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DNA (Protein synthesis (Components (Involves RNA as building block (Types…

- - - - Types of RNA
        
        tRNA (15%): small nucleotide seq and transport a.a to site of protein synthesis
        
        rRNA (80%): variable nucleotide seq and combines with proteins to form ribosomal subunits
        
        mRNA (5%): variable nucleotide seq and used as template for polypeptide synthesis
        
        small nuclear RNA: small nucleotide seq for pre-transcriptional modification of mRNA to mature form
        
        small interfering RNA: affect gene expression (possible inhibitor?)
        
        micro RNA: affect gene expression and incolved in growth & expression
      - RNA consists of pyrimidines (C/U - U is similar to T with absence of methyl side chain at C=C portion of ring) and purines (A/G) bonded to ribose sugar (consists of 2 hydroxyl groups)
    - - Universal: used by eukaryotes & prokaryotes with little exceptions
        
        Highly specific/non-ambiguous: one codon codes for a specific amino acid
        
        Degenerate/redundant nature: many codons code for same amino acid (except for Met & Trp) to mitigate effects of single base/point mutations, hence 20 aa but with 61 codons (last 3: UAA, UAG & UGA for stop) and usually is the degenerate nature of 3rd base/wobble base eg GGA/GGG/GGC/GGU all code for Gly
        
        Code is non-overlapping (i.e. read in sequences of triplet base) & punctuated (contains start/stop codon)
        
        Codons coding for same amino acids/amino acids with similar R group properties are similar in seq eg GAU/GAC code for Aspartic Acid & GAA/GAG code for Glutamic acid
        Codon bias with codons of C/G preferred over other degenerate codons due to more H bonds, conferring greater stability
    - - Each tRNA contains an unique anticodon (that base-pairs to complementary seq on mRNA) and each tRNA has its specific amino-acyl tRNA synthetase that bonds the corresponding a.a to its tRNA at the 3' end (ATP involved), and is termed a.a activation. tRNA has a clover-leaf shape (stem-loop structure) with 5' end ending in G and 3' end ending with CCA (Asp)
- - - - Nucleoside/nucleotide analogs: mimic the molecular structure of natural nucleosides and acts as competitive inhibitors for enzymes that binds to nucleic acids, affecting transcription process. Example: Use of allopurinol to block synthesis of uric acid to treat hyperuricemia (uric acid accumulation due to increased production/reduced metabolism of uric acid that can lead to gout eg purine-rich diet). Xanthine oxidase (XO) is involved in purine metabolism (from hypoxanthine to xanthine and to uric acid) and allopurinol inhibits the formation of xanthine while alloxanthine (metabolised by XO due to structural similarity at the 5-membered ring with the position of C=N interchanged) inhibits the second step.
        Other egs include zidovudine/Retrovir (anti-HIV) and 5-fluorouracil that mimics uracil (Anti-cancer)
      - Oligonucleotides
        
        Anti-sense oligonucleotides (ASO): base-pairs with target mRNA sequences (sequence similar to anti-sense DNA strand), preventing translation of RNA segment eg fomivirsen(1998, discontinued in 2002) used as anti-viral agent by binding to mRNA sequence of a critical gene in cytomegalovirus with a 21 nucleotide sequence: 5' GCG TTT GCT CTT CTT CTT GCG 3'. Nucleases will affect efficacy (degradation), hence oligonucleotide mimetics designed at the pentose group or sugar-phosphate backbone eg fomivirsen: phosphorothioate (P=S) replacing phosphate (P=O) backbone (refer to lecture notes)
        Other egs include mipomersen(2013) for familial hypercholesterolemia, nusinersen(2016) and eteplirsen(2016) for muscular dystrophy
        coding sequence of mRNA must be known beforehand
        
        Small-interfering RNA (siRNA)/short hairpin RNA (shRNA) that is converted to siRNA binds to mRNA to target for RNA degradation
      - Gene therapy
    - - Inhibit binding to DNA
        
        Alkylating agents: covalent binding of agents (electrophiles eg mechlorethamine/nitrogen mustard & cyclophosphamide (anti-cancer drug) binds to N in imidazole side chain of guanine & adenine to form a dimer (no base-pairing) and disrupt transcription/replication process.
        
        Intercalactors: highly planar molecules that insert themselves between adjacent nucleotides due to pi-pi stacking interactions between aromatic rings and drug (strong interactions with DNA) eg doxorubicin (anti-cancer), disrupting the major & minor grooves.
        
        Groove binders: crescent-shaped molecules that fits into the grooves of the DNA double helix through Van der Waals interactions eg pentamidine (anti-microbial) or can affect the stability of DNA by interacting with the negatively-charged sugar-phosphate backbone.
      - Target DNA replication
        
        Inhibitor of DNA topoisomerase
        
        Eg Camptothecin (CPT) that forms H bonds with DNA & topoisomerase I to form a stable ternary complex (ESI complex) and prevent DNA religation, thus damaging cellular DNA (accumulation of supercoiling and strand breaks upon collision with helicase/polymerase) during replication to arrest cell dvision and used as anti-cancer drug.
        Eg Fluoroquinolone-class of drugs (nalidixic acid [Gen 1], oxolinic acid [Gen 1], norfloxacin [Gen 2], Ciprofloxacin [Gen 2], Levofloxacin [Gen 3], Moxifloxacin [Gen 3] and Gemifloxacin [Gen 4]) that inhibits bacterial topisomerase II (not human), resulting in accumulation of cleavage complexes that has bactericidal effect.
        
        Inhibitor of DNA polymerase
        
        Eg Acyclovir (structural similiarity to viral nucleoside: deoxyguanosine but the deoxyribose lacks a complete sugar ring and is a prodrug, hence needs 3 step phosphorylation to form the active drug) and is incorporated into viral DNA strand and causes premature termination of chain (lack free OH group at 3' end for elongation) and used in antiviral (cream & oral forms with 5 times a day as viral replication is very rapid & drug has short half-life) & anticancer drugs
      - Target protein synthesis
        
        Inhibit RNA polymerase (prokaryotes)
        
        Eg Rifampicin (from Streptomyces mediterranei) binds to b-subunit of RNA polymerase, preventing RNA elongation (steric hindrance to addition of free RNA nucleotides to strand) but does not prevent initiation as the first few RNA nucleotides can still bind to the polymerase. Used in cocktail of drugs for TB treatment
        
        Inhibit translation (prokaryotes)
        
        Eg tetracycline binds to 30s ribosomal subunit and prevent recruitment of amino-acyl tRNA to RNA-ribosomal complex, inhibiting protein synthesis; Oxazolidinones bind to 50s ribosomal subunit and prevent binding to complex; Chloramphenicol blocks peptidyl transferase; macrolides & aminoglycosides prevents complex from moving downstream/translocation.