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Dihydrofolate Reductase, Beta-Lactamase, p300, and Macrophage Infectivity Potentiator Overview

This presentation explores the roles of Dihydrofolate Reductase (DHFR), Beta-Lactamase, p300, and the Macrophage Infectivity Potentiator (MIP) in microbial resistance and cell growth. DHFR is pivotal for amino acid and nucleic acid synthesis in Escherichia coli, while Beta-Lactamase contributes to antibiotic resistance. The p300 acetyltransferase is crucial for transcriptional activation and cellular processes. MIP enhances virulence in Legionella pneumophila, responsible for Legionnaires' disease. This analysis discusses mechanisms, structures, and potential therapeutic targets.

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Dihydrofolate Reductase, Beta-Lactamase, p300, and Macrophage Infectivity Potentiator Overview

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  1. PRESENTATION II NAME Dihydrofolate Reductase Beta lactmase p300 Macrophage Infectivity Potentiator By Christine Harvey

  2. Dihydrofolate Reductasein Escherichia coli

  3. Class: oxidoreductase • Reduces dihydrofolate (DHF) to tetrahydrofolate (THF) • THF is a precursor to amino acids, purine and thymidylate. • DHFR is imperative to cell life http://en.wikipedia.org/wiki/DHFR

  4. Function Source: Schweitzer, Barry I., et al. The FASEB Journal Vol 4, “Dihydrofolate reductase as a therapeutic target.” May 1990.

  5. Mechanism http://en.wikipedia.org/wiki/DHFR

  6. Structure

  7. Binding Pocket

  8. MOVIE

  9. Sequence Alignment

  10. Phylogenetic Tree

  11. Beta-Lactamasein Escherichia coli

  12. Class: Hydrolase • Beta Lactamase is produce by bacteria after being exposed to beta lactam antibiotics • Responsible for beta lactam antibiotic resistance

  13. Penicillin • Contains beta lactam ring

  14. Mechanism

  15. 21

  16. p300In Homo Sapiens

  17. Class: Transferase • p300 transfers an acetyl group from acetyl coenzyme A to an active site lysine • Transcriptional activation occurs upon acetyl transfer

  18. Title • p300 is responsible for cell growth before and after birth • Cancer suppressor

  19. Domains Taz2 KIX Bromodomain HAT Zinc Fingers (3) Taz2 Creb

  20. Histone Acetyl Transferase • Active site tyrosine acts as nucleophile Source: http://www.bmolchem.wisc.edu/labs/denu/images/hats/sequential.jpg

  21. Docking

  22. 39

  23. Macrophage Infectivity Potentiatorin Legionella pneumophila

  24. Legionella pneumophila • gram negative bacteria • Causes Legionnaires’ disease • Carried in aerosols from man-made water systems

  25. MIP • Class: Isomerase • Catalyzes the isomeration of the N-terminal on proline • Cause of virulence in Legionnaires’ disease • Located on outer membrane protein • 25 kDa

  26. Crystalization • Solution: 100 mM MES (pH 6.1–6.5), 15–20% (w/v) PEG 8000 and 500 mM zinc acetate. Protein concentration was 10 mg ml–1in 20 mM HEPES, pH 7.0 • Crystals were grown for 2-3 weeks at 288K • X-ray data was collected at 100K in a nitrogen gas stream (dried paraffin oil) at 2.4 Angstrom resolution • Multiwavelength anomalous dispersion (MAD) with zinc was used for phasing

  27. Source: Riboldi-Tunnicliffe, Alan et al., Nature Structural Biology, vol.8: 9. “Crystal structure of Mip, a prolylisomerase from Legionella pneumophila.” September 2001. 44

  28. Mechanism • Peptidyl-prolyl cis-trans isomerases’ (PPIases) mechanism is not currently know Source: Park, Steven T., et al. Journal of Biological Chemistry. Vol. 267 No.5, “PPIase Catalysis by Human Fk506-binding Protein Proceeds Through a Conformational Twist Mechanism.” February 1992.

  29. Source: Riboldi-Tunnicliffe, Alan et al., Nature Structural Biology, vol.8: 9. “Crystal structure of Mip, a prolylisomerase from Legionella pneumophila.” September 2001.

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