17.17 Steroids and use of fungi to make chemical transformations
Steroid compounds are among the most widely marketed products of the pharmaceutical industry. Today manufactured steroids are used for a very wide range of ‘over-the-counter’ remedies as well as ethical (prescription-only) therapies. Common functions include anti-inflammatory, immunosuppressive, diuretic, anabolic, contraceptives and progesterone analogues. Manufactured steroids are also used in treatments of some forms of cancer, osteoporosis and adrenal insufficiencies, for avoidance of coronary heart disease, as antifungal agents, anti-obesity agents, and, by inhibition of HIV integrase, prevention and treatment of infection by HIV and AIDS. The isolation from natural sources of new steroids and sterols with potential therapeutic applications is an active field of current research (Fernandes et al., 2003).
Research efforts in this topic were prompted in 1949, with the discovery at the Mayo Clinic of the dramatic effect of cortisone, an endogenous steroid, in alleviating the symptoms of rheumatoid arthritis. However, steroid molecules are complex and chemical synthesis is difficult; even carrying out the highly specific modification reactions required to produce clinically useful compounds with commercial value is difficult and costly. Consequently, the production of steroid drugs and hormones and growth of the industry in the latter half of the 20th century is one of the best examples of the successful application of microbial technology in large scale industrial processes.
Soon after the Mayo discovery, the Upjohn Company announced that cultures of the fungus Rhizopus are able to introduce (enzymically) a hydroxyl group to a very specific position in the female hormone progesterone (namely, 11α-hydroxylation of progesterone), which had been synthesised from the soybean sterol stigmasterol (Hogg, 1992).
This discovery provided a one-step solution to a chemical modification that requires a multistep procedure to achieve by conventional organic chemistry. Indeed the total synthesis of steroids has only recently been reported (Honma & Nakada, 2007) as an approximately 20-step process (‘approximately’ because it depends what you start with and what you want to end with) and it is interesting to compare this publication with the equivalent papers of the mid-20th century (Chamberlin et al., 1951; Peterson & Murray, 1952).
Microbial reactions for the transformation of steroids have proliferated since then, and specific microbial transformation steps have been included in many large scale production syntheses of new drug and hormone steroids. Modified steroids are favoured over their natural counterparts because of increased potency, longer half-lives in the blood stream, simpler delivery methods and reduced side effects.
The preference for using cultures of intact whole cells over enzymes as the biocatalysts for production of such pharmaceutical derivatives is mostly a matter of the additional cost burden of enzyme isolation, purification and stabilisation.
A wide range of very different microorganisms can be used as biocatalysts for steroid transformations (Donova, Egorova & Nikolayeva, 2005):
- various species of bacteria (Pseudomonas, Comamonas, Bacillus, Brevibacterium, Mycobacterium, Streptomyces, etc.),
- filamentous fungi (Phycomyces, Mucor, Rhizopus, Aspergillus, Penicillium, etc.),
- yeasts (Hansenula, Pichia, Saccharomyces, etc.),
- algae (Chlorella, Chlorococcum, etc.), and
- protozoa (Pentatrichomonas, Trichomonas).
The search for novel steroid-like compounds with potential therapeutic applications is extending into wider ranges of natural sources, including endophytic fungi, corals and sponges (Fernandes et al., 2003).
Updated December 17, 2016