Reaction thermodynamics as a constraint on piscine steroidogenesis flux distributions.
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abstract
While a considerable amount is known of the dynamics of piscine steroidogenesis during reproduction, the influence of thermodynamics constraints on its control has not been studied. In this manuscript, Gibbs free energy change of reactions was calculated for piscine steroidogenesis using the in silico eQuilibrator thermodynamics calculator. The analysis identified cytochrome P450 (cyp450) oxidoreductase reactions to have more negative Gibbs free energy changes relative to hydroxysteroid (HSD) and transferase reactions. In addition, a more favorable Gibbs free energy change was predicted for the 5 (cyp450 catalyzed) vs. 4 (HSD catalyzed) steroidogenesis branch-point, which converts pregnenolone to 17-hydroxypregnenolone or progesterone respectively. Comparison of in silico predictions with in vivo experimentally measured flux across the 5 vs. 4 branch-point showed higher flux through the thermodynamically more favorable 5 pathway in reproducing or spawning vs. non-spawning fathead minnows (Pimephales promelas). However, the exposure of fish to endocrine stressors such as hypoxia or the synthetic estrogen 17-ethinylestradiol (EE2), resulted in increased flux through both 5 and 4 pathways, indicating an adaptive response to increase steroidogenic redundancy. The correspondence of elevated flux through the 5 branch-point in spawning fish indicated the use of a thermodynamically favorable pathway to optimize steroid hormone productions during reproduction. We hypothesize that such selective use of a thermodynamically favorable steroidogenesis pathway may conserve reduced equivalents or transcriptional costs for investment to other biosynthetic or catabolic reactions to support reproduction. If generalizable, such an approach can provide novel insights into the structural principles and regulation of steroidogenesis or other metabolic pathways.
