Steroid biosynthesis

Overview
No description specified

Programme: SARCHI: Mechanistic modelling of health and epidemiology

SEEK ID: https://fairdomhub.org/projects/110

Public web page: Not specified

Organisms: Homo sapiens

FAIRDOM PALs: No PALs for this Project

Project created: 19th Jun 2018

Related items

SARCHI: Mechanistic modelling of health and epidemiology

The currently used mathematical models for medical treatment at the individual or population level are largely phenomenological and have limited quantitative predictive power. It is usually not possible to predict the effect of an intervention in a specific process or to predict the effect of a pharmaceutical drug since the step or enzyme on which the intervention/drug works is not explicit in the model.

Taking HIV pathogenesis as an example, the immune system response, vaccine exposure, and drug ...

Projects: Whole body modelling of glucose metabolism in malaria patients, Steroid biosynthesis, Yeast glycolytic oscillations, Computational pathway design for biotechnological applications

Web page: http://sacemaquarterly.com/mathematical-modelling/sarchi-project-mechanistic-modelling-health-epidemiology.html

Stellenbosch University

Country:  South Africa

City: Not specified

Web page: Not specified

Prostate cancer
Steroid biosynthesis
No description specified

Snapshots: No snapshots

Substrate preferences for AKR1C3, and implications of varying AKR1C3:17BHSD2 ratios
Steroid biosynthesis
No description specified

Person responsible: Jacky Snoep

Snapshots: No snapshots

11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer
Steroid biosynthesis

Abstract (Expand)

The progression of castration resistant prostate cancer (CRPC) is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 … (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. The oxidation of androgens to their inactive form is catalysed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2), but little attention is given to the expression levels of this enzyme. In this study, we show that the 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3. In particular we show that the enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. Using three independent experimental systems and a computational model we subsequently show that increased ratios of AKR1C3:17βHSD2 sig- nificantly favours the flux through the 11-oxygenated androgen pathway as compared to the classical or 5α- androstanedione pathways. Our findings reveal that the flux through the classical and 5α-androstanedione pathways are limited by the low catalytic efficiently of AKR1C3 towards classical androgens combined with the high catalytic efficiency of 17βHSD2, and that the expression of the oxidative enzyme therefore plays a vital role in determining the steady state concentration of active androgens. Using microarray data from prostate tissue we confirm that the AKR1C3:17βHSD2 ratio is significantly increased in patients undergoing androgen deprivation therapy as compared to benign tissue, and further increased in patients with CRPC. Taken together this study therefore demonstrates that the ratio of AKR1C3:17βHSD2 is more important than AKR1C3 expression alone in determining intratumoral androgen levels and that 11-oxygenated androgens may play a bigger role in CRPC than previously anticipated.

Authors: Monique Barnard, Jonathan L. Quanson, Elahe Mostaghel, Elzette Pretorius, Jacky L. Snoep, Karl-Heinz Storbeck

Date Published: 1st Oct 2018

Publication Type: Not specified

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