Mathematical Modelling of Steroid Synthesis in Steroid-Producing Tissues and Steroid Partitioning in Circulation
Year: 2012
Type: dissertation
Abstract: Steroid hormones are involved in a wide range of processes in development and reproduction. This thesis focuses on the regulation of the synthesis of steroids in steroid-producing organs such as placenta, ovarian follicles, and testis. The synthesis of steroids uses a common precursor substrate, pregnenolone (P5), and consists of several interlinked pathways. Many steroidogenic enzymes can catalyze more than one substrate, and therefore substrates compete with each other for their common enzymes. Similarly, the enzymes also share common substrates and compete with each other for the substrates. The multiple reactions, interactions within the network of reactions make its function complex. Moreover, steroidogenic enzymes can be compartmentalized at different levels such as into different organelles of a cell, or into different cells. Mathematical models developed in this dissertation improve the understanding of the control of steroid synthesis by the way steroidogenic reactions are connected biochemically and spatially. At the first stage, no spatial distribution of steroidogenic enzymes is considered. Models using ordinary differential equations (ODEs) are developed that help understand some important aspects of the regulation of steroid synthesis by enzyme activity and substrate availability. Firstly, due to the competitive inhibition of substrates catalyzed by common enzymes, the syntheses of sex steroids can paradoxical decrease when the supply rate of the precursor substrate P5 is increased above certain levels. Secondly, the preference of the 17α- hydroxylase/17,20-lyase cytochrome P450 enzyme (P450c17) for 17OH-P5 as substrate for its 17,20 lyase activity, in the Δ⁵-species, determines the paradoxical increase in sex steroids synthesis when the 3β-hydroxysteroid dehydrogenase/ Δ5-Δ4 isomerase (3β-HSD) activity is inhibited. Lastly, changes in the reactions at initial part of steroidogenic networks (i.e. P5 supply, 3β-HSD, and/or P450c17) can also affect the balance of products further down the Δ⁵-pathway, sex steroids. At the second stage, the effects of enzyme compartmentalization are investigated. Reaction-diffusionn models using partial differential equations (PDEs) are developed that show that the partitioning of steroidogenic enzymes into different cells is an important control of steroid synthesis.
Author: Phuong Nguyen
Language: English
Subfield: Endocrinology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2622506589