• Three acetyl-CoA molecules condense to from HMG-CoA
• HMG-CoA reduces to form mevalonate
• HMG-CoA reductase is a target of statins, cholesterol-lowering drugs.

Fates of Cholesterol After Synthesis

• Most cholesterol synthesized in the liver is exported
• Cholesterol is exported as bile acids, biliary cholesterol, or cholesteryl esters
• Bile is stored in the gall bladder and secreted after meals
• Bile acids emulsify dietary fats by surrounding droplets of fats, increasing their surface area for attack by lipases
• Cholesterol is converted into other compounds, such as steroid hormones

Four Major Classes of Lipoprotein Particles

• Lipoprotein particles are named based on sedimentation (density) in a centrifuge
• TAG is less dense than water, hence as TAG % increases, density decreases
• The composition varies between class
• The particles include chylomicrons, VLDL, LDL, and HDL

Cholesterol Uptake by Receptor-Mediated Endocytosis

• LDL receptor binds apoB-100, initiates endocytosis, and internalizes LDL
• LDL receptor is segregated to vesicles, recycled to surface for further LDL binding and receptor-mediated endocytosis
• Lytic enzymes degrade apoB-100 and cholesteryl esters releasing amino acids, fatty acids and cholesterol

Blood Lipoproteins

• Blood lipoproteins transport TG and cholesterol from one tissue to another.
• Chylomicrons and VLDL carry TG's; lipoprotein lipase degrades TGs.
• Elevated VLDL and LDL (or both) are indicators of potential cardiovascular issues

Regulation of Cholesterol Metabolism

• Cholesterol metabolism is regulated by various factors including insulin and glucagon.
• Insulin promotes cholesterol synthesis, while glucagon inhibits it
• AMPK inhibits HMG-CoA reductase (a cholesterol biosynthesis key enzyme)

Steroid Hormones Derived from Cholesterol

• Steroid hormones are derived from cholesterol.
• Pregnenolone is a precursor to progesterone, cortisol, corticosterone, testosterone, and estradiol
• These hormones affect various physiological processes such as metabolism, immune response, and reproduction.