v0
Ext = P5
v1
P5 = P4
v10
P4 = Ext
v11
OH17P4 = Ext
v12
A4 = Ext
v2
OH17P5 = OH17P4
v3
DHEA = A4
v4
P5 = OH17P5
v5
OH17P5 = DHEA
v6
P4 = OH17P4
v7
P5 = Ext
v8
OH17P5 = Ext
v9
DHEA = Ext
Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.
Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis.
J. Steroid Biochem. Mol. Biol. 2012;
128
:
12
- PubMed: 22024430
- DOI: 10.1016/j.jsbmb.2011.10.003
- ISSN: 1879-1220
- URL: http://ncbi.nlm.nih.gov/pubmed/22024430
Abstract
The 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4) isomerase (3β-HSD) and 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17) enzymes are important in determining the balance of the synthesis of different steroids such as progesterone (P4), glucocorticoids, androgens, and estrogens. How this is achieved is not a simple matter because each of the two enzymes utilizes more than one substrate and some substrates are shared in common between the two enzymes. The two synthetic pathways, Δ(4) and Δ(5), are interlinked such that it is difficult to predict how the synthesis of each steroid changes when any of the enzyme activities is varied. In addition, the P450c17 enzyme exhibits different substrate specificities among species, particularly with respect to the 17,20-lyase activity. The mathematical model developed in this study simulates the network of reactions catalyzed by 3β-HSD and P450c17 that characterizes steroid synthesis in human, non-human primate, ovine, and bovine species. In these species, P450c17 has negligible 17,20-lyase activity with the Δ(4)-steroid 17α-hydroxy-progesterone (17OH-P4); therefore androstenedione (A4) is synthesized efficiently only from dehydroepiandrosterone (DHEA) through the Δ(5) pathway. The model helps to understand the interplay between fluxes through the Δ(4) and Δ(5) pathways in this network, and how this determines the response of steroid synthesis to the variation in 3β-HSD activity or in the supply of the precursor substrate, pregnenolone (P5). The model simulations show that A4 synthesis can change paradoxically when 3β-HSD activity is varied. A decrease in 3β-HSD activity to a certain point can increase A4 synthesis by favouring metabolism through the Δ(5) pathway, though further decrease in 3β-HSD activity beyond that point eventually limits A4 synthesis. The model also showed that due to the competitive inhibition of the enzymes' activities by substrates and products, increasing the rate of P5 supply above a certain point can suppress the synthesis of A4, DHEA, and 17OH-P4, and consequently drive more P5 towards P4 synthesis.
No additional notes are available for this model.