Microbial transformation of steroids, an old and novel drug opportunity strategy: a review
Introduction Steroids comprise a wide range of naturally common compoundsdistributed in all the animal and plant kingdoms, with huge physiologically active derivatives that play crucial roles in biological systems[1-4].Steroids are key components of cell membranes, for stability and growth in cellularand development. Steroidsare precursors to bile acids and steroid hormones[5-8].Steroids have base structure consisting of 17 carbon atoms in a tetracyclic ring system well known as cyclopentanoperhydrophenanthrene, now as gonane and estrane[3-6].Steroid products are found indiversityof living species, ecdysteroids in insects, phytosterols and diosgenin in plants, cholesterol and corticosteroids: glucocorticoids, mineralocorticoids as well as sex hormones, bile acids, and vitamin D; neurosteroids, in vertebrates, and in yeasts and fungi are ergosterol and ergosteroids as part of its membrane cells [7,8,10].Steroids and its diversity areessential in medical practice, functioning as scaffolds for synthesizing new pharmacologically potent compounds [5,11,13,14].Steroids control a cascade of physiological activities at target sites and play key roles in cancer research [5,8,11,12].The physiological activity of steroids is closely associated to their molecular structure, as well as, the number, spatial orientation, and reactivity of functional groups in the steroid nucleus, as well as the oxidation state of the rings [1,4,13,15-17].For example, the presence of an oxygenated group at C-11β is essential for anti-inflammatory activity, besides a hydroxyl group at C-17β determines androgenic properties [3,5,8,19,20]. Aromatization of steroids at the A-ring affects estrogenic activity, and corticosteroids feature a 3-keto-5-ene group or a pregnane side chain at C-17 [2,11,14,21,22].In steroids functional modifications involve simple, chemically defined reactions catalyzed by microbial enzymes [1,4,13,15].Genetic MIT ability provides these enzymes to facilitate the transformation reactions, enhancing the efficiency and specificity of steroidsby MIT[6,7,9,23,24].The chemical modification of steroids, which requires high temperatures, pH, expensive reagents, and protective groups for reactive centers, has been a chemical method to obtain valuable new or improved drugs [3,8,16,17,25]. However, MIT offers an alternative approach that enables the production of biologically active steroid derivatives with high regio- and stereoselectivity under mild, environmentally friendly conditions [17-19,27-31].The aim of this short review is to analyze the potential of microbial biotransformation of steroidal compounds of value in the pharmaceutical industry and its connection with other related industries. Microbial transformation of steroids There are currently around 300 known steroidal drugs, used for several aims: immunosuppression, anti-inflammation, and contraception. Steroid applications have expanded to treating cancers, osteoporosis, human immunodeficiency virus (HIV)Infections or Acquired Immune Deficiency Syndromeor AIDS[3-5,7,8,32]. The therapeutic effects of certain steroid hormones are related to its interaction to intracellular receptors that regulate gene expression as transcription proprieties[13,20-22].Some steroids, as well as dehydroepiandrosterone, progesterone, pregnenolone, and itsproducts, like 17β-estradiol and allopregnanolone, are classified as neurosteroids due to steroidsactivity on the central nervous system[1,2,14].The MIT of exogenous steroid compounds is commonly by wide groups of bacteria and fungi, to enhancepharmacological activityand efficiency[27,30,33,34]. Several types of MIT reactions, as well as hydroxylation, dehydrogenation, side-chain degradation, ring A aromatization, reduction and esterification are used to achieve specific modifications [16-19, 22,23].MIT techniques diverse processes in culture media with microorganisms, free enzymes, biphasic systems, liposomes, microemulsions, methods altering cell wall permeability and the use of immobilized cells and enzymes [1,6,15,17,24].The spectrum of steroids that can be transformed by microbial cells is wide [4,7,9,18,25].Most advances in steroid happenedin 1950 at that time researchers had not clear idea about the pharmacological properties of cortisol and progesterone [8,14,16,30]. Researchers also discovered that genus fungi as well-knownspecies, could biotransform11α-hydroxylation, a critical reaction essential for synthesizing biologically active steroids [11,25,34,36,]; includingfungal transformation of Azorellane and Aqulinanetypes diterpenoids have unique tricyclic fused 5-, 6-, and 7-membered systems and a wide spectrum of biological properties: antimicrobial, antiprotozoal, spermicidal, gastroprotective [3,8,9,17,26].These discoveries marked the onset of a basic of development of steroids as a pharmaceutical, and the main point potential of microbial systems in the synthesis of valuable steroid compounds[10,11,13,32].Currently, the main objectives in steroid pharmaceutical research and development in target on identifying, and isolating microbial strains with unique activities or improving transformation capabilities [33-35, 37-39]. Genetic engineering and metabolic engineering of bacteria, fungi, and plants play a keyrole in these tasks[15,22,24,28,40]. Industrially, microbial hydroxylation activities, like are: C-11α, C-11β, C-15α, and C-16α, are performed with high yields and enantioselectivity [2,9,13,14, 22,27]. Since steroids have hydrophobicity, which caused steroids to be tolerant to biodegradation, the mechanisms of steroid metabolism by both aerobic and anaerobic microorganisms have been investigated [18,23,26,28-30].For effective MIT, precursor steroids are required, that are then converted into valuable intermediates and final products [7,11,17,25,31].MIT are: regiospecific and stereospecific, allowing the modification of compounds into suitable isomers through simple, chemically defined reactions catalyzed by microbial enzymes [1,3,15,32-33]. These enzymes act on compounds to design highly selective reactions, with easy techniques of isolation and purification of the new target compounds [3,6,17,19,22,27]. Besides, MITare is easy to use with necessary sterility conditions and allows for repeated working withthese enzymes [15,31,34]. SteroidMITare possible under several conditions of pressure and temperature, which is a viable alternative to chemical and ecological synthesis [2,23,24,40,41]. Although challenges such as productivity and chemical purity of steroids released, have non risk of contamination, microbial cells are systems can optimize and reduce costs by eliminating the need for isolating, purifying, and stabilizing pure enzymes [1,7,9,25]. Microbes naturally secrete all necessary cofactors and provide a stable environment for the enzymes, preventing protein structural changes and maintaining enzyme reactivity for many repeated processingto optimize steroid transformation[26,30,34,].Oxidation of steroid[6,12,35,].Common steroid precursors including cholesterol, steroidal alkaloids, steroidal sapogenins, and phytosterols, are readily available for MIT processes [16,18,19]. Types of steroids Cholesterols and corticosteroid Figure 1 illustrates the classification of steroids according to their biological functions or activities, including: bile acids, steroid hormones, cardioactive glycosides, aglycones, and steroid saponins[2,6,25]. Steroid hormones Estrogens and androgens play a crucial role in maintaining homeostasis and regulating development [34,36,40]. The gut microbiota significantly influences systemic sex hormone levels by metabolizing these hormones into various derivatives [24,27,32,37]. Under normal physiological conditions, estrogens undergo rapid deactivation in the liver through processes such as glycosylation, sulfation, or methylation, followed by their elimination via urine and feces [30,31,37,38]. Gut microbes can alter this process by enzymatically reactivating estrogens, … Read more