Prosthetic group synthesis

Flavin mononucleotide was first isolated from the yellow en2yme in yeast by Warburg and Christian in 1932 (4). The yellow en2yme was spHt into the protein and the yellow prosthetic group (coen2yme) by dialysis under acidic conditions. Flavin mononucleotide was isolated as its crystalline calcium salt and shown to be riboflavin-5Lphosphate its stmeture was confirmed by chemical synthesis by Kuhn and Rudy (94). It is commercially available as the monosodium salt dihydrate [6184-17 /, with a water solubiUty of more than 200 times that of riboflavin. It has wide appHcation in multivitamin and B-complex solutions, where it does not require the solubili2ers needed for riboflavin. 

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. 

Complexes III and IV have Fe-porphyrin prosthetic groups (hemes), complex IV also contains copper atoms which are involved in electron transport. Complexes I, III, and IV use the energy of electron transport to pump protons out of the matrix so as to maintain a pH gradient and an electrical potential difference across the inner membrane required for ATP synthesis (see below and Appendix 3). It is important to remember that all dehydrogenations of metabolic substrates remove two protons as well as two electrons and that a corresponding number of protons are consumed in the final reduction of dioxygen (Figures 5, 6). 

As mentioned before, the main problem for the application of such oxidizing enzymes in organic synthesis is the availability of an effective reactivation method for the prosthetic groups or the freely dissociated cofactors. Especially, the long-term stability of the whole system is the limiting factor [25]. All oxidases mentioned previously can be reactivated by an aerobic... 

The structure of cobalamin is more complex than that of folic acid (Figure 15.2 and 15.3). At its heart is a porphyrin ring containing the metal ion cobalt at its centre. In catalytic reactions the cobalt ion forms a bond with the one-carbon group, which is then transferred from one compound to another. Vitamin B12 is the prosthetic group of only two enzymes, methylmalonyl-CoAmutase and methionine synthase. The latter enzyme is particularly important, as it is essential for the synthesis of nucleotides which indicates the importance of vitamin B12 in maintenance of good health. 

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. 

FIGURE 19-33 Bacterial respiratory chain, (a) Shown here are the respiratory carriers of the inner membrane of E. coli. Eubacteria contain a minimal form of Complex I, containing all the prosthetic groups normally associated with the mitochondrial complex but only 14 polypeptides. This plasma membrane complex transfers electrons from NADH to ubiquinone or to (b) menaquinone, the bacterial equivalent of ubiquinone, while pumping protons outward and creating an electrochemical potential that drives ATP synthesis. 

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. 

After malonyl-CoA synthesis, the remaining steps in fatty acid synthesis occur on fatty acid synthase, which exists as a multienzyme complex. In the initial reactions acetyl-CoA and malonyl-CoA are transferred onto the protein complex by acetyl-CoA transacylase and malonyl-CoA transacylase (step 1 and step 2 in fig. 18.12a). The acceptor for the acetyl and malonyl groups is acyl carrier protein (ACP). ACP also carries all of the intermediates during fatty acid biosynthesis. The prosthetic group that binds these intermediates is... 

A subclass of lyases, involved in /J-hydroxy-a-amino acid metabolism, utilizes pyridoxal 5 -phosphate (PLP) as a prosthetic group for imine/enamine type activation. These enzymes are not only of interest for the synthesis of the naturally occurring prototypes L-serine (Sect. 6.8) or L-threonine, but also offer a potential entry to rare or non-natural analogs. 

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.)... 

Answer Thiamine is required for the synthesis of thiamin pyrophosphate (TPP), a prosthetic group in the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes. A thiamin deficiency reduces the activity of these enzyme complexes and causes the observed accumulation of precursors. 

It is important to keep in mind that hydrophilic prosthetic groups are important for renal rather than hepatobiliary clearance. Wester et al. [62] have demonstrated this with their carbohydrated analogs. Since 18F possesses inherent imaging advantages, the development of a simple and rapid synthesis which will enable 18F-SSTr ligands to be clinically practical is also important. 

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