Fatty acid synthesis biotin

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). 

H Biotin Coenzyme in carboxylation reactions in gluco-neogenesis and fatty acid synthesis Impaired fat and carbohydrate metabolism, dermatitis... 

W3. Wakil, S. J., and Gibson, D. M., Studies on the mechanism of fatty acid synthesis. VIII. The participation of protein bound biotin in the biosynthesis of fatty acids. Biochim. et Biophys. Acta 41, 122-129 (1960). 

Scheme 21 Tethered biotin in carboxyiase activity. Biotin is tethered to carboxyiase proteins and serves as the hoider of CO2 units for fatty acid synthesis.

Acetyl CoA carboxylase Fatty acid synthesis of raw eggs (contain avidin, a biotin-binding protein)... 

The key enzyme in fatty acid synthesis is acetyl CoA carboxylase (see p. 162), which precedes the synthase and supplies the malonyl-CoA required for elongation. Like all carboxylases, the enzyme contains covalently bound biotin as a prosthetic group and is hormone-dependently inactivated by phosphorylation or activated by dephosphorylation (see p. 120). The precursor citrate (see p. 138) is an allosteric activator, while palmitoyl-CoA inhibits the end product of the synthesis pathway. 

The energy for the carbon-to-carbon condensations in fatty acid synthesis is supplied by the process of carboxylation and then decarboxylation of acetyl groups in the cytosol. The carboxylation of acetyl CcA to form malonyl CoA is catalyzed by acetyl CoA carboxylase (Figure 16.7), and requires HC03 )and ATP. The coenzyme is the vitamin, biotin, which is covalently bound to a lysyl residue of the carboxylase. 

The regulated step in fatty acid synthesis (acetyl CoA - malonyl CoA) is catalyzed by acetyl CoA carboxylase, which requires biotin. Citrate is the allosteric activator, and long-chain fatty acyl CoA is the inhibitor. The enzyme can also be activated in the presence of insulin and inactivated in the presence of epinephrine or glucagon. 

In the ruminant mammary tissue, it appears that acetate and /3-hydroxybutyrate contribute almost equally as primers for fatty acid synthesis (Palmquist et al. 1969 Smith and McCarthy 1969 Luick and Kameoka 1966). In nonruminant mammary tissue there is a preference for butyryl-CoA over acetyl-CoA as a primer. This preference increases with the length of the fatty acid being synthesized (Lin and Kumar 1972 Smith and Abraham 1971). The primary source of carbons for elongation is malonyl-CoA synthesized from acetate. The acetate is derived from blood acetate or from catabolism of glucose and is activated to acetyl-CoA by the action of acetyl-CoA synthetase and then converted to malonyl-CoA via the action of acetyl-CoA carboxylase (Moore and Christie, 1978). Acetyl-CoA carboxylase requires biotin to function. While this pathway is the primary source of carbons for synthesis of fatty acids, there also appears to be a nonbiotin pathway for synthesis of fatty acids C4, C6, and C8 in ruminant mammary-tissue (Kumar et al. 1965 McCarthy and Smith 1972). This nonmalonyl pathway for short chain fatty acid synthesis may be a reversal of the /3-oxidation pathway (Lin and Kumar 1972). 

In this cycle, one molecule of acetyl-CoA is formed from two molecules of bicarbonate (Figure 3.5). The key carboxylating enzyme is the bifunctional biotin-dependent acetyl-CoA/propionyl-CoA carboxylase. In Bacteria and Eukarya, acetyl-CoA carboxylase catalyzes the first step of fatty acid biosynthesis. However, Archaea do not contain fatty acids in their lipids, and acetyl-CoA carboxylase cannot serve as the key enzyme of fatty acid synthesis rather, it is responsible for autotrophy. 

The pathway The first committed step in fatty acid biosynthesis is the carboxylation of acetyl CoA to form malonyl CoA which is catalyzed by the biotin-containing enzyme acetyl CoA carboxylase. Acetyl CoA and malonyl CoA are then converted into their ACP derivatives. The elongation cycle in fatty acid synthesis involves four reactions condensation of acetyl-ACP and malonyl-ACP to form acetoacetyl-ACP releasing free ACP and C02, then reduction by NADPH to form D-3-hydroxybutyryl-ACP, followed by dehydration to crotonyl-ACP, and finally reduction by NADPH to form butyryl-ACP. Further rounds of elongation add more two-carbon units from malonyl-ACP on to the growing hydrocarbon chain, until the C16 palmitate is formed. Further elongation of fatty acids takes place on the cytosolic surface of the smooth endoplasmic reticulum (SER). 

CoA to form malonyl CoA using C02 in the form of bicarbonate HC03 (Fig. 2). This reaction is catalyzed by the enzyme acetyl CoA carboxylase which has biotin as a prosthetic group, a common feature in C02-binding enzymes. One molecule of ATP is hydrolyzed in the reaction, which is irreversible. The elongation steps of fatty acid synthesis all involve intermediates linked to the terminal sulfhydryl group of the phosphopantetheine reactive unit in ACP phosphopantetheine is also the reactive unit in CoA. Therefore, the next steps are the formation of acetyl-ACP and malonyl-ACP by the enzymes acetyl transacylase and malonyl transacylase, respectively (Fig. 2). (For the synthesis of fatty acids with an odd number of carbon atoms the three-carbon propionyl-ACP is the starting point instead of malonyl-ACP.)... 

Biotin (60), a water-soluble vitamin with widespread application in the growing market for health and nutrition, acts as a co-factor for carboxylase enzymes and its essential fatty acid synthesis. The key step in the chemical synthesis of biotin is the asymmetric reduction of the tetrasubstituted olefins 61 by in situ Rh(I)-4i catalyst (Scheme 12.1 S).79-83-85-86 Substrate-to-catalyst ratios of 2000 with diastereoselectivities of 99% de were achieved with Rh-4i at the multi-ton scale before production was terminated.87... 

Biotin is important in a number of metabolic reactions, especially in fatty acid synthesis. The biotin supply of the human organism is only partly derived from the diet. 

Synthesis of malonyl-CoA is the first committed step of fatty acid synthesis (Figure 5.1) the enzyme that catalyses this reaction, acetyl-CoA carboxylase (ACC), is the major site of regulation of fatty acid synthesis (this reaction also requires a biotin prosthetic group). 

The major functions of pantothenic acid are in CoA (Section 12.2.1) and as the prosthetic group for AGP in fatty acid synthesis (Section 12.2.3). In addition to its role in fatty acid oxidation, CoA is the major carrier of acyl groups for a wide variety of acyl transfer reactions. It is noteworthy that a wide variety of metabolic diseases in which there is defective metabolism of an acyl CoA derivative (e.g., the biotin-dependent carboxylase deficiencies Sections 11.2.2.1 and 11.2.3.1), CoA is spared by formation and excretion of acyl carnitine derivatives, possibly to such an extent that the capacity to synthesize carnitine is exceeded, resulting in functional carnitine deficiency (Section 14.1.2). 

Figure 4.46 shows the first step (acetyl-CoA carboxylase catalyzed) in the fatty acid synthesis pathway. The enzyme is biotin-requiring, and the product is malonyl-CoA. Note that the activities of about 100 different enzymes have been foxmd to be controlled by phosphorylation (Shacter et ah, 1986). In all cases, the phosphorylation is reversible. The phosphate donor may be ATP or GTP. 

Would you expect a biotin deficiency to result in greater impairment of the Cori cycle or in fatty acid synthesis, on the basis of the data in Figure 9.33 ... 

Carboxylation. Gluconeogenesis begins with the carboxylation of pyruvate to yield oxaloacetate. As in the third step of fatty acid synthesis (Figure 29.8), the reaction requires ATP and the coenzyme biotin, acting as a carrier of CO2. 

H Biotin Coenzyme in carboxyiation reactions in giuconeogenesis and fatty acid synthesis roie in reguiation of ceii cycie impaired fat and carbohydrate metaboiism dermatitis... 

The answer is d. (Murray, pp 627-661. Scrivcr, pp 3897-3964. Sack, pp 121—138. Wilson, pp 287-320.) The key enzymatic step of fatty acid synthesis is the carboxylation of acetyl CoA to form malonyl CoA. The carboxyl of biotin is covalently attached to an -amino acid group of a lysine residue of acetyl CoA carboxylase. The reaction occurs in two stages. In the first step, a carboxybiotin is formed ... 

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