Lactation fatty acid synthesis

Fatty acids are predominantly formed in the liver and adipose tissne, as well as the mammary glands during lactation. Fatty acid synthesis occurs in the cytosol (fatty acid oxidation occurs in the mitochondria compartmentalisation of the two pathways allows for distinct regulation of each). Oxidation or synthesis of fats utilises an activated two-carbon intermediate, acetyl-CoA, but the acetyl-CoA in fat synthesis exists temporarily bound to the enzyme complex as malonyl-CoA. Acetyl-CoA is mostly produced from pyruvate (pyruvate dehydrogenase) in the mitochondria it is condensed with oxaloacetate to form citrate, which is then transported into the cytosol and broken down to yield acetyl-CoA and oxaloacetate (ATP citrate lyase). 

Glycolysis, the pentose phosphate pathway, and fatty acid synthesis are all found in the cytosol. In gluconeo-genesis, substrates such as lactate and pyruvate, which are formed in the cytosol, enter the mitochondrion to yield oxaloacetate before formation of glucose. 

The most active organs in fatty acid synthesis are the liver and the lactating mammary gland. 

Alternate fates of pyruvate Compounds other than lactate to which pyruvate can be converted ALTERNATE FATES OF PYRUVATE (p. 103) Pyruvate can be oxidatively decarboxylated by pyruvate dehydrogenase, producing acetyl CoA—a major fuel for the tricarboxylic acid cycle (TCA cycle) and the building block for fatty acid synthesis. Pyruvate can be carboxylated to oxaloacetate (a TCA cycle intermediate) by pyruvate carboxylase. Pyruvate can be reduced by microorganisms to ethanol by pyruvate decarboxylase. 

Grunnet, I. and Knudsen, J. 1979. Fatty-acid synthesis in lactating goat mammary gland, I. Medium chain fatty acid synthesis. Evr. J. Biochem. 95, 497-502. 

Knudsen, J., Clark, S. and Dils, R. 1976. Purification and some properties of a medium chain hydrolase from lactating-rabbit mammary gland which terminates chain elongation in fatty acid synthesis. Biochem. J. 160, 683-691. 

Libertini, L. J. and Smith S. 1978. Purification and properties of thioesterase from lactating rat mammary gland which modifies the product specificity of fatty acid synthesis. J. Biol. Chem. 253, 1398. 

Smith, S. and Stern, A. 1981. Development of the capacity of mouse mammary glands for medium chain fatty acid synthesis during pregnancy and lactation. Biochim. Biophys. Acta 664, 611-615. 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

Hansen, J.K., Knudsen, J. 1980. Transacylation as a chain-termination mechanism in fatty acid synthesis by mammalian fatty acid synthetase. Synthesis of butyrate and hexanoate by lactating cow mammary gland fatty acid synthetase. Biochem. J. 186, 287-294. 

Mellenberger, R.W., Bauman, D.E. 1974. Fatty acid synthesis in rabbit mammary tissue during pregnancy and lactation. Biochem. J. 138, 373-379. 

Pyruvate has several metabolic fates. It can be reduced to lactate, converted to oxaloacetate in a reaction important in gluconeogenesis (Chapter 15) and in an anaplerotic reaction of the TC A cycle (see below), transminated to alanine (Chapter 17), or converted to acetyl-CoA and CO2. Acetyl-CoA is utilized in fatty acid synthesis, cholesterol (and steroid) synthesis, acetylcholine synthesis, and the TCA cycle (Figure 13-6). 

Biotin serves as the prosthetic group of several enzymes that catalyse the transfer of carbon dioxide from one substrate to another. In animals there are three biotin-dependent enzymes of particular importance pyruvate carboxylase (carbohydrate synthesis from lactate), acetyl coenzyme A carboxylase (fatty acid synthesis) and propionyl coenzyme A carboxylase (the pathway of conversion of propionate to succinyl-CoA). The specific role of these enzymes in metabolism is discussed in Chapter 9. 

In animal cells and yeasts, multienzyme complexes localised in cytosol, referred to as type I fatty acid synthase (FAS I), carry out the bulk of the de novo fatty acid synthesis. In animals, it occurs primarily in the liver, adipose tissue, central nervous system and lactating mammary gland. FAS I contains seven distinct catalytic centres and is arranged around a central acyl carrier protein (ACP) containing bound pantothenic acid (see Section 5.9.1). In prokaryotes and plants, distinct soluble enzymes localised in mitochondria and plastids, referred to as type II fatty acid synthase (FAS II), carry out the reactions. 

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