Drug targets (enzymes and transporters)

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kimch

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  • What are enzymes?
    -Biological catalysts that speed up the pace of chemical reactions.
    -Protein machines that carry out tasks within cells
    -Central to all aspects of cellular function, both bacterial and eukaryotic
    -Enzymes have specialised binding/active sites that are specific for certain substrates
    -Once bound the substrate is modified
  • What is vmax?
    -The maximum rate at which an enzyme can carry out a reaction
  • What is the km?
    -Substrate concentration at which the enzyme will work at ½ Vmax
  • How can you alter enzyme activity?
    -By direct binding to active site
    -Using enzyme inhibitors which reduce or abolish enzyme activity
    -Can be reversible, irreversible, competitive & non-competitive
  • What is competitive inhibition?
    -The inhibitor will bind to an enzyme at the active site, competing with the substrate.
    -As a result, the KM will increase, and the Vmax will remain the same
  • What is non-competitive inhibition?
    -The inhibitor will bind to an enzyme at its allosteric site, away from the active site.
    -Binding affinity/inverse of KM of the substrate with the enzyme will remain the same
  • What is the most common therapeutic approach to enzyme control?
    -Inhibition
    -Most common & important drugs in medicine are enzyme inhibitors
  • Enzymes against infectious agents:
    -Enzymes that are found in bacteria and viruses which are not found in human cells can be targeted to treat infectious disease.
    -If enzymes produced by infectious agents can be switched off, this can be fatal for the bacteria or virus
    -Most bactericidal drugs target enzymes produced by bacteria that are not found, or are different, in humans
    -Viral enzymes can be targeted to prevent viral replication by targeting enzymes that are not found in humans
    -
  • What are DD Transpeptidases ?
    -Also known as penicillin binding protein (PBP)
    -Carries out crosslinking of peptidoglycan wall subunits for bacteria
    -Beta lactam antibiotics bind to and irreversibly inhibit DD Transpeptidase preventing building of new bacterial cell walls
  • How do bacteria counter the impact of beta lactam drugs?
    -Producing enzymatic defence systems
    -Beta lactamases responsible for some forms of antibiotic resistance
  • What is HIV Protease?
    -Activity central to HIV replication
    -Cleaves viral virion proteins required for formation of active virus
  • What is Atazanavir?
    -Inhibits HIV protease that cuts viral polyproteins into functional viral proteins
  • What is Remdesivir?
    -Binds to active site of RNA-dependent RNA polymerase
  • Targeting human enzymes:
    -Altering regulatory enzyme function will alter the physiological function downstream of that enzyme
    -Targeting enzyme function can be used to modulate human physiology
    -Changes in protein sequence, caused by mutations, leads to a host of human diseases due to altered enzymatic function
    -Drugs can be used to correct these changes
  • What are Cyclo-oxygenase inhibitors?
    -Inhibits the fatty acid cyclo-oxygenase (COX) enzyme
    -This group includes the 'traditional' NSAIDs and the more selective Coxibs
    -NSAIDs are among the most widely used of all medicines 50+ different examples on the global market.
    -Provide symptomatic relief from fever, pain and swelling in chronic joint disease, as well as in more acute inflammatory conditions
  • What is the role of Cyclo-oxygenase?
    -Responsible for the synthesis of prostaglandins
    -These are involved in inflammatory response
    -COX inhibitors reduce the synthesis of prostaglandins by inhibiting COX enzymes
  • What is COX-1?
    -Constitutive enzyme expressed in most tissue
    'housekeeping' role
    -Inhibited by aspirin & Ibuprofen
  • What is COX-2?
    -Inducible enzyme
    -Production of mediators of inflammation
    -Inhibited by aspirin, Ibuprofen & celecoxib (selectively)
  • What do COX inhibitor drugs do?
    -Inhibit COX enzymes & production of prostaglandin
    -Anti-inflammatory, antipyretic and analgesic effects
    -COX-2 selective drugs have less GI toxicity
  • Examples of COX inhibitor drugs?
    -Aspirin, Ibuprofen & Celecoxib
  • What is angiotensin converting enzyme (ACE)?
    -Involved in regulating the function of the kidney
    -Component of the renin-angiotensin system (RAS),which controls blood pressure by regulating the volume of fluids in the body.
    -Acts as a protease, cleaving angiotensin I and converting it into angiotensin II, the active form of the peptide
    -Various downstream consequences including increase water retention
  • ACE I & II
    -Angiotensin I is inactive but is converted by ACE to Angiotensin II
    -Angiotensin II is a potent vasoconstrictor.
  • How does Ramipril work?
    - Inhibits the proteolytic activity of ACE
    -Decreases the production of Angiotensin II, decreasing fluid retention resulting in lowered blood pressure
  • Why are protein kinases important?
    -Form an integral part of signalling cascades within the cell
    -They hydrolyse ATP, transferring the gamma phosphate onto other proteins
    -Covalent modification with phosphate groups modifies protein function
  • What is Bcr/Abl kinase?
    -Kinase domain that is hyperactive in chronic myelogenous leukaemia (CML)
  • How do molecules get across the membrane?
    -Passive diffusion
    -Facilitated diffusion
    -Primary active transport
    -Secondary active transport
  • What is passive transport?
    -No protein required, e.g. glycerol
  • What is facilitated diffusion
    -Protein required, substance flows along concentration gradient e.g. glucose transporters
  • What is primary active transport?

    -Protein required
    -Substance flows against concentration gradient
    -Energy required provided directly by ATP hydrolysis. e.g. Na+K+ATPase
  • What is secondary active transport?

    -Protein required -Substance flows against concentration gradient
    -Energy required & provided indirectly by ATP hydrolysis.
    -Gradient of ion used to couple transport (usually sodium)
    -Can be symport or antiport mechanism
  • What are the 3 transporter families?
    -Ion and pumps e.g., Sodium potassium ATPase
    -Metabolite
    -Neurotransmitters e.g., vascualr or plasma membrane
  • Pumps

    -4 types
    -3 used for ion transport
  • P-class pumps function:

    -Transport all types of ions
    -Each type of pump is specific to only one or two kinds of ions. -Some P-class pumps can transport more than one type of ion at a time, e.g. the Na+/K+ pump.
  • V class pumps function:
    -Only transport H+.
    -Have a very different structure to P-class pumps.
    -V-class pumps are normally used to maintain a low pH in vacuoles and lysosomes
  • F-class pumps function:

    -Only transport H+.
    -Transport protons down their electrochemical gradient, to power ATP synthesis, such as the ATP synthase pump found in mitochondria.
  • What are ABC (ATP Binding Cassette) Pumps ?
    -Superfamily pumps
    -A very diverse class of pumps which can transport all kinds of molecules, including polysaccharides and proteins.
    -All pumps in the ABC superfamily contain two transmembrane domains and two cytosolic domains which bind ATP.
  • CFTR -Cystic fibrosis transmembrane conductance regulator
    -Part of ABC family
    -The CFTR pump in the membrane of epithelial cells, which can cause cystic fibrosis if mutated.
  • Drug/Metabolite transporters:

    -31 families
    -Important drug targets
    -EXAMPLE: Chloroquine
  • Neurotransmitter transporters vesicular roles :
    -Vesicular inhibitory amino acid transporter.
    -Vesicular excitatory amino acid transporter.
    Vesicular amine transporters.
  • Neurotransmitter transporters in plasma membrane:
    -Located in pre-synaptic, postsynaptic & glial
    -NET- noradrenaline transporter
    -DAT- dopamine transporters
    -5-HT transporters
    -EAAT- excitatory amino acid transporters
    -GAT- GABA transporters
    -GlyT- glycine transporters