Hydroxybutyrate hydrolysis

Poly(orthoesters) represent the first class of bioerodible polymers designed specifically for dmg deUvery appHcations (52). In vivo degradation of the polyorthoester shown, known as the Al amer degradation, yields 1,4-cydohexanedimethanol and 4-hydroxybutyric acid as hydrolysis products (53). 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

Hydrolysis of these polymers regenerates the diol and produces Y-butyrolactone, which rapidly hydrolyzes to w-hydroxybutyric acid. Because poly (ortho esters) are acid-sensitive, a base is used to neutralize the hydroxybutyric acid and to maintain the hydrolysis process under control. 

Hydrolysis of end-labeled 3-hydroxybutyrate oligomers by purified A. faecalis T poly(3HB) depolymerase showed that the enzyme mainly cleaved the second and third ester linkage from the hydroxyl terminus [69]. However, since the enzyme also hydrolyzes cyclic oligomers, the A. faecalis depolymerase has endo-hydrolase activity in addition to exo-hydrolase activity [18, 70]. Results of... 

The first products of enzymatic hydrolysis of poly(3HB) by purified poly(3HB) depolymerases are a mixture of monomeric and/or oligomeric 3-hydroxybuty-rate esters. Some enzymes are able to hydrolyze oligomers and dimers to monomeric 3-hydroxybutyrate after prolonged time of hydrolysis in the presence of an excess of the appropriate depolymerase. These poly(3HB) depolymerases have high endogenous dimer-hydrolase activities (e.g., the poly(3HB) depolymerases of Comamonas strains, P. stutzeri, S. exfoliatus, and the depolymerases... 

The physiological pathway for oxidation of ketone bodies starts with the hydrolysis of triacylglycerol in adipose tissue, which provides fatty acids that are taken up by the liver, oxidised to acetyl-CoAby P-oxidation and the acetyl-CoA is converted to ketone bodies, via the synthetic part of the pathway. Both hydroxybutyrate and acetoacetate are taken up by the tissues, which can oxidise them to generate ATP (Figure 7.19). 

Some free acetoacetate is formed by direct hydrolysis of acetoacetyl-CoA. In rats, 11% of the hydroxybutyrate that is excreted in the urine comes from acetoacetate generated in this way.64 However, most acetoacetate arises in the liver indirectly in a two-step process (Eq. 17-5) that is closely related to the synthesis... 

However, if the electron transport between 3-hydroxybutyrate and cytochrome b562 is tightly coupled to the synthesis of one molecule of ATP, the observed potential of the carrier will be determined not only by the imposed potential E of the equilibrating system but also by the phosphorylation state ratio of the adenylate system (Eq. 18-7). Here AG atp is the group transfer potential (-AG of hydrolysis) of ATP at pH 7 (Table 6-6), and n is the number of electrons passing through the chain required to synthesize one ATP. In the upper part of the equation n is the number of electrons required to reduce the carrier, namely one in the case of cytochrome b562. 

This was nicely outlined with the observed unusually high enantiopurity of the dehalogenation consecutive product ethyl L-3-hydroxybutyrate (l-4 Pathways II, III). Ester hydrolysis product 16 acts as an inhibitor of D-directing /3-ketoacyl reductase of the fatty acid synthase (FAS) complex (EC 1.1.1.100) [69, 70], whereupon the fraction of l-4 increased from 97% ee to >99.5% ee. 

Aryl esters of 4-hydroxybutyric acid, 5-hydroxyvaleric acid, 2-hydroxyphenylacetic acid, and 3-(2-hydroxyphenyl)propionic acid lactonize with rate constants proportional to iopH picw (Capon et al., 1973). The second-order rate constant at 30° for lactonization of phenyl 4-hydroxybutyrate is ca. 3000 times greater than kOH for hydrolysis of phenyl acetate at 25°. Lactonization of phenyl 4-hydroxybutyrate is catalysed by acetate and phosphate buffers in... 

Excess acetate (C2) can be converted to the mobile ketone body energy source aceto-acetate (C4) and thence its reduced form hydroxybutyrate (C,) for transport throughout the body. Excess acetate can be carboxylated (via acetylCoA carboxylase) to form malonylCoA (C3), the donor for further C2 additions (with C02 elimination) in the anabolic synthesis of long chain fatty acids. Fatty acids are components of the phospholipids of cellular membranes and are also stored as triacylglycerols (triglycerides) for subsequent hydrolysis and catabolic fatty acid oxidation to yield reduced coenzymes and thence ATP (see Chapter 2). 

Three ketone bodies are formed during the breakdown (metabolism) of fats acetoacetate, p-hydroxybutyrate, and acetone. They are produced to meet the energy requirements of other tissues. Fatty acids, produced by the hydrolysis of triglycerides, are converted to ketone bodies in the liver. They are removed by the kidneys... 

Disposition in the Body. Readily absorbed after oral administration. The major metabolite is free bromide ion hydrolysis to an active metabolite, 2-bromo-2-ethylbutyramide, also occurs followed by oxidation to 2-bromo-2-ethyl-3-hydroxybutyramide other metabolites include 2-ethylbutyrylurea and 2-ethyl-2-hydroxybutyric acid. Carbromal is excreted in the urine mainly as bromide ion and partly as 2-ethyl-2-hydroxybutyric acid, with very little as unchanged drug. Peak bromide excretion is attained after about 48 hours. 

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