Vitamin fatty acid synthesis

Pantothenic acid (vitamin B5) is both present in many nutrientcients and it is also produced by intestinal bacteria. Deficiency is therefore thought to be unlikely. Its active form, 4-phosphopantetheine, is an element of both coenzyme-A and acyl-carrier protein and thus participates in fatty acid synthesis and in the posttranslational modification of proteins. Acetylcoenzyme-A is important for the synthesis of the neurotransmitter acetylcholine. 

FIGURE 21-4 Acyl carrier protein (ACP). The prosthetic group is 4 -phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis. 

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 remaining series of reactions of fatty acid synthesis in eukary-l otes is catalyzed by the multifunctional, dimeric enzyme, fatty acid synthase. Each fatty acid synthase monomer is a multicatalytic polypeptide with seven different enzymic activities plus a domain that covalently binds a molecule of 4 -phosphopantetheine. [Note 4-Phosphopantetheine, a derivative of the vitamin pantothenic add (see p. 379), carries acetyl and acyl units on its terminal thiol (-SH)j group during fatty acid synthesis. It also is a component of 00-enzyme A.] In prokaryotes, fatty acid synthase is a multienzyme complex, and the 4 -phosphopantetheine domain is a separate protein, referred to as the acyl carrier protein (ACP). ACP is used below to refer to the phosphopantetheine-binding domain of the eukaryotic fatty acid synthase molecule. The reaction numbers in1 brackets below refer to Figure 16.9. [Note The enzyme activities listed are actually separate catalytic domains present in each mulf-1 catalytic fatty acid synthase monomer.]... 

For some time, the effects of and responses to vitamin E have been interpreted in terms of an antioxidant mechanism of action. However, several observations have raised the question as to whether other mechanisms could be involved. For example, the effects of selenium and vitamin E on growth and polyunsaturated fatty acid synthesis in cultured mouse fibroblasts could not be reproduced by artificial antioxidants [198, 199]. The specific requirement of (+ )-a-toco-pherol for the phenotypic differentiation of the rotifer [200] may not be through an antioxidant mechanism. The effects of vitamin E on differentiation of neuroblastoma cells [201] and metamorphosis of various species [202] are likely to be due to a growth-factor-like action. A study on the interaction... 

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... 

The reaction is very useful synthetically in the synthesis of polyenes, vitamins, fatty acids, and the annulenes. Baeyer used the reaction in his historic synthesis of indigo as long ago as 1882. The reaction allowed the unequivocal establishment of the carbon skeleton of this dye ... 

Neurological complications also are associated with vitamin B-12 deficiency and result from a progressive demyelination of nerve cells. The demyelination is thought to result from the increase in methylmalonyl-CoA that result from vitamin B-12 deficiency. Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in fatty acid biosynthesis as well as being able to substitute for malonyl-CoA in any fatty acid biosynthesis that may occur. Since the myelin sheath is in continual flux the methylmalonyl-CoA-induced inhibition of fatty acid synthesis results in the eventual destruction of the sheath. The incorporation methylmalonyl-CoA into fatty acid biosynthesis results in branched-chain fatty acids being produced that may severely alter the architecture of the normal membrane structure of nerve cells... 

Which vitamin play a central role in fatty acid synthesis ... 

Niacin is a water-soluble vitamin. The RDA of niacin for the adult man is 19 mg. Niacin is converted in the bi>dy to the cofactor nicotinamide adenine dinucleotide (NAD). NAD also exists in a phosphorylated form, NADP The phosphate group occurs on the 2-hydrr>xyl group of the AMP half of the coenzyme, NAD and NADP are used in the catalysis of oxidation and reduction reactions. These reactions are called redox reactions. NAD cycles between the oxidized form, NAD, and the reduced form, NADH + H. The coenzyme functions to accept and donate electrons. NADP behaves in a similar fashion. It occurs as NADP and NADPH + HT The utilization of NAD is illustrated in the sections on glycolysis, the malatc-aspartate shuttle, ketone body metabolism, and fatty acid oxidation. The utilization of NADP is illustrated in the sectirrns concerning fatty acid synthesis and the pentose phosphate pathway. 

As can be seen from the equations above, the necessary amount of malonyl CoA is synthesized. Palmitate is subsequently synthesized from malonyl CoA and one initial acetyl CoA. Thus, acetyl CoA, NADPH, ATP, and HCOs are all necessary in this process. In contrast, FADH, is not utilized in fatty acid synthesis, but is one of the products of fatty acid oxidation. Vitamin is required for conversion of propionic acid to methylmalonic acid, a step in the p oxidation of odd-numbered fatty acid chains. 

Cardinale, G.J., Carty, T. J., and Abeles, R. H., 1970, Effect of methylmalonyl coenzyme A, a metabolite which accumulates in vitamin Bj2 deficiency, on fatty acid synthesis, J. Biol. Chem. 245 3771. 

Cobalamin (vitamin B12) a water-soluble B vitamin, normally involved in the human body metabolism, affecting DNA synthesis and regulation, fatty acid synthesis and energy production. Supplied by animal food, its defieiency leads to macrocytic anaemia, decreased bone marrow cell production, neurological problems, as well as metabolic issues (methylmalonyl-CoA acidosis, hyperhomocysteinemia). 

Mammals cannot synthesize biotin and depend on a regular dietary supply of this water-soluble vitamin (Zempleni et al., 2009). The Adequate Intake for biotin in adults is 30 pg/d (National Research Council, 1998). The classical role of biotin in mammalian intermediary metabolism is to serve as a covalently bound coenzyme in five carboxylases (Zanpleni et al., 2D09). Both the cytoplasmic acetyl-CoA carboxylase 1 (ACCl) and the mitochondrial acetyl-CoA carboxylase 2 (ACC2) catalyze the binding of bicarbonate to acetyl-CoA to generate malonyl-CoA, but the two isoforms have distinct functions in intermediary metabolism (Kim et al., 1997). ACCl produces malonyl-CoA for the synthesis of fatty acid synthesis in the cytoplasm ACC2... 

Pyruvate is converted to phosphoenolpyruvate for glucose synthesis by a two-step reaction, with the intermediate formation of oxaloacetate. As shown in Figure 5.31, pyruvate is carboxylated to oxaloacetate in an ATP-dependent reaction in which the vitamin biotin (section 11.12) is the coenzyme. This reaction can also be used to replenish oxaloacetate in the citric acid cycle when intermediates have been withdrawn for use in other pathways, and is involved in the return of oxaloacetate from the cytosol to the mitochondrion in fatty acid synthesis — see Figure 5.26. Oxaloacetate then undergoes a phosphorylation reaction, in which it also loses carbon dioxide, to form phosphoenolpyruvate. The phosphate donor for this reaction is GTP as discussed in section 5.4.4, this provides regulation over the use of oxaloacetate for gluconeogenesis if citric acid cycle activity would be impaired. 

Several of the B vitamins are essential for normal fatty-acid metabolism (Table 2). Pantothenic acid is a constituent of CoA and is thus required for numerous reactions of fatty acids. Niacin and riboflavin are necessary for the synthesis of oxidized and reduced NAD(P) and FAD, respectively. These compounds play essential roles in fatty-acid oxidation, synthesis, and elongation. Biotin is a constituent of acetyl-CoA carboxylase and pyruvate carboxylase, both of which are involved in the synthesis of fatty acids from glucose. Thiamine is required for activity of the pyruvate dehydrogenase complex, which also participates in fatty-acid synthesis from glucose. 

In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP). However, in yeast, mammals, and birds, the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA. It contains the vitamin pantothenic acid in the form of 4 -phosphopan-tetheine (Figure 45-18). The use of one multienzyme functional unit has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. 

Besides watet, the diet must provide metaboEc fuels (carbohydrate and fat) fot bodily growth and activity protein fot synthesis of tissue proteins fiber for roughage minerals for specific metabolic functions cettain polyunsamtated fatty acids of the n-3 and n-6 famihes fot eicosanoid synthesis and other functions and vitamins, otganic compounds needed in small amounts for many varied essential functions. 

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