Steroid biotransformations

In Table 2 antibiotic and steroid biotransformations are only poorly represented compared to their actual frequency more than 50 examples of antibiotic transformations were already reported in 1975 [9, 38, 39] a hsting of steroid microbial transformations, published in 1981, covers 853 substrates [40], while more than 1000 examples have been hsted for the 1979-1992 period [41-44]. However, most of the examples reported in those areas have been essentially oriented towards the preparation of new active compounds rather than towards a study of detoxification metabohtes derived from drugs. Alkaloids represent another group of biologically active natural substances where microbial metabolism was explored relatively early and exhaustively [40,45-47]. 

Arukwe, A., L. Forlin and A. Gokspyr. Xenobiotic and steroid biotransformation enzymes in Atlantic salmon (Salmo salar) liver treated with an estrogenic compound, 4-nonylphenol. Environ. Toxicol. Chem. 16 2576-2583, 1997. 

The early literature on monoterpene biotransformation was highly influenced by the approach used in steroid biotransformations and mainly focused on terpenoids accumulated by fungal strains which do not mineralize the substrate but partly oxidize it by fortuitous cometabolism. These studies often resulted in the accumulation of a mixture of different products in low yields and at low concentrations [1]. Several bacteria which completely mineralize monoterpenes have been described more recently. It has become obvious from the later studies that multiple pathways are involved in the degradation of monoterpenes in many of these microorganisms, and consequently it has been difficult to obtain mutants allowing the accumulation of partially oxidized products. 

If foam formation caimot be avoided, it can be destroyed mechanically by foam breakers, physically by ultrasound, heat or electrical methods, or chemically by antifoam agents [33]. In industrial production, with a few exceptions, mechanical foam breakers (e.g. steroid biotransformation [34]) are not used because of their high power input demand, which is often higher than the power input by the stirrer. Physical methods are not used either, because ultrasovmd, heat or electric treatment can impair the viabiUty of the microorganisms. Therefore, only chemical methods are considered in this review. 

Terpenoid terpenoid biosynthesis terpenoidogenesis steroid biotransformation and degradation... 

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. 

Aquatic organisms, such as fish and invertebrates, can excrete compounds via passive diffusion across membranes into the surrounding medium and so have a much reduced need for specialised pathways for steroid excretion. It may be that this lack of selective pressure, together with prey-predator co-evolution, has resulted in restricted biotransformation ability within these animals and their associated predators. The resultant limitations in metabolic and excretory competence makes it more likely that they will bioacciimiilate EDs, and hence they may be at greater risk of adverse effects following exposure to such chemicals. 

Biotransformation, in which the main product is formed from substrate through one or more reactions catalysed by enzymes in the cells. Examples steroid hydro xylation. 

After discussing the biological capability to transform steroids, we briefly examine foe biotransformation of other terpenoids to ensure that the reader develops an awareness of the potential of biotechnology to modify or produce derivatives of a wide range of natural materials that are of tremendous potential, commercial value in the food and health care sectors. We also include a brief consideration of the use of biocatalysts to transform a range of other hydrocarbon compounds. 

The enzymatic transformation of natural products is by for file most attractive option. In this approach, it can be envisaged that sterols, which are relatively abundant, may be selectively modified to produce desired products. Hie diversity of enzyme activities, their reaction specificity, regiospecificity and stereospedfidty are all features which could contribute to carrying out the desired changes. This does not mean, however, that transformations using enzyme systems are simple. Nevertheless, biotransformations have become of vital importance in the production of steroids. 

In the following sections we will explain some applications of enzymes (and cells) in the transformation of sterols and steroids. You should realise, however, that for each process a decision has to be made whether to use an enzyme-mediated transformation or to use a chemical reaction. In many instances the biotransformation process is foe most attractive but, as we will see later, this is not always the case. 

Most of these enzymes have steroids or fatty acids as their substrates (Table 1). Many P450s in endogenous biotransformation pathways are characterized by usually very narrow substrate and product specificity and by tight regulatory systems, especially those involved in steroid hormone biosynthesis. 

Dr. G. A. LeBlanc of North Carolina State University is evaluating effects of potentially endocrine-disrupting chemicals, including endosulfan, on steroid hormone biotransformation/elimination processes in daphnids, fish, and mice, and is constructing models of the processes. The work is being funded by the U.S. Department of Agriculture. 

This enantiomeric specificity has been of interest in other contexts, and stereospecific biotransformation has been observed. Examples include the enantiomeric oxidation of sulfides to sulfoxides (Chapter 11, Part 2) and steroid and triterpene hydroxylation (Chapter 7, Part 2). 

APA from penicillin G, 7-ACA from cephalosporin C, 7-ADCA from desaacetoxy cephalosporin G Biotransformation in steroids, e.g. cortexolone to hydrocortisone and prednisolone Food additives Lactic Acid (now a bulk chemical for making polylactate). Citric acid, L-Glutamate, L-Lysine, etc. Vitamines C, B2, B12 Acarbose (antidiabetic drug)... 

Octonol is an intermediate for the production of several optically active pharmaceuticals, such as steroids and vitamins. The asymmetric reduction of 2-octanone to (5)-2-octonol by baker s yeast was inhibited severely by substrate and product concentration of 10 him and 6 mM respectively. Whole-cell biotransformation of 2-octanone in a water-ra-dodecane biphasic system yielded a high product concentration of 106him with 89% ee in 96h [37],... 

The science of biotransformations has been investigated since the days of Pasteur[1l However, progress in the use of enzymes and whole cells in synthetic organic chemistry was relatively slow until the 1950s, when the use of microorganisms to modify the steroid nucleus was studied in industry and academic laboratories. Thus conversions such as the transformation of 17a-acetoxy-l 1-deoxycortisol into cortisol (hydrocortisone) (1), using the microorganism... 

With the exception of two dehydrogenases, all of the steroidogenic enzymes belong to the cytochrome P-450 (abbreviated as CYP) family of enzymes. The CYP enzymes are often involved with redox or hydroxylation reactions, and are also found in the liver where they are key players in biotransformation reactions (see Section 6.4). Different members of the CYP family are therefore involved with both synthesis in adrenal and gonads and hepatic inactivation of steroid hormones. 

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