Molecular modeling study of the testosterone metabolizing enzyme UDP-glucuronosyltransferase 2B17

Ingmar Trane,Georg Sager,Erik Sveberg Dietrichs,Aina Westrheim Ravna

doi:10.1016/j.bmc.2021.116060

Abstract

The dominant sex hormone testosterone is mainly metabolized by liver enzymes belonging to the uridine-diphospho (UDP) glucuronosyltransferase (UGT) family. These enzymes are the main phase II enzymes, and they have an important role in the detoxification of endogenous and exogenous compounds in humans. The aim of the present study was to improve the understanding of the binding properties of UGT2B17. A homology modelling procedure was used to generate models of the UGT2B17 enzyme based on templates with known crystal structures. Molecular docking of inhibitors was performed to gain further insights in the interactions between ligand and binding site, and to determine which of the models had the best accuracy. ROC curves were made to evaluate the ability of the models to differentiate between binders (inhibitors) and non-binders (decoys). When comparing the four models, which were based on four different crystal structures, the model based on the 4AMG crystal structure was the most accurate in distinguishing between true binders and non-binders. Investigating pharmacological UGT2B17 inhibition may provide novel treatment for patients with low testosterone levels. Such treatment may elevate endogenous testosterone levels and provide a more predictable increase in serum concentrations rather than un-physiological elevation of serum levels through direct treatment with testosterone, and this could be favorable both for giving a predictable treatment regime with reduced chances of serious adverse effects. The present study may serve as a tool in the search for novel drugs aiming for increasing testosterone levels.

Highlights

Testosterone is the dominant male sex hormone, and it plays a key role in the male pubertal development of testes and prostate, as well as promoting masculine characteristics such as increased muscle and bone mass, height, and the growth of body hair
Testosterone is produced in testicular Leydig cells, while in females, testosterone is produced in the ovaries, giving serum concentrations of between 5 and 10% of male levels
UGTs are the main phase II enzymes, and they have an important role in the detoxification of endogenous and exogenous compounds in humans.[19]

Summary

Introduction

Testosterone is the dominant male sex hormone, and it plays a key role in the male pubertal development of testes and prostate, as well as promoting masculine characteristics such as increased muscle and bone mass, height, and the growth of body hair. Through adolescence testosterone helps maintain the libido, sperm production, muscle and bone mass, and male hair pattern. Male hypogonadism is a clinical condition characterized by low serum testosterone levels in combination with a variety of symptoms and signs such as reduced libido and vitality, reduced muscle mass, increased fat mass and depression.[30]. UGTs are the main phase II enzymes, and they have an important role in the detoxification of endogenous and exogenous compounds in humans.[19] UGTs catalyze the transfer of a glucuronyl group to a lipo philic substrate following the phase I reaction, forming a more water soluble and more rapidly excreted compound. The glucuronyl group is transferred from the uridine-diphosphoglucuronic acid (UDPGA) co-substrate.[14]

Objectives

Methods

Results

Conclusion