Ch 23 biochemistry

Biosynthesis of Fatty Acids & Eicosanoids

• Fatty acids are synthesized by an extramitochondrial system in the cytosol, forming palmitate from acetyl-CoA.
• In most mammals, glucose is the primary substrate for lipogenesis; in ruminants, acetate is more prevalent.
• Critical diseases of the fatty acid pathway synthesis have not been reported in humans.
• Inhibition of lipogenesis occurs in type 1 diabetes mellitus, and variations in its activity affect obesity.
• Unsaturated fatty acids in phospholipids maintain cell membrane fluidity.
• A high polyunsaturated fatty acid to saturated fatty acid ratio (P:S ratio) benefits coronary heart disease prevention.
• Animal cells have limited fatty acid desaturation capacity, requiring dietary polyunsaturated fatty acids from plants.
• Essential fatty acids (EFAs) produce eicosanoids—prostaglandins, thromboxanes, leukotrienes, and lipoxins.
• Prostaglandins regulate inflammatory responses, pain, sleep, blood clotting, and reproduction.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting prostaglandin synthesis.
• Leukotrienes affect muscle contractions and attract immune cells (chemotaxis), contributing to inflammation and allergic reactions.
• Lipoxins also play roles in inflammation.

The Main Pathway for De Novo Synthesis of Fatty Acids (Lipogenesis)

• Fatty acid synthesis primarily occurs in the cytosol.
• The cofactors for this process include NADPH, ATP, manganese, biotin, and bicarbonate.
• Acetyl-CoA is the direct precursor, and the final product is palmitate.

Production of Malonyl-CoA

• Bicarbonate is required and acetyl-CoA carboxylase is present.
• This complex enzyme is a multienzyme protein, containing biotin, biotin carboxyl carrier protein, biotin carboxylase, and carboxyl transferase.
• The enzyme has a regulatory allosteric site and its function is critical to regulating fatty acid synthesis.
• The reaction occurs in two steps: carboxylation of biotin and transfer of the carboxyl group to acetyl-CoA.

The Fatty Acid Synthase Complex

• The synthase complex contains 6 enzymes and is a homodimer with two identical subunits.
• Its structure is arranged in an X shape, potentially close to the 3-ketoacyl reductase enzyme domain.
• The complex's function involves combining malonyl-CoA with an initiating acetyl-CoA molecule to gradually extend the fatty acid chain.
• The complex utilizes pantothenic acid in the form of 4'-phosphopantetheine.

Fatty Acid Synthesis in the Mitochondria

• Acetyl CoA is the main building block formed from glucose via pyruvate oxidation in the mitochondria.
• Acetyl CoA is not readily diffusible across the mitochondrial membranes, necessitating a dedicated transport mechanism—using citrate.
• Citrate, produced by combining acetyl CoA with oxaloacetate, is carried into the cytosol then converted to acetyl CoA and oxaloacetate.
• NADPH is needed, supplied by the pentose phosphate pathway (it's hydrogen is used in the reductive synthesis of fatty acids)
• Alternative sources of NADPH for lipogenesis include reactions of malate to pyruvate catalyzed by "malic enzyme" and the isocitrate dehydrogenase reaction.
• Ruminants rely more on acetate as a precursor for lipogenesis via the extramitochondrial pathway.

Elongation of Fatty Acid Chains

• The microsomal system elongates saturated and unsaturated acyl-CoAs with from 10 to more carbon atoms.
• This process uses malonyl-CoA as an acetyl donor with NADPH as the reducing equivalent.
• The microsomal fatty acid elongases are responsible for this pathway.

Nutritional Control of Lipogenesis

• Lipogenesis rate is high in well-fed animals due to a higher carbohydrate intake.
• Depressed by calorie restrictions, high-fat diets, and insulin deficiency like in diabetes mellitus.
• An inverse relationship between hepatic lipogenesis and circulating free fatty acids.
• Lipogenesis is elevated when glucose is replaced in the diet with sucrose due to the fructose bypassing the key regulatory point in glycolysis.
• Regulating mechanisms are short-term (allosteric and covalent modifications of enzymes) or long term (gene expression).
• Acetyl-CoA carboxylase is the most important regulatory enzyme for lipogenesis, activated by citrate.
• Pyruvate dehydrogenase is also regulated by acyl-CoA, leading increased intramitochondrial ATP/ADP ratios and inactivation of the enzyme.
• Insulin increases glucose transport into cells, enabling more pyruvate and glycerol-3-phosphate for fatty acid synthesis and activation of pyruvate dehydrogenase.

Essential Fatty Acid Deficiency and Eicosanoids

• Deficiency symptoms occur when EFAs are missing from the diet, particularly in rats fed purified nonlipid diets.
• Deficiency may be cured by including EFAs such as linoleic, alpha-linolenic, and arachidonic acids.
• EFAs are concentrated in vegetable oils and present in animal carcasses (though in lower quantities).
• They are part of the structure of phospholipids in the cell and mitochondrial membranes.
• EFAs are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation.

Clinical Aspects

• Symptoms of essential fatty acid deficiency in humans may include skin lesions and/or impaired lipid transport.
• Abnormal essential fatty acid metabolism occurs in various diseases, often connected to dietary deficiencies.
• Very-long-chain polyunsaturated fatty acids are elevated in some brain diseases such as Zellweger syndrome.
• High P:S ratios of diests correlate with lower cholesterol levels and reduced risk for coronary heart disease.
• Trans fatty acid intake has potential negative consequences on health affecting various disorders.
• Specific aspects of prostaglandins, thromboxanes, leukotrienes, and lipoxins play key roles in the CNS, inflammation, immune response, reproductive processes, and the cardiovascular system.