Abstract
Nowadays steroid manufacturing occupies a prominent place in the pharmaceutical industry with an annual global market over $10 billion. The synthesis of steroidal active pharmaceutical ingredients (APIs) such as sex hormones (estrogens, androgens, and progestogens) and corticosteroids is currently performed by a combination of microbiological and chemical processes. Several mycobacterial strains capable of naturally metabolizing sterols (e.g., cholesterol, phytosterols) are used as biocatalysts to transform phytosterols into steroidal intermediates (synthons), which are subsequently used as key precursors to produce steroidal APIs in chemical processes. These synthons can also be modified by other microbial strains capable of introducing regio- and/or stereospecific modifications (functionalization) into steroidal molecules. Most of the industrial microbial strains currently available have been improved through traditional technologies based on physicochemical mutagenesis and selection processes. Surprisingly, Synthetic Biology and Systems Biology approaches have hardly been applied for this purpose. This review attempts to highlight the most relevant research on Steroid Biotechnology carried out in last decades, focusing specially on those works based on recombinant DNA technologies, as well as outlining trends and future perspectives. In addition, the need to construct new microbial cell factories (MCF) to design more robust and bio-sustainable bioprocesses with the ultimate aim of producing steroids à la carte is discussed.
Highlights
Steroids are a family of terpenoid lipids widely distributed in nature that present a relatively rigid common structure named gonane formed by four fused alicyclic rings (Figure 1)
This review aims to compile the most relevant microbial bioprocesses of synthesis and/or functionalization of steroidal compounds described to date, focusing mainly on those designed in the light of the new metabolic engineering approaches
In recent years the optimization of several bioprocesses has been addressed through recombinant DNA technology approaches, these techniques have not been hardly applied for steroid synthesis (Lee et al, 2016; Nielsen and Keasling, 2016; Silber et al, 2016)
Summary
Steroids are a family of terpenoid lipids widely distributed in nature that present a relatively rigid common structure named gonane formed by four fused alicyclic rings (Figure 1). Steroidal compounds play important biological roles in different organisms, including cell membrane stabilization and regulation of relevant cellular processes such as cell proliferation and tissue differentiation. Steroid-based drugs present a broad range of therapeutic applications and represent the highest marketed category of pharmaceuticals after antibiotics with an annual production of more than one million tons. Steroidal active pharmaceutical ingredients (APIs) have been classically synthesized by chemical processes (Herráiz, 2017). The potential of microbial steroid biotransformation is known since several decades since its application offer a number of advantages over chemical synthesis: (i) regio- and/or stereospecific functionalization of molecules at positions not always available for chemical agents, (ii) multiple consecutive reactions carried out in a single operation step, (iii) more ecofriendly processes (i.e., mild reaction conditions, aqueous media). The steroid hormone testosterone (TS) is chemically synthesized from the steroidal intermediate 4-androstene-3,17dione (AD), which is previously obtained from natural sterols by microbial biotransformation (Fernández-Cabezón et al, 2017a)
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