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Magic Bullets

A Case on Enzyme Inhibition



Author:

Sarah A. Wojiski
Biology Department
Southern Connecticut State University
wojiskis1@southernct.edu

Abstract:

This clicker case was designed to teach students about basic enzyme structure, mechanisms of enzyme inhibition, and mechanisms of drug resistance. The story follows Oliver Casey, a patient afflicted with Chronic Myelogenous Leukemia (CML). CML is caused by a chromosomal mutation that affects the tyrosine kinase ABL, an enzyme important in regulating cell growth and proliferation. The chromosomal mutation gives rise to the BCR-ABL fusion gene that produces a constitutively active ABL kinase, which causes the leukemia. In May 2001, the Food and Drug Administration approved the use of a rationally designed tyrosine kinase inhibitor, imatinib (Gleevec®), for the treatment of CML. During that same month, Gleevec made the cover of TIME magazine, described as "new ammunition in the war on cancer." The case is structured for a flipped classroom environment in which students view preparatory videos (including one by the author) on their own before beginning the case. Written for a first-year introductory biology course, the case could also be adapted for AP/Honors high school biology or a cancer biology course.

Objectives:
  • Define catalyst and describe the role of enzymes in biological systems.
  • Define substrate and active site, and explain the "induced fit" model of enzyme-substrate interactions.
  • Explain how different factors in the cellular environment, such as pH and temperature, affect enzyme activity.
  • Distinguish between competitive and non-competitive inhibition, and explain how competitive and non-competitive inhibitors alter an enzyme's activity.
  • Describe how enzyme inhibition can be used to treat certain forms of cancer.
  • Explain how mutations can lead to resistance to enzyme inhibition.
Keywords: Enzyme; enzyme inhibition; induced fit; kinase; leukemia; active site; substrate; competitive inhibition; chronic myelogenous leukemia; CML; hematopoiesis; Philadelphia chromosome; Gleevec; resistance
Topical Area: N/A
Educational Level: High school, Undergraduate lower division
Formats: PDF, PowerPoint
Type/Method: Clicker, Flipped
Language: English
Subject Headings: Biology (General)   Cell Biology   Medicine (General)  
Date Posted: 1/29/2016
Date Modified: N/A
Copyright: Copyright held by the National Center for Case Study Teaching in Science, University at Buffalo, State University of New York. Please see our usage guidelines, which outline our policy concerning permissible reproduction of this work.

Teaching Notes


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Answer Key


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Supplemental Materials


The following supplemental materials can be used with this case study:

  Data Points Activity: Efficacy of a Treatment for Chronic Myeloid Leukemia hhmi/
This figure and activity depicts data from Dr. Brian Druker and colleagues monitoring of white blood cell counts in six patients with chronic myeloid leukemia treated with the drug, STI571, which blocks the activity of the cancer-causing tyrosine kinase BCR-ABL. Each patient (denoted by a different colored line) received 500 mg of STI571 per day for 150 days. The dotted line represents the upper limit of the normal white blood cell count range. Download the educator guide PDF, which includes questions to guide a class discussion on the graph characteristics and what the data show.
  3D Model Print File for Gleevec-resistant BCR-ABL, a mutated form of BCR-AB hhmi/

  3D Model Print File for Dasatinib, a drug that can inhibit BCR-ABL and Gleevec-resistant BCR-ABL hhmi/

  3D Model Print File for BCR-ABL, an unregulated kinase that causes cancer hhmi/

  3D Model Print File for Imatinib (Gleevec), a drug that mimics ATP and inhibits BCR-ABL hhmi/

  3D Model Print File for Adenosine Triphosphate (ATP) hhmi/

Videos

The following video(s) are recommended for use in association with this case study.

  Animated Tutorial: BCR-ABL: Cancer Protein Structure and Function hhmi/
This self-paced animated tutorial (Click and Learn) supports the 2013 Holiday Lectures on Science and describes how understanding the structure of the BCR-ABL kinase led to the development of an effective treatment for chronic myeloid leukemia. It provides an example of how advances in molecular biology, structural biology, and DNA sequencing have revolutionized the treatment of certain types of cancer. Produced by HHMI BioInteractive.

  Animation: Gleevec Inhibits Cancer-Causing Kinase BCR-ABL hhmi/
This short animation explains the mechanism of the the drug Gleevec and how it binds to and inactivates BCR-ABL, a mutant kinase that causes chronic myeloid leukemia. Running time: 3:31 min. Produced by HHMI BioInteractive.

  Animation: Gleevec-Resistant Form of Kinase BCR-ABL hhmi/
This animation describes the mechanism of the drug, dasatinib. Dasatinib is used to treat Gleevec resistant CML. Running time: 2:14 min. Produced by HHMI BioInteractive.

  Animation: Gleevec hhmi/
This animation shows how the drug Gleevec is designed to interfere with the stimulation of growth in leukemia cells. Running time: 1:04 min. Produced by HHMI BioInteractive.

  Lecture: Cancer As a Genetic Disease hhmi/
Lecture from the 2013 HHMI Holiday Lecture Series. Dr. Sawyers presents an overview of cancer biology and describes how understanding the molecular mechanisms involved in a type of cancer, chronic myeloid leukemia, resulted in the development of Gleevec, one of the first targeted cancer drugs. Running time: 58:33 min. Produced by HHMI BioInteractive.

  Enzyme Function and Inhibition
A brief narrated animation describing basic enzyme structure (active site, substrate) and competitive versus non-competitive inhibition. Running time: 1:07 min. Produced by JubbaTheHott, uploaded to YouTube in 2009.

  Enzymes and … Pac-Man?
Funny animation making an analogy between enzymes and Pac-Man from the vintage video game. It discusses active site, substrate, optimal temperature/pH, and denaturation. Running time: 4:50 min. Produced by the Amoeba Sisters, 2013.

  Enzyme Function and Inhibition
An animation describing the basic structure of an enzyme and the environmental factors that influence proper enzyme folding. The induced fit model of enzyme-substrate interaction is demonstrated, and competitive and non-competitive inhibition are described, including real-world examples of each. Running Time: 5:13 min. Produced by Sarah A. Wojiski for the National Center for Case Study Teaching in Science, University at Buffalo, 2015.

Great activity. Used it with my AP Bio class. First assigned metabolism chapter. Quick discussion. Then used this activity to apply what they had learned. Ready for a quiz. Thanks for sharing it.


Gian Toyos
Science
Saint John's School
San Juan
gtoyos@gmail.com
10/27/2016



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