Evolutionconnection ribosomes

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  • We’ve just learned how ribosomes play a key role in the cell in protein synthesis. Obviously this is an important job: if a cell can’t make proteins, it can’t grow, reproduce—or live for long.
    Medical science has taken advantage of this with antibiotics that target the ribosome. By taking bacterial ribosomes out of commission, the drug keeps the bacteria from reproducing. Streptomycin, tetracycline, erythromycin, and many related antibiotics work by interfering with ribosomes in different ways, blocking protein synthesis.
    Does anyone see any potential problems with taking an antibiotic that interferes with ribosomes?
  • If I take an antibiotic, what’s to stop the antibiotic from attacking my own ribosomes? After all, human cells have ribosomes too . . .
  • The answer relies on evolutionary history.
    The ribosome evolved very early in the history of life--before the last common ancestor of all life. (CLICK) That’s why all living things have them.
    We all inherited them from our common ancestor. (CLICK) And we all inherited ribosomes that share a similar structure: similar rRNA sequences, a small subunit that decodes mRNA, and a large subunit that joins amino acids together.
    (If you have discussed the RNA world hypothesis, you may wish to describe how the evolution of the ribosome happened during the RNA world.)
    (Note to instructor: This tree of life is based on the evolutionary similarities among small subunit ribosomal RNA sequences.)
  • The ribosome evolved very early in the history of life. However, along the way, some differences in our ribosomes evolved as lineages split from one another (CLICK, CLICK, CLICK, CLICK) . . . including differences that affect whether antibiotics like streptomycin can disrupt the functioning of the ribosome.
    (CLICK) These small evolutionary changes deep in our history have had a big impact on modern medicine.
    (Note to instructor: This tree of life is based on the evolutionary similarities among small subunit ribosomal RNA sequences.)
  • For example, let’s look at antibiotics like streptomycin. These antibiotics (called aminoglycosides) bind to the decoding region of the small subunit of the ribosome (CLICK). Specifically, they bind to the A site where the correct tRNA is associated with the codon in the mRNA.
    (CLICK) But not in eukaryotic ribosomes. Why not?
  • Because of a small change deep in our evolutionary history, streptomycin-like antibiotics can’t bind to the eukaryotic ribosome:
    (CLICK) At position 1408 of one of the stretches of rRNA that makes up the small ribosomal subunit (this subunit is called 16 S; it’s about 1500 nucleotides long), there was a small change deep in our evolutionary history. Bacteria have the adenine nucleotide (A) (CLICK), and eukaryotes have guanine (G) (CLICK). That’s just one tiny change in 1500 bases!
    (Note to instructor: We can’t tell which is the ancestral sequence. Some Archaea have adenine at this position and others have guanine.)
  • The result is that the antibiotic can clog up bacterial ribosomes, but not eukaryotic ones. These images show how the antibiotic paromycin (in gold) interacts with the bacterial ribosome (red) and the eukaryotic one (blue). Antibiotics and ribosomes have such complicated 3-D structures that one base-change can disrupt things enough that the two molecules no longer fit together. You can see how the antibiotic is in a slightly different position on each ribosome.
    There is, however, one exception to the rule about these types of antibiotics not binding to ribosomes in eukaryotic cells. Based on the evolutionary history of eukaryotic cells, can anyone guess which ribosomes those are?
    (Josh: images from http://puglisi.stanford.edu/pdf/pub58.pdf)
  • Ribosomes in our mitochondria are vulnerable to these bacteria-specific antibiotics. Why?
    Because they are the product of endosymbiosis and evolved from free-living bacteria.  They have the adenine nucleotide at position 1408 and are vulnerable to streptomycin.
    Does it cause any problems if I take an antibiotic and it disrupts my mitochondrial ribosomes? Luckily, most people seem to suffer few negative effects. However, sometimes taking this class of antibiotics can destroy hair cells in the cochlea and cause permanent hearing loss. This seems to be caused in part by the antibiotics’ effect on mitochondrial ribosomes. People carrying certain mutations in the gene that codes for their mitochondrial ribosome are more likely to suffer hearing loss as a result of using these antibiotics.
    (Note for instructors: In case your students are curious, here is some additional information about aminoglycoside induced deafness. People carrying certain mitchondrial mutations have a much higher risk of becoming deaf after taking aminoclycosides; however, it *can* happen to anyone. These mutations are relatively rare (a study in the UK found that 1 in 500 children carried the mutation). Luckily, these antibiotics are not commonly used—they are used almost exclusively in the case of acute, life-threatening infections, such as tuberculosis. Genetic screening for the most common of these mutations is not currently standard medical practice; however, there is discussion of whether people likely to be treated with these antibiotics (e.g., children with cystic fibrosis, people living where TB is common) should be screened for the mutations.)
  • Evolutionconnection ribosomes

    1. 1. Evolution connection: RibosomesEvolution connection: Ribosomes Learning goals: Students will understand that 1) some antibiotics work by attacking the ribosome, 2) tiny differences that evolved in the ribosomes of prokaryotes and eukaryotes are responsible for the specificity of those drugs towards bacterial ribosomes, 3) our mitochondria are vulnerable to such drugs because these organelles evolved via endosymbiosis from bacteria, and 4) our evolutionary history matters in our everyday lives. For the instructor: This short slide set connects the topic of cellular ribosomes to both our evolutionary history and modern medicine. Slide 9 may be skipped to save time. Throughout the notes, optional information is included in parentheses in case the instructor wants to go into more detail. To integrate these slides best, use them immediately after you’ve discussed the structure of ribosomes and their role in the cell. Alternatively, you may wish to use these slides when you discuss translation later in the semester.
    2. 2. Evolution connection: RibosomesEvolution connection: Ribosomes Ribosomes: An achilles heel for bacteria Petri dish photo from CDC; researcher photo from CDC/Dr. U.P. Kokko; photo of various medicines from National Institute of Health
    3. 3. Why don’t antibiotics like streptomycin harm our own cells? Evolution connection: RibosomesEvolution connection: Ribosomes
    4. 4. Evolution connection: RibosomesEvolution connection: Ribosomes Ribosomes evolved early in the history of life All ribosomes share: • similar rRNA sequences • small subunit that decodes mRNA • large subunit that joins amino acids together The ribosome evolved back here.
    5. 5. Evolution connection: RibosomesEvolution connection: Ribosomes Ribosomes evolved early in the history of life The ribosome evolved back here. ... and evolved modifications as life’s lineages diversified. Small evolutionary changes  big impact
    6. 6. Evolution connection: RibosomesEvolution connection: Ribosomes Streptomycin-like antibiotics bind to the ribosome Antibiotic binds here and interferes with protein synthesis … … but not in eukaryotic ribosomes. A site antibiotic ribosome
    7. 7. Evolution connection: RibosomesEvolution connection: Ribosomes … because of position 1408 In the small ribosomal subunit. Streptomycin-like antibiotics can’t bind to the eukaryotic ribosome … G A
    8. 8. Evolution connection: RibosomesEvolution connection: Ribosomes Streptomycin-like antibiotics can’t bind to the eukaryotic ribosome … Images provided by Joseph D. Puglisi.
    9. 9. Evolution connection: RibosomesEvolution connection: Ribosomes But eukaryotic mitochondrial ribosomes are vulnerable. G A Mitochondrion ribosomes
    10. 10. ReferencesReferences Bokov, K., and Steinberg, S. V. (2009). A hierarchical model for evolution of 23S ribosomal RNA. Nature. 457: 977-980. Lynch, S. R., and Puglisi, J. D. (2001). Structural origins of aminoglycoside specificity for prokaryotic ribosomes. Journal of Molecular Biology. 306: 1037- 1058. Pace, N. R. (1997). A molecular view of microbial diversity and the biosphere. Science. 276: 734-740. Recht, M. I., Douthwaite, S., and Puglisi, J. D. (1999). Basis for prokaryotic specificity of action of aminoglycoside antibiotics. The EMBO Journal. 18: 3133-3138. Selimoglu, E. (2007). Aminoglycoside-induced ototoxicity. Current Pharmaceutical Design. 13: 119-126.
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