Steroid transformations

As is apparent at a glance, cortisone is an intricate molecule with a wealth of functionality. Steroid transformations in the corticoid series require serious strategic planning in order to provide the appropriate protecting groups and to introduce substituents in the proper order. It is therefore easy in a discussion of this chemistry to get lost in a welter of detail. 

Using this simple example, we have illustrated how the principles we established in discussing steroid transformation may be applied to a much wider range of organic materials. 

FIGURE 52-4 Some steroid transformations that are carried out by neural tissue. 

During the past 50 years, numerous experiments have been performed in attempts to unravel the complex pathways whereby steroid hormones, that is the corticosteroids, androgens and oestrogens, are formed in mammalian and other tissues. A very large number of books and reviews have already been written on the subject and this present chapter will seek to (a) summarize the pathways concerned and how the evidence for these was obtained and (b) provide an update of advances over the past decade, particularly with regard to the properties of the steroid transforming enzymes involved and the mechanism of the reactions catalysed by such enzymes. 

Some steroid transformations, which are difficult to achieve by ordinary chemical means may also be accomplished readily by microbiological methods. Salicylic acid may be obtained in a 94% yield, on a weight for weight basis, by the action of Pseudomonas aeruginosa on naphthalene [69] (Eq. 16.25). 

Combined use of microbial enzymes as biocatalysts with chemical synthesis has its origin in the steroid transformation developed in the USA in the early 1950s. Arima and his group [11] invented a unique microbial conversion process, in which the aliphatic side-chain of cholesterol was cleaved to produce a steroid core as a starting material for chemical synthesis of steroid hormones. Yamada et al. discovered the reverse reaction of the pyridoxal-containing L-amino acid lyases and applied them to synthesize L-tryptophan and l-DOPA [12] from pyruvate, ammonia and corresponding aromatic compounds. Since these early achievements, a variety of unique processes with newly screened microbial enzymes as biocatalysts have been invented. 

For a detailed account of steroid transformations by microorganisms the reader is referred to Dorfman and Ungar (1965) and lizuka and Naito (1968). 

An old paper by Lintner and von Liebig in 1911 on the reduction of furfural to furfurol by yeast attracted the interest in 1937 of Mamoh and Vercellone, former students of C. Neuberg. It inspired them to use yeast to reduce 4-androstenedione to testosterone. This was the first example of a successful microbial steroid transformation, to be followed by many more in the early 1950s. 

Staphylococcus aureus 618,619 starch-modifying enzymes 416 steroid transformations 13 Stigmatella aurantiaca 459 stimulants 676 Streptomyces... 

Turfitt (T-1029, T-1030, T-1031, T-1032, T-1034) studied the use of steroids, as a sole source of carbon for microbial growth, and the steroid transformation products produced thereby. The key observations he made, which lay fallow until greater understand ] of the field developed [cf. the work of Whitmarsh -1111) and particularly of Sih and his collaborators (Ap-79, Ap-83, Ap-95) ] were that cholestenone and 3-keto-4-cholenic acid were transformed by Proactinomyces erythropolis, albeit to a very minor degree, into 3-keto-4-androstene-17 -carboxylic acid. The idea which this illustrated was that cholesterol conceivably m t be transformed by a microbiological degradative method into useful steroid entities of substantially lower molecular weight... 

Biological demands of nutrients, biological optimum (cf. Fig. 5.1), maintenance, mutation Impure, inactive, and diluted ( unconventional raw materials cellulose, starch, oil) One-stage possible without intermediary product recovery (e.g., steroid transformation) Potentially better for environment Mainly slow reaction rates Low concentrations High demand in sophisticated apparatus/equipment, supplementary education Demon of nature (biological material, infections, mutations)... 

Type 0. Type-0 production as a supplementary case occurs even in resting cells that use only a little substrate for their own metabolism. The microbial cells function only as enzyme carriers. Steroid transformation and vitamin E synthesis by Saccharomyces cerevisiae are examples. 

Maximum conversion is achieved by complete utilization of the substrate in the later stages and maximum productivity in the first stage. This is essential in the case of expensive substrates, for example, steroid transformation, or in the case of environmental problems, for example, waste water treatment. 

Donova MV, Egorova OV (2012) Microbial steroid transformations current state and prospects. Appl Microbiol Biotechnol 94 1423-1447... 

In vitro synthesis of PHA granules from activated substrates may eventually become commercially feasible. In R. eutropha, the maximum rate of PHA synthesis occurs early in accumulation phase and deteriorates slowly thereafter. One would therefore expect that the maximum amount of PHA accumulation would depend on enzymatic activity or on NAD PH or substrate supply. However the most detailed published study on this process points to a physical limitation (86) where polymer synthesis slows to a virtual stop simply because there is no more space available. If this is indeed the case, then the way around such a hmitation is to produce the PHA granules outside the cells. This has been achieved (87,88). Commercial exploitation of this process requires a source of the biosynthetic enz3rmes (easily achievable through molecular biological techniques), substrates, NADP, and a method for NADP reduction already used in commercial steroid transformation processes. This would eliminate or greatly reduce separation costs. The present economic and technical barrier to this process is the lack of an inexpensive method to link coenzyme A to the appropriate carboxylic acid. 

It is possible that the intestinal bacteria may play an important role in the hydrolysis, oonji tion, and metabolism of steroids and their conjugates in the intestinal tract, but this aspect of steroid transformation has not been studied sufficiently to warrant even superficial conclusions. 

In the past, various authors have reviewed different aspects of the steroid transformations in the fetal and placental compartments (Davis and Plots, 1956a Diczfalusy and Troen, 1961 Fuchs, 1962 Diczfalusy el al., 1965 Eik-Nes and Hall, 1965 Klevit, 1966 Siiteri and MacDonald, 1966 Mitchell, 1967 Solomon et al., 1967 Diczfalusy, 1968 Solomon and Friesen, 1968). Here the metabolic conjugation and hydrolysis of steroid hormones in the fetoplacental unit will be described according to the different groups of steroids as follows ... 

In spite of the important development in knowledge of steroid metabolism, it is not yet possible to establish whether tlierc are different steroid transformations in male and female fetuses. 

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