Teaching
Case 10: Messing with Synthesis

Session Objectives

Students will be able to:
  • Describe the synthetic pathways for steroid hormones, and how some enzymes make bottlenecks in this pathway
  • Explain the special position estrogen seems to hold in that pathway
  • Describe the unusual nature of the genetics of the P450 enzymes
  • Identify compounds which might create endocrine disruption by messing with synthesis of steroid hormones
In this class students examine the biosynthetic pathway for steroid hormones and test their hypotheses about the effects of disabling specific enzymes.

Show the students the main page of the supplementary webpages, and look at the overall pattern of the pathways. Sequentially ask them the questions below and then test their hypothesis by clicking on the specified enzyme to see its effect.

Looking at the displayed diagram of steroid hormone biosynthesis, make a prediction. Do you think each step is controlled by a unique enzyme?

Click on the arrow between pregnenolone and 17-HO pregnenolone. Discuss with them what you see.

Where in the diagram are the corticosteroids? Is there one enzyme that forms a bottleneck in their synthesis?

Click now on the arrow between progesterone and 11-deoxycorticosterone. Discuss with them what you see.

What is special about the positions of Testosterone and Estradiol in the pathways?

Click now on the arrow between androstenedione and testosterone, 5-alpha reductase, and testosterone and estradiol. Talk about these special patterns.

Which enzymes control multiple pathways?

Divide the class into 4 groups, giving each two model sets and assigning them one of the chemical pairs below.

This simulation has given some hints about the functions of the enzymes in these pathways. Now you are going to work in groups to build the chemicals on either side of an enzyme, comparing them to see what work the enzyme has done. It will probably be easiest to make the first chemical and then change it into the second, noting what changes you make.

Group 1: Pregnenolone and Progesterone
Group 2: Testosterone and Estradiol
Group 3: Testosterone and Dihydrotestosterone
Group 4: 17-OH Progesterone and 11-Deoxycortisol


Case Assignment

Research on endocrine disruption by way of enzymatic or synthetic disruption is sparse. There is some indication that Atrazine's effects are due to inhibition of P450 aromatase (cyp 19) activity. This enzyme is also sometimes a therapeutic target in cancer or other diseases. The aromatase step is intriguing for development of SERMs, since its activity varies across tissues.

Your assignment this week is a little different than in past weeks. Instead of working in groups to come up with answers to different questions, you will be working in groups to come up with answers to the same question: What are some chemicals that might cause endocrine disruption with mechanisms involving steroid synthesis? Write answers that will distinguish yours from the common ones by suggesting specific research studies to investigate the candidates you have identified.


References

  • Henley, DV, and Korach, KS. 2006. Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function. Endocrinology 147(6): S25-S32
  • Y Hong and S Chen. 2006. Aromatase Inhibitors: Structural Features and Biochemical Characterization. Annals of the New York Academy of Sciences 1089:237-251.
  • J T Sanderson. 2006. The Steroid Hormone Biosynthesis Pathway as a Target for Endocrine-Disrupting Chemicals. Toxicological Sciences 94(1):3-21.