Hydroxylation of steroids

Biotransformations are carried out by either whole cells (microbial, plant, or animal) or by isolated enzymes. Both methods have advantages and disadvantages. In general, multistep transformations, such as hydroxylations of steroids, or the synthesis of amino acids, riboflavin, vitamins, and alkaloids that require the presence of several enzymes and cofactors are carried out by whole cells. Simple one- or two-step transformations, on the other hand, are usually carried out by isolated enzymes. Compared to fermentations, enzymatic reactions have a number of advantages including simple instmmentation reduced side reactions, easy control, and product isolation. 

Table 9.6 Examples of hydroxylation of steroid nuclei by micro-organisms. (Data derived from Neidleman, SL "Industrial Chemicals Fermentation and Immobilised Cells" in "Biotechnology the Science and the Business", edited by Moses V and Cape RB, published by Harwood Academic, London 1991).

Cytochromes P450 Are Monooxygenases Important for the Detoxification of Many Drugs for the Hydroxylation of Steroids... 

The hydroxylation of steroids at various positions is carried out by a range of fungi, and probably involves the cytochrome P450 system (Breskvar and Hudnik-Plevnik 1977). 

Recently, Breslow19 reported a regioselective and stereoselective hydroxylation of steroid substrates catalyzed by manganese porphyrin... 

Pellissier, H. and Santelli, M. (2001) Chemical and biochemical hydroxylations of steroids. A review. Organic Preparations and Procedures International, 33 (1), 1-58. 

The answer is a. (Hardman, pp 1482—1483. Katzung, pp 673-674.) Metyrapone inhibits 11-hydroxylation of steroid precursors, which prevents formation of cortisone and cortisol. These precursors are then diverted into aldosterone and androgen production pathways, which explains the adverse effects of hirsutism and edema... 

This heme-thiolate-dependent enzyme [EC 1.14.15.4], also known as steroid 11/3-monooxygenase, catalyzes the reaction of a steroid with reduced adrenal ferredoxin and dioxygen to produce an 11/3-hydroxysteroid, oxidized adrenal ferredoxin, and water. The enzyme also catalyzes the hydroxylation of steroids at the 18-position and can catalyze the conversion of 18-hydroxycorticosterone into aldosterone. 

Side reactions of microbiological oxidation using the very same microorganisms can cause hydroxylation of steroids in different positions, using easily accessible progesterone [1-5] as an initial substance [1-5]. 

A vast amount of research resulted in the improvement of this bioconversion, as well as the development of many other microbiological reactions. Some of these include Ci-dehydrogenation, C 6-a-hydroxylation, and Cj i-P-hydroxylation of steroids [45-52]. Other... 

Mitochondrial system The function of the mitochondrial cyto chrome P450 monooxygenase system is to participate in the hydroxylation of steroids, a process that makes these hydropho bic compounds more water soluble. For example, in the steroid hormone-producing tissues, such as the placenta, ovaries, testes, and adrenal cortex, it is used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones. The liver uses this system in bile acid synthesis (see p. 222), and the kidney uses it to hydroxylate vitamin 25-hydroxycholecalciferol (vitamin D, see p. 384) to its biologically active 1,25-hydroxylated form. 

Ionizing Radiation. In general, ionizing radiation reduces the rate of metabolism of xenobiotics both in vivo and in enzyme preparations subsequently isolated. This has occurred in hydroxylation of steroids, in the development of desulfuration activity toward azinphosmethyl in young rats, and in glucuronide formation in mice. Pseudocholinesterase activity is reduced by ionizing radiation in the ileum of both rats and mice. 

Beauveria suffiirescens (ATCC7159) Fungi imperfect 1 la-Hydroxylation of steroids, hydroxylation of cyclic and acyclic amides, tricyclic terpenes and aromatics... 

The greatest contribution towards understanding the structural features in the substrate that effect, or indeed control, the selectivity in microbial hydroxylation of steroids was carried out by Jones and Meakins and their work is recorded in a series of papers entitled Microbiological Hydroxylation . Their last report was published in 1980, and serves as a source of references to earlier material. ... 

Generally speaking fungi are of greatest use in the hydroxylation of steroids, and five genera in particular have been found to be extremely useful these are Rhizopus, Calonectria, Aspergillus, Curvularia and Cunninghamella. 

ChemoselectiviQr is indeed a very complex issue in the hydroxylation of steroids, but microorganisms capable of chemoselective transformations can often be selected on precedent. 

Aspects of regioseleetivity in the microbial hydroxylation of steroids have been reviewed most recently by Kieslich. ... 

Since silver salts are expensive, other cheaper reagents have been sought which can bring about the same type of conversion, and the iodine- tassium iodate- tassium acetate combination has been found to provide a useful alternative. Thallium(I) acetate may be used in place of silver acetate in the Woodward procedure, and syn hydroxylation of steroidal alkenes with dialliumflll) acetate in acetic acid has been performed. ... 

Practical aspects are much as discussed earlier, and a good laboratory steroid hydroxylation procedure has been published. Numerous additives (e.g. surfactants, antibiotics and fungicides) have been used to improve microbial hydroxylation of steroids, and some of these have been discussed previously... 

The value of microbial hydroxylation of steroids has long been that they allow functionalization of positions not easily accessible by normal chemical methods. For this reason yields of a few percent have often been tolerated, but yields approaching quantitative can be achieved in many instances. The objective of much current work is to improve the selectivity of microbial hydroxylations. This can be achieved in a number of ways, for example by structural modifications of the substrate, optimization of fermentation conditions and by strain improvement. The latter is most likely to yield the most significant improvements in selectivity, and has previously been discussed at length. ... 

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