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1、Targeting Protein Synthesis for Antimicrobials and Synthetic Biology,Jiqiang Ling Department of Microbiology and Molecular Genetics University of Texas Houston Medical School,Lecture 1: Overview of Protein Synthesis Lecture 2: Translational Fidelity Lecture 3: Protein Synthesis and Human Diseases Le
2、cture 4: Antibiotic Resistance and Tolerance Lecture 5: Mistranslation and Bacterial Stress Responses Lecture 6: Genetic Code and Synthetic Biology,Lecture 1: Overview of Protein Synthesis,DNA replication,Transcription,Decoding,Aminoacylation,Amino acid,tRNA,aaRS,aa-tRNA,Ribosome,Gene expression,(Ro
3、y & Ibba, 2006, Nature ),Nobel Prizes for Gene Expression,The Nobel Prize in Physiology or Medicine 1958 Joshua Lederberg “for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria“ The Nobel Prize in Physiology or Medicine 1959 Severo Ochoa and Ar
4、thur Kornberg “for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid“ The Nobel Prize in Physiology or Medicine 1962 Francis Harry Compton Crick, James Dewey Watson and Maurice Hugh Frederick Wilkins “for their discoveries concerning the mole
5、cular structure of nucleic acids and its significance for information transfer in living material“ The Nobel Prize in Physiology or Medicine 1965 Franois Jacob, Andr Lwoff and Jacques Monod “for their discoveries concerning genetic control of enzyme and virus synthesis“ The Nobel Prize in Physiology
6、 or Medicine 1968 Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg “for their interpretation of the genetic code and its function in protein synthesis“ The Nobel Prize in Physiology or Medicine 1969 Max Delbrck, Alfred D. Hershey and Salvador E. Luria “for their discoveries concerning
7、the replication mechanism and the genetic structure of viruses“ The Nobel Prize in Chemistry 1972 Christian B. Anfinsen “for his work on ribonuclease, especially concerning the connection between the amino acid sequence and the biologically active conformation“ Stanford Moore and William H. Stein “f
8、or their contribution to the understanding of the connection between chemical structure and catalytic activity of the active centre of the ribonuclease molecule“,Nobel Prizes for Gene Expression,The Nobel Prize in Chemistry 1980 Paul Berg “for his fundamental studies of the biochemistry of nucleic a
9、cids, with particular regard to recombinant-DNA” Walter Gilbert and Frederick Sanger “for their contributions concerning the determination of base sequences in nucleic acids“ The Nobel Prize in Chemistry 1989 Sidney Altman and Thomas R. Cech “for their discovery of catalytic properties of RNA“ The N
10、obel Prize in Physiology or Medicine 1993 Richard J. Roberts and Phillip A. Sharp “for their discoveries of split genes“ The Nobel Prize in Chemistry 1993 Kary B. Mullis “for his invention of the polymerase chain reaction (PCR) method“ The Nobel Prize in Chemistry 2004 Aaron Ciechanover, Avram Hersh
11、ko and Irwin Rose “for the discovery of ubiquitin-mediated protein degradation“ The Nobel Prize in Chemistry 2006 Roger D. Kornberg “for his studies of the molecular basis of eukaryotic transcription“ The Nobel Prize in Chemistry 2009 Venkatraman Ramakrishnan, Thomas A. Steitz and Ada E. Yonath “for
12、 studies of the structure and function of the ribosome“,(Ambrogelly et al., 2007, Nat Chem Biol),Genetic code: 1968 Nobel Prize in Physiology or Medicine,Robert W. Holley,Har Gobind Khorana,Marshall W. Nirenberg,aaRS,ACG,Ribosome,CAG,tRNAVal,Aminoacylation,Decoding,Lys,Protein synthesis: aminoacylat
13、ion and decoding,Q: How many natural amino acids have been found to be used in protein synthesis? 20 21 22 Over 100,aaRS,ACG,Ribosome,CAG,tRNAVal,Aminoacylation,Decoding,Lys,Protein synthesis: aminoacylation and decoding,An aaRS ligates the correct amino acid to the 3-end of the corresponding tRNA O
14、ne amino acid, one aaRS tRNA anticodon matches mRNA codon on the ribosome,Two steps in aminoacylation,The aaRS catalyzes aminoacylation (ligation of amino acid to tRNA) in two steps The amino acid is first activated by ATP to form aminoacyl-adenylate (aa-AMP) in the active site The same active site
15、then catalyze transfer of the amino acid from AMP to the 3-end of the tRNA,(Ling et al., 2009, Annu. Rev. Microbiol. ),Structure of tRNA,(Hori, 2014, Front. Genet. ),tRNA forms cloverleaf secondary structure and L-shaped tertiary structure,tRNAs are heavily modified,(Phizicky E),tRNAs are the most h
16、eavily-modified RNAs Over 10% of the protein-coding genes are used for tRNA modifications Modifications stabilize the tertiary structure and ensures correct codon-anticodon pairing Some modifications are required for tRNA recognition by aaRS and ribosome,Two classes of aaRSs,(Ibba, 1997, Science; Yang, 2003, PNAS; ODonoghue, 2003, Microbiol. Mol. Biol. Rev.),Two classes of evolutionary distinct aaRS Active site: Rossman fold (Class I) and anti-parallel sheet (Class II
