Browsing Pathways

Amikacin is an aminoglycoside antibiotic that inhibits bacterial protein synthesis. Amikacin binds irreversibly to the bacterial 30S ribosomal subunit protein and 16S rRNA and prevents the formation of the initiation complex with messenger RNA. More specifically, amikacin binds four nucleotides of the 16S rRNA and a single amino acid of protein S12. This interferes with the decoding site in the vicinity of nucleotide 1400 in 16S rRNA of the 30S subunit. This region interacts with the wobble base of the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so that incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides, and the breakup of polysomes into nonfunctional monosomes. Aminoglycosides are useful in treating infections from mycobacteria such as, tuberculosis, and aerobic Gram-negative bacteria including, Pseudomonas, Acinetobacter and Enterobacter. Aminoglycosides can also treat Gram-positive bacterial infections but are inferior to other available antibiotics. Aminoglycosides may be used in combination with penicillin type antibiotics. Aminoglycosides are not an effective treatment for anaerobic bacteria, fungi and viruses.

Lymecycline is a tetracycline antibiotic that inhibits cell growth by inhibiting translation. Lymecycline is lipophilic and can diffuse across bacterial cell membranes or travel through membrane porin channels. Once inside the bacterial cell, it reversibly binds to the bacterial 30S ribosomal subunit and prevents aminoacyl tRNA from binding to the A site of the ribosome-RNA complex; aminoacyl tRNA binding inhibition likely occurs through steric hindrance. This results in inhibition of bacterial protein synthesis and hence cell growth.

Spectinomycin (also named Togamycin or Trobicin) is an aminocyclitol antibiotic for the treatment of gonorrhea infections such as penicillin-resistant Neisseria gonorrhoeae (experimental studies shows that spectinomycin equips with bacteriostatic effect against most Neisseria gonorrhoeae strains). It is produced from Streptomyces spectabilis, which is a soil microorganism. Spectinomycin reversibly interferes with the interaction between mRNA and the bacterial 30S ribosomal subunit. It is structurally similar to aminoglycosides, but does not cause misreading of mRNA. It is structurally similar to aminoglycosides, but does not cause misreading of mRNA.

Pyruvate Dehydrogenase (PDH) Deficiency is an X linked disease where individuals have a reduced number of functioning PDH complexes ultimately affecting the mitochondria’s energy metabolism. In a healthy individual, PDH complex catalyzes the conversion of pyruvate to acetyl coenzyme A, therefore PDH deficiency can cause the accumulation of excess pyruvate and lactic acid. PDH deficiency presents itself in a variety of ways, however since the brain obtains most of it’s energy from aerobic oxidation of glucose, all PDH deficient individuals have some degree of neurological impairment. Other symptoms range from fatal lactic acidosis in the newborns, chronic neurodegenerative conditions, brain lesions, cerebral atrophy and much more. Due to the fatal nature of the disease many with this condition do not live past childhood, however there are some that survive to adolescents and adulthood. Treatments have tried to minimize systemic lactic acid accumulation by feeding patients high fat/low carbohydrate diets. However, this does not reverse neurological structural damage already present and therefore does little to influence the end results.

Dihydromorphine (also known as Paramorfan or Paramorphan) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of dihydromorphine acetate will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.

The branched chain amino acid (BCAA) leucine is able to signal transduction pathways that modulate translation initiation for protein synthesis in skeleton muscles. In the presence of leucine, hyperphosphorylation of 4E-BP1 causes its affinity for eIF4E to be lowered. This allows eIF4F protein complexes to recognize, unfold and guide the mRNA to the 43S preinitiation complex thereby increasing translation initiation. In addition, leucine has a transient affect on the release of insulin and/or enhances sensitivity of muscle cells to insulin. A culmination of both signals at the mammalian target of rapamycin (mTOR) and perhaps other signaling, such as PKCδ, are needed for maximum translation initiation to occur.

Buprenorphine, trade name subutex, suboxone, zubsolv and bunavail, is a partial agonist of mu-opioid receptors and a kappa-opioid receptor antagonist and is prescribed for opioid addiction to prevent cravings and symptoms of withdrawal. The binding of these receptors causes hyperpolarization and decreased neuronal excitability. Buprenorphine has a longer duration of action due to its slow dissociation from the receptor. This long rate of action causes a long clinical effect and decreases physical dependence. Buprenorphine can also prevent opioid use by inhibiting exogenous opioid effects. This elimination of the rush from the opioid can block the reinforcing behaviour of the drug and may treat opioid addiction. Buprenorphine is available on its own or in combination with naloxone.

Levomethadyl acetate (also known as LAAM) is a synthetic synthetic opioid analgesic with multiple actions quantitatively similar to those as morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. However, levomethadyl acetate is more active and more toxic than morphine. Levomethadyl acetate can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of levomethadyl acetate will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Therefore, methadyl acetate can reduce nerve conduction and decrease neurotransmitter release; so that perception of pain signals can be blocked. Levomethadyl acetate can also open calcium-dependent inwardly rectifying potassium channels (OP1 receptor agonist) to reduce neuronal excitability as well as lead to hyperpolarization.

Lincomycin is a lincosamid antibiotic that can effectively aganist aerobic gram-positive cocci, aerobic gram-positive bacilli as well as anaerobic gram-positive sporeforming bacilli in vitro. Lincomycin is derived from yeast Streptomyces lincolnensis. Lincomycin can bind and inhibit 50S subunits of bacterial ribosomes to prevent protein synthesis, which result in cell death.

The discovery of AIDS prompted the search for agents that block the HIV replication process. Zidovudine (AZT) is a nucleoside analogue of thymidine, and was shown to reduce considerably the mortality of patients with AIDS. Zidovudine is toxic to the hemtopoietic system, causing anemia and neutropenia. It is clear, however, that disease progression can occur during continued administration of zidovudine. Moreover, zidovudine is not effective in treating Kaposi sarcoma, a common complication of HIV infection. Zidovudine therapy is also associated with a high incidence of toxicity, primarily bone marrow suppression, that requires dosage reduction or discontinuation of the therapy.