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Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
CYP106 obtained from B. megaterium, is a potential candidate for the preparative scale biotechnological production of hydroxysteroids (Rauschenbach et al., 1993; Schmitz et al., 2014). Chul-Ho Yun and his group in their study with CYP106A1 from B. megaterium ATCC 14581 strain showed that the enzyme can hydroxylate steroids (e.g., testosterone, progesterone, 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol). Monohydroxylated compounds are produced as major metabolites by hydroxylation (Lee et al., 2015). Hydroxylation by CYPs can be useful to produce intermediates or to structurally modify steroids for therapeutic applications (Sedlaczek and Smith, 1988). Enzymatic reactions by CYP106A1 could replace several chemical reaction steps in the industrial manufacturing of natural hormones and steroidal drugs (Lee et al., 2015). Recently, studies conducted on B. megaterium DSM319 strain have identified the potential of CYP106A1 to convert pentacyclic triterpene 11-keto-β-boswellic acid (KBA), a constituent of resin extracts, used to treat inflammatory disorders and arthritis. Conversion rate of KBA by CYP106A1 whole system was found to be 100 min−1 with 80% selectivity towards the main product. The hydroxylated KBA derivatives obtained from this enzymatic reaction are assumed to possess enhanced bioavailability, improved pharmacological activities, or can be modified by chemical methods (Brill et al., 2014). CYP106A2 hydroxylases tricyclic diterpene and pentacyclic triterpene acids (Bleif et al., 2012). A research group led by Rita Bernhardt, screened a steroid library to identify new substrates for CYP106A2, which included dehydroepiandrosterone (DHEA) and pregnenolone. At a preparative scale, they were able to hydroxylate DHEA and pregnenolone primarily at 7β position. Conversion rate of DHEA to 7β-OH-DHEA using B. megaterium was high with a volumetric yield of 103 mg/L/h (Schmitz et al., 2014).
Circulating biomarkers associated with performance and resilience during military operational stress
Published in European Journal of Sport Science, 2022
Meaghan E. Beckner, Luana Main, Jamie L. Tait, Brian J. Martin, William R. Conkright, Bradley C. Nindl
Dehydroepiandrosterone (DHEA) is an endogenous hormone and precursor to testosterone that modulates the negative consequences of elevated cortisol, providing beneficial behavioural and neurotrophic effects (Morgan et al., 2004; Morgan et al., 2009; Taylor et al., 2007). DHEA is secreted by the adrenal cortex and can be further converted to dehydroepiandrosterone sulfate (DHEA-S) by sulfotransferase in the adrenals, liver, and small intestine, which accounts for the majority of DHEA in circulation due to a longer biological half-life (15–30 mins vs. 7–10 h, respectively) (Morgan et al., 2009). Collectively, these two hormones are often referred to as DHEA(S), unless specified otherwise, as they induce many of the same physiological effects (Morgan et al., 2009). Provided that DHEA(S) can counter some of the catabolic effects of cortisol, examining the ratio of these two hormones, rather than absolute abundance, has been used as an assessment of hormonal imbalance or stress vulnerability (Wu et al., 2013).