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INTRODUCTION

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OBJECTIVES

After studying this chapter, you should be able to:

  • Describe the reaction catalyzed by acetyl-CoA carboxylase and understand the mechanisms by which its activity is regulated to control the rate of fatty acid synthesis.

  • Outline the structure of the fatty acid synthase multienzyme complex, indicating the sequence of enzymes in the two peptide chains of the homodimer.

  • Explain how long-chain fatty acids are synthesized by the repeated condensation of two carbon units, with formation of the 16-carbon palmitate being favored in most tissues, and identify the cofactors required.

  • Indicate the sources of reducing equivalents (NADPH) for fatty acid synthesis.

  • Understand how fatty acid synthesis is regulated by nutritional status and identify other control mechanisms that operate in addition to modulation of the activity of acetyl-CoA carboxylase.

  • Identify the nutritionally essential fatty acids and explain why they cannot be formed in the body.

  • Explain how polyunsaturated fatty acids are synthesized by desaturase and elongation enzymes.

  • Outline the cyclooxygenase and lipoxygenase pathways responsible for the formation of the various classes of eicosanoids.

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BIOMEDICAL IMPORTANCE

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Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In most mammals, glucose is the primary substrate for lipogenesis, but in ruminants it is acetate, the main fuel molecule they obtain from the diet. Critical diseases of the pathway have not been reported in humans. However, inhibition of lipogenesis occurs in type 1 (insulin-dependent) diabetes mellitus, and variations in the activity of the process affect the nature and extent of obesity.

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Unsaturated fatty acids in phospholipids of the cell membrane are important in maintaining membrane fluidity (see Chapter 40). A high ratio of polyunsaturated fatty acids to saturated fatty acids (P:S ratio) in the diet is considered to be beneficial in preventing coronary heart disease. Animal tissues have limited capacity for desaturating fatty acids, and require certain dietary polyunsaturated fatty acids derived from plants. These essential fatty acids are used to form eicosanoic (C20) fatty acids, which give rise to the eicosanoids prostaglandins, thromboxanes, leukotrienes, and lipoxins. Prostaglandins mediate inflammation, pain, and induce sleep and also regulate blood coagulation and reproduction. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen act by inhibiting prostaglandin synthesis. Leukotrienes have muscle contractant and chemotactic properties and are important in allergic reactions and inflammation.

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THE MAIN PATHWAY FOR DE NOVO SYNTHESIS OF FATTY ACIDS (LIPOGENESIS) OCCURS IN THE CYTOSOL

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This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue. Its cofactor requirements include NADPH, ATP, Mn2+, biotin, and HCO3 (as a source of CO2). Acetyl-CoA is the immediate substrate, and free palmitate is the end product.

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Production of Malonyl-CoA Is the Initial & Controlling Step in Fatty Acid Synthesis

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