Synthesis fatty acid

Very Htfle data are available regarding effects of anaboHc steroid implants on the Hpid metaboHsm in growing mminants. Lipogenic enzyme activity and fatty acid synthesis in vitro were elevated in subcutaneous adipose tissue from bulls implanted with estradiol (44), which may account for the increase in fat content of carcasses reported in some studies. TBA implants have no effect on Hpogenesis in intact heifers, and only tend to reduce Hpogenic enzyme activities in ovariectomized heifers (45). 

In the chloride shift, Ck plays an important role in the transport of carbon dioxide (qv). In the plasma, CO2 is present as HCO, produced in the erythrocytes from CO2. The diffusion of HCO requires the counterdiffusion of another anion to maintain electrical neutraUty. This function is performed by Ck which readily diffuses into and out of the erythrocytes (see Fig. 5). The carbonic anhydrase-mediated Ck—HCO exchange is also important for cellular de novo fatty acid synthesis and myelination in the brain (62). 

Naphthoquiaomycias A (67) and B (68) are isolated from Streptomyces S-1998 (223) and the stmctures for (67) and (68) assigned on the basis of spectral data. Naphthoquiaomycias A and B inhibit fatty acid synthesis ia E. coli. Actamycia (69) is obtaiaed from Streptomyces sp. EJ784 and its stmcture arrived at on the basis of spectral data and degradation studies (224,225). 

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

FIGURE 20.23 Export of citrate from mitochondria and cytosolic breakdown produces oxaloacetate and acetyl-CoA. Oxaloacetate is recycled to malate or pyruvate, which re-enters the mitochondria. This cycle provides acetyl-CoA for fatty acid synthesis in the cytosol. 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

Intermediates in fatty acid synthesis are linked covalently to the suifhydryl groups of special proteins, the acyl carrier proteins. In contrast, fatty acid breakdown intermediates are bound to the —SH group of coenzyme A. Fatty acid synthesis occurs in the cytosol, whereas fatty acid degradation takes place in mitochondria. 

In animals, the enzymes of fatty acid synthesis are components of one long polypeptide chain, the fatty acid synthase, whereas no similar association exists for the degradative enzymes. (Plants and bacteria employ separate enzymes to carry out the biosynthetic reactions.)... 

The coenzyme for the oxidation-reduction reactions of fatty acid synthesis is NADP /NADPH, whereas degradation involves the NAD /NADH couple. 

Formation of Malonyl-CoA Activates Acetate Units for Fatty Acid Synthesis... 

The design strategy for fatty acid synthesis is this ... 

Eukaryotic cells face a dilemma in providing suitable amounts of substrate for fatty acid synthesis. Sufficient quantities of acetyl-CoA, malonyl-CoA, and NADPH must be generated in the cytosol for fatty acid synthesis. Malonyl-CoA is made by carboxylation of acetyl-CoA, so the problem reduces to generating sufficient acetyl-CoA and NADPH. 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

FIGURE 25.1 The citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents (electrons) for fatty acid synthesis. The shuttle collects carbon substrates, primarily from glycolysis but also from fatty acid oxidation and amino acid catabolism. Most of the reducing equivalents are glycolytic in origin. Pathways that provide carbon for fatty acid synthesis are shown in blue pathways that supply electrons for fatty acid synthesis are shown in red. 

Acetate Units Are Committed to Fatty Acid Synthesis by Formation of Malonyl-CoA... 

Rittenberg and Bloch showed in the late 1940s that acetate units are the building blocks of fatty acids. Their work, together with the discovery by Salih Wakil that bicarbonate is required for fatty acid biosynthesis, eventually made clear that this pathway involves synthesis of malonyl-CoA. The carboxylation of acetyl-CoA to form malonyl-CoA is essentially irreversible and is the committed step in the synthesis of fatty acids (Figure 25.2). The reaction is catalyzed by acetyl-CoA carboxylase, which contains a biotin prosthetic group. This carboxylase is the only enzyme of fatty acid synthesis in animals that is not part of the multienzyme complex called fatty acid synthase. 

FIGURE 25.2 (a) The acetyl-CoA carboxylase reaction produces malonyl-CoA for fatty acid synthesis, (b) A mechanism for the acetyl-CoA carboxylase reaction. Bicarbonate is activated for carboxylation reactions by formation of N-carboxybiotin. ATP drives the reaction forward, with transient formation of a carbonylphosphate intermediate (Step 1). In a typical biotin-dependent reaction, nncleophilic attack by the acetyl-CoA carbanion on the carboxyl carbon of N-carboxybiotin—a transcarboxylation—yields the carboxylated product (Step 2). 

The enzymes that catalyze formation of acetyl-ACP and malonyl-ACP and the subsequent reactions of fatty acid synthesis are organized quite differently in different organisms. We first discuss fatty acid biosynthesis in bacteria and plants, where the various reactions are catalyzed by separate, independent proteins. Then we discuss the animal version of fatty acid biosynthesis, which involves a single multienzyme complex called fatty acid synthase. 

The selection of a suitable and relevant organism is an important part of any biochemical investigation. The studies that revealed the secrets of fatty acid synthesis are a good case in point. 

The paradigm for fatty acid synthesis in plants has been the avocado, which has one of the highest fatty acid contents in the plant kingdom. Early animal studies centered primarily on... 

Fatty Acid Synthesis in Eukaryotes Occurs on a Multienzyme Complex... 

FIGURE 25.8 In yeast, the functional groups and enzyme activities required for fatty acid synthesis are distributed between a and /3 subunits. 

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

FIGURE 25.17 Hormonal signals regulate fatty acid synthesis, primarily through actions on acetyl-CoA carboxylase. Availability of fatty acids also depends upon hormonal activation of triacylglycerol lipase. 

In bacteria, each step in fatty-acid sjmthesis is catalyzed by separate enzymes. In vertebrates, however, fatty-acid synthesis is catalyzed by a large, multienzyme complex called a synthase that contains two identical subunits of 2505 amino acids each and catalyzes all steps in the pathway. An overview of fatty-acid biosynthesis is shown in Figure 29.5. 

Steps 1-2 of Figure 29.5 Acyl Transfers The starting material for fatty-acid synthesis is the thioesteT acetyl CoA, the ultimate product of carbohydrate breakdown, as we ll see in Section 29.6. The synthetic pathway begins with several priming reactions, which transport acetyl CoA and convert it into more reactive species. The first priming reaction is a nucleophilic acyl substitution reaction that converts acetyl CoA into acetyl ACP (acyl carrier protein). The reaction is catalyzed by ACP transacyla.se. 

Problem 29.4 Write a mechanism for the dehydration reaction of /3-hydroxybutyryl ACP to yield crotonyl ACP in step 7 of fatty-acid synthesis. 

Fatty acid synthesis 1 Acetyl-CoA carboxylase-1 l Activity All cells ... 

Fatty acid synthesis 1 SREBP-1c, HNF-4a l Expression ACC1, fatty acid synthase Liver... 

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