Cell Biology and drug targets Flashcards
(220 cards)
1
Q
drug
A
any substance (other than food) with a know chemical structure that produces a biological effect when administered to a living organism
2
Q
medicinal product/drug product
A
anu drug substance or combination of drug substances together with added ingredients that is intended to treat, prevent, diagnose or relieve symptoms of a disease or abnormal condition
3
Q
drug target
A
a molecule in the body, typically a protein, that is intrinsically associated with a particular disease process and that could be targeted by a drug/medicinal product to reach a therapeutic effect
4
Q
example of a drug, drug product and drug target all within the same concept
A
salbutamol, used to treat asthma
ventolin, airomir, easyhaler and several other drug products all containing salbutamol
drug target = adrenergic beta-2 receptors in the alveoli (air sacs) in the lungs targeted by salbutamol
5
Q
what started things off before we could have the diverse species of life
A
oocyte containing DNA
6
Q
how are organ systems made up?
A
cells –> tissues –> organs –> systems
7
Q
what do all of the diverse cells in the body have?
A
a specific protein repertoire which form drug targets
8
Q
what form drug targets in the body?
A
all of the cells in the body having a specific protein repertoire
9
Q
why can cardiomyocytes for example be targeted by drugs?
A
they have receptors that are expressed in that specific tissue
10
Q
what do actin filaments do?
A
form a dynamic cytoskeleton to provide structural support to cells
11
Q
where is the cell membrane?
A
around the outside of cells
12
Q
components of the cell membrane
A
phospholipids (60%)
proteins (integral and peripheral) (40%)
other lipids (cholestrol)
13
Q
which proteins do drugs primarily target?
A
the proteins embedded in the cell membrane bilayer (70% of drugs target these)
14
Q
describe the structure of a phospholipid and the properties of these structures
A
head (phosphate group) is polar = hydrophilic
tails (fatty acids) are non-polar = lipophilic
15
Q
which part of a phospholipid is polar and which part is non-polar? words for this?
A
head (phosphate group) is polar = hydrophilic
tails (fatty acids) are non-polar = lipophilic
16
Q
what do phospholipids do in the cell membrane?
A
form the phospholipid bilayer
17
Q
what does the phospholipid bilayer surround?
A
all mammalian cells
18
Q
list the properties of the cell membrane
A
- provides structural support
- asymmetric and dynamic
- selective permeability barrier
- communicaton
19
Q
describe and give examples of molecules that can pass through the phospholipid bilayer
A
small polar (e.g - H2O, EtOH) and any non-polar molecules (O2, CO2, lipid soluble molecules such as cortisol and benzene) can pass through the lipid bilayer and thus diffuse into the cell down the concentration gradient
20
Q
how do small polar and non-polar molecules pass into the cell and why?
A
they diffuse into the cell down the concentration gradient since they can pass through the lipid bilayer
21
Q
what type of transport is diffusion?
A
passive
22
Q
give examples of molecules that can’t pass through the phospholipid bilayer via diffusion
A
charged particles (Na+, K+, Ca^2+)
large polar molecules (glucose, neurotransmitters)
23
Q
how are charged particles and large polar molecules passed through the cell membrane?
A
proteins allow the transport of them since they’re still required for life
24
Q
what is H2O an example of?
A
a small polar molecule that can pass through the phospholipid bilayer
25
what are O2, CO2, cortisol and benzene examples of?
non-polar molecules (cortisol and benzene are lipid soluble)
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what are glucose and neurotransmitters examples of?
large polar molecules
27
what is cholestrol?
the structural molecule of the cell membrane
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structural molecule of the cell membrane
cholesterol
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what does cholesterol do?
provides structure to the cell membrane and stops it moving so much
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how do we know that cholesterol is a structural molecule in the cell?
parts of the cell membrane that are enriched with cholesterol can't move as much
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mitochondria
the cell's power houses
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how many mitochondria in each cell?
1000s/size of bacterium
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describe the structure of mitochondria and explain why this is important
double membrane structure that's important in oxidative phosphorylation which is how ATP is generated
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what are mitochondria important for?
aerobic respiration
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what happens during aerobic respiration?
atp is created to power reactions in the cell
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what do mitochondria contain enzymes for?
the krebs cycle
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what goes in and what comes out of mitochondria?
nutrients and O2 in, energy (ATP, GTP) and CO2 out
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how much ATP can one molecule of glucose generate and through which process?
24 ATP
aerobic respiration
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where do the food molecules for mitochondria come from?
cytosol
40
what is the nucleus of a cell surrounded by and why?
a nuclear envelope to stop things from getting in and out easily
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how many membranes make up the nuclear envelope surrounding the nucleus of a cell?
two
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list the things that the nuclear envelope surrounding the nucleus of a cell contains
nuclear pores
chromatin
endoplasmic reticulum
nucleolus
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role of nuclear pores in the nuclear envelope
allow material in and out of the nucleus (e.g- mRNA)
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example of something important that nuclear pores allow in and out of the nucleus
mRNA
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what is chromatin?
combination of DNA and proteins that make up the genetic contents of the nucleus of a cell
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what makes up the genetic contents of the nucleus of a cell?
chromatin
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what does chromatin do to DNA and why is this important?
packages it into a smaller volume to help prevent DNA damage
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what packages DNA into a smaller volume to help prevent DNA damage?
chromatin
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where is the endoplasmic reticulum found and what does it do?
attached and sits outside nucleus
main site of protein synthesis
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describe the nucleolus of the nucleus of a cell
non-membrane bound structure (25% total volume of nucleus) made of proteins and nucleic acids
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what does the nucleolus of a cell contain predominantly and why?
rRNA since it produces ribosomes
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which part of the nucleus of a cell contains predominantly rRNA and why?
nucleolus
it produces ribosomes
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what is the other thing apart from ribosome production that the nucleolus of a nucleus is involved in?
mRNA export/degradation
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two things the nucleolus of a nucleus is involved in
produces ribosomes
involved in mRNA export/degradation
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what is the central dogma of molecular biology?
the flow of genetic information within a biological system
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state the central dogma of molecular biology
DNA makes RNA, and RNA makes protein
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what contains all of the genetic material?
DNA
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stages in going from DNA to protein
RNA synthesis (transcription)
RNA to protein (translation)
post-translational modification
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what does RNA polymerase from?
from DNA to RNA
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where would RNA polymerase be found?
the nucleus
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what is DNA made up of?
sugar phosphate backbone and hydrogen bonded base pairs
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where would RNA be converted into a protein?
ribosomes
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where does post-translational modification take place?
ER and golgi
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what is a protein made up of?
amino acids
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transcription vs translation
transcription = RNA synthesis from DNA
translation = RNA to protein
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RNA synthesis from DNA
transcription
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RNA to protein
translation
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what happens at ribosomes?
rna to protein
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where are ribosomes found?
endoplasmic reticulum
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what happens at the ER and golgi?
post-translational modification
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give all the differences between DNA and RNA
RNA has uracil instead of thymine
base pair up to make double strand in DNA
DNA only found in nucleus and mitochondria and every time the cell divides it makes more
RNA found outside the nucleus and is associated with ribosomes
RNA can't make RNA but DNA can make RNA
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what's found at the endoplasmic reticulum?
ribosomes
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different base in RNA to DNA
uracil instead of thymine in RNA
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where is the only place DNA is found in a cell?
nucleus and mitochondria
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where is RNA found?
outside the nucleus and is associated with ribosomes
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intermediate between DNA and protein
mRNA
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list all of the stages in going from DNA to protein
1. chromatin remodelling
2. transcription
3. RNA processing
4. mRNA stability
5. translation
6. post-translational modification
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what happens during RNA processing?
the primary transcript (pre-mRNA) is converted into mature mRNA
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what happens during the mRNA stability stage of going from DNA to protein? explain
degraded mRNA is discarded (mRNA life span varies)
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describe how translation happens
base pairs in mRNA are recognised by ribosome (3 base pairs = 1 amino acid)
ribosome reads along mRNA and adds correct amino acid onto the chain
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examples of post-translational modification
phosphorylation
lipidation
ubiquitination
disulfide bond
acetylation
glycosylation
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describe where the different stages of going from DNA to a protein occur in a cell
chromatin remodelling, transcription and RNA processing = nucleus
mRNA stability, translation and post-translational modification = cytoplasm
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what does post-translational modification involve?
folding the peptide correctly to make a protein
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what type of modifications can we have during post-translational modification? explain
non-covalent interactions - folding and cofactor binding
covalent modification - glycosylation, phosphorylation, acetylation, binding to other protein subunits
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what happens during all post-translational modification and where does it happen?
mature the protein to make it work
happens in golgi apparatus
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phosphorylation (post-translational modification)
adds a phosphate to serine, threonine or tyrosine
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lipidation (post-translational modification)
attaches a lipid, such as a fatty acid, to a protein chain
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ubiquitination (post-translational modification)
adds ubitquitin to a lysine residue of a target protein marking it for destruction
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disulfide bond (post-translational modification)
covalently links the "S" atoms of two different cysteine residues (pair of cystines)
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acetylation (post-translational modification)
adds an acetyl group to the N-terminus of a protein to increase stability
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glycosylation (post-translational modification)
attaches a sugar, usually to an "N" or "O" atom in an amino acid side chain
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describe and give all of the stages of protein traffic
1. protein synthesis on bound ribosomes and transport into the ER for folding by chaperone proteins, formation of disulfide bridges, glycosylation etc
2. budding and fusion of ER vesicles to Golgi network (secreted and membrane proteins only)
3. progression across the golgi network
4. sorting to lysosomes
5. transport of membrane proteins to cell membrane
6. regulated secretion - proteins transported to cell surface to be used
93
common drug targets
receptors
ion channels
enzymes
transporters (carrier molecules)
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where are most drug targets?
embedded in the cell membrane
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which common drug targets are embedded in the cell membrane?
receptors (e.g - GPCRs)
ion channels
transporters
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which common drug targets are found in the cytosol?
enzymes
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where are enzyme drug targets found?
cytosol
98
where are receptors, ion channels and transporter drug targets found?
embedded in the cell membrane
99
explain how ion channels can act as drug targets
conformational change in the channel increases ion conductance
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how many drug targets are there in just one cell type?
a lot
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what do different drugs target?
different proteins and enzymes
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what do most drugs interfere with?
cellular communication
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how do drugs interfere with cellular communication?
either mimic or modulate communication
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drugs mimicing cellular communication
do what the cell does but maybe better
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drugs modulating cellular communication
switching off signalling from that cell
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types of cellular communication
intercellular
intracellular
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intercellular communication
communication between cells
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communication between cells
intercellular communication
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intracellular communication
communication within cells
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communication within cells
intracellular communication
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what do both inter and intracellular communication result in?
a change in biological outcome
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what is the intracellular signalling pathway?
when something binds on the outside causing a change within the cell
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where can drugs affect in the intracellular signalling pathway?
a number of points but they mostly affect the opening step (ligand and receptor)
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opening step of the intracellular signalling pathway
ligand and receptor
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how do drugs affect the ligand and receptor stage of the intracellular signalling pathway?
drugs can affect how a ligand binds to the receptor or bind to the receptor itself and this affects signalling pathways by switching it on or off, making it bigger or smaller etc, which is ultimately going to change the functional response
116
what happens when a drug affects the intracellular signalling pathway?
ultimately is going to change the functional response
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example of a drug affecting the intracellular pathway
salbutamol binding to a receptor in an air sac which changes the functional response of the cell
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intracellular signalling
the mechanism by which the binding of a drug (single molecule) causes a change in biological function
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the mechanism by which the binding of a drug (single molecule) causes a change in biological function
intracellular signalling
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what do drugs do to the different stages of intracellular signalling?
increase or decrease different steps, therefore causing a change in biological function
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result of intracellular signalling on a metabolic enzyme
altered metabolism
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result of intracellular signalling on a gene regulatory protein
altered gene expression
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result of intracellular signalling on a cytoskeletal protein
altered cell shape or movement
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is intracellular signalling fast or slow?
can be both
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example of fast intracellular signalling
muscle contraction
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example of slow intracellular signalling
altering protein synthesis, such as with steroids
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what can receptor proteins used in intracellular signalling be?
cell-surface receptors or intracellular receptors
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what happens when a ligand binds to a receptor protein in intracellular signalling?
causes an effect in the cell
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examples of effects on cells from cell-surface receptors binding to a ligand
effect histamine on acid release
effect insulin on fat cells
effect adrenaline on heart
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examples of effect on cells from intracellular receptors binding to ligands
effect testosterone on muscle development
effect thyroid hormone on energy expenditure
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extracellular
outside
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intracellular
inside
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are receptor proteins always on the cell surface?
no, sometimes ligands can get across the cell membrane and aren't targeting the cell surface receptors
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what does protein phosphorylation do?
changes the function of the protein
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what does protein kinase do?
takes a phosphate from ATP and adds it to the protein of interest
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what does protein phosphatase do?
the opposite of protein kinase - removes a phosphate from the protein of interest
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what is protein phosphorylation all based around?
the phosphorylation of 3 specific residues on a protein - Ser, Thr and Tyr
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what can take a phosphate from ATP and add it to the protein of interest and what does the opposite?
protein kinase
protein phosphatase
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what can the addition of phosphates to proteins do and how?
change protein functionality
increase/decrease activity
generate binding sites
targeting for degradation
= changes in the cell
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how can adding phosphates to proteins change protein functionality and ultimately cause changes in the cell?
increase/decrease activity
generate binding sites
targeting for degradation
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list the different ways that the ligand that's binding to the surface protein in intercellular signalling can be presented to the cell
contact-dependent
paracrine
synaptic
endocrine
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contact-dependent intercellular signalling
the signal cell contains a membrane-bound signal that activates another receptor on a target cell
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paracrine intercellular signalling
mediator released and goes into signalling cell that then produces mediators that go on to effect target cells
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synaptic intercellular signalling
electrical signal runs along the axon and releases neurotransmitters to activate the target cell (released into a small area around target cell)
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endocrine intercellular signalling
endocrine cell releases hormone into bloodstream which binds to its target receptor on the target cell
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example of endocrine intercellular signalling
insulin released from pancreatic cells and tries to find fat cells and cause a release of glucose
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what type of signalling is intercellular signalling?
long-range
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is intercellular signalling fast or slow?
can be both
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example of slow long range intercellular signalling
endocrine signalling
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example of fast long range intercellular signalling
synaptic signalling
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does each molecule give one signal?
no, each molecule can give a variety of signals
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example of a molecule that provides a variety of signals
acetylcholine
153
explain how acetylcholine provides a variety of signals
binds to heart muscle cell = decreased rate and force of attraction
binds to skeletal or smooth muscle cell = contraction
binds to salivary gland cell = secretion
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how come acetylcholine provides a variety of signals in different cells?
because it binds to different receptors which are different in different cells
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why is drug selectivity important?
since it can provide a variety of signals in different cells and we want it to only bind to the receptor that will cause the desired effect in a cell
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why can't we use random drugs for targeting specific cells? explain
each drug provides a variety of signals in different cells since they can bind to different receptors in different cells
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what is the essence of pharmacology?
finding a drug that only binds to the one receptor we want
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what is proranolol?
a beta blocker to reduce heartrate and stop adrenaline from binding
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explain the variety of signals that the singular molecule adrenaline can cause
when it binds to receptors in the heart it stimulates it to pump more blood around the body
when it binds to receptors in the lungs it relaces the airway so that more oxygen gets into the lungs
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what does adrenaline do to the heart and how?
binds to receptors in the heart and stimulates it to pump more blood around the body
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what does adrenaline do to the lungs and how?
binds to receptors in the lungs and relaxes the airways so that more oxygen gets into the lungs
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what can happen when the lungs can get more oxygen in due to adrenaline?
heart can pump more oxygen around the body
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why can't we just give someone adrenaline to relax their airways?
since adrenaline also stimulates the heart by binding to receptors in the heart
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what does salbutamol bind to?
beta 1 receptors
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what does propranolol bind to?
beta 2 receptors
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what's the difference between salbutamol and propranolol?
they bind to different proteins on the surface of these cells
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is salbutamol an agonist or antagonist?
agonist
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is propranolol an agonist or antagonist?
antagonist
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what does propranolol do?
binds to receptors and stops adrenaline from binding (antagonist). adrenaline is an agonist and can't bind anymore
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is adrenaline an agonist or antagonist?
agonist
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what does salbutamol do?
activates the receptor and makes more adrenaline bind
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what type of proteins do drugs target the most?
G protein-coupled receptors
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GPCRs
G protein coupled receptors
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how many different types of GPCRs are there in the human genome?
approximately 800 different types
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what do over a half of GPCRs play a role in?
sensory functions (taste, light, smell)
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what do the remaining GPCRs that don't play a role in sensory functions do?
they mediate signalling by ligands
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why are G protein coupled receptors important?
major drug targets in clinical usage
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what do 30% of drugs target?
GPCRs
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why are GPCRs called this?
they couple to G proteins
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why are G proteins called this?
they bind to small molecules called Guanine nucleotides (e.g - GTP)
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what do G proteins bind to?
small molecules called guanine nucleotides
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example of a guanine nucleotide
GTP
183
do GPCRs all work in a similar way?
yes
184
summarise how G protein activation occurs
activated GPCR (bound to ligand)
G protein binds to GTP
G protein is activated
G protein can go off and do things for cellular function
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give some examples of types of G proteins and what they do
Gs (alpha) - activation adenylyl cyclase
Gi (alpha) - inhibition adenylyl cyclase
Gq (alpha) - activation phospholipase C
Gi (beta gamma) - opening ion channels (K+)
186
what do we call the protein that happens with G protein coupled receptors?
an intracellular cascade
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explain what happens when receptors in the heart bind adrenaline
Gs (alpha) receptor (beta - adrenergic receptors) bind adrenaline = Gs protein is activated and binds to AC and releases cAMP which causes a protein (PKA) to be synthesised
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simplified stages of the intracellular cascade with G protein coupled receptors
1st messenger
1st effector
2nd messenger
2nd effector
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what does the first messenger do in the intracellular cascade?
binds to cell surface
190
what does a G protein bind to?
1st effector
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what is released from a G protein?
2nd messenger
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propranolol
beta blocker to reduce heartrate
193
how does propranolol reduce heartrate?
adrenaline can't bind to the G-protein coupled receptor = no intracellular cascade
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where are different receptors found?
in different tissues
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how does salbutamol activate the lungs?
there are beta 2 receptors in the lungs that would activate the intracellular cascade
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what does salbutamol do?
activates the lungs
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how do salbutamol and propranolol behave differently?
propranolol stops the intracellular cascade, salbutamol activates it
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what are activated by GPCRs?
intracellular signalling cascades
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why are intracellular signalling cascades such complicated systems? explain
to amplify what's happening. the first messenger amplifies what happens to the second effector.
200
explain the intracellular signalling cascade with Gq (alpha)
activates a different type of effector (PLC) which causes a generation of a different type of messenger (DAG) = activates a different protein but similar pathway still
201
which G protein coupled receptor does the opposite to Gs (alpha)?
Gi (alpha)
202
describe and explain the intracellular signalling cascade with the Gi (beta gamma) GPCR
Gi protein
beta-gamma subunits separate from the Gi protein and are able to signal themselves and bind to K+ channels
opens K+ channels
more difficult to depolarise the cell
muscle relaxation
203
explain how the Gi beta-gamma GPCR binding to K+ channels causes muscle relaxation
opens K+ channels = more difficult to depolarise the cell = muscle relaxation
204
give 4 examples of therapeutically used drugs that target G protein-coupled receptors
propranolol
salbutamol
atropine
cimetidine
205
antagonist
opposes a certain action
205
agonist
creates a certain action
205
something that opposes a certain action
antagonist
206
something that creates a certain action
agonist
207
propranolol - antagonist or agonist?
antagonist
208
salbutamol - antagonist or agonist?
agonist
209
atropine - antagonist or agonist?
antagonist
210
cimetidine - antagonist or agonist?
antagonist
211
explain how propranolol orks
blocker of the Gs coupled Beta-adrenergic receptor. stops the effects of adrenaline on the heart (used for high blood pressure and panic attacks)
212
what does propranolol block?
the Gs coupled beta-adrenergic receptor
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what does salbutamol do?
agonist of the Gs coupled beta 2-adrenergic receptor. mimics the action of adrenaline on lungs (used in asthsma)
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what is salbutamol used in?
asthsma
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what does atropine do? how?
blocker of the muscarinic coupled acetylcholine receptor (mAchR)
blocks effects acetylcholine on heart, dilates pupils and inhibits secretion
216
what does atropine block?
the muscarinic coupled acetylcholine receptor (mAchR)
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what does cimetidine do and how?
competitive antagonist of the Gs coupled H2 receptor, blocks acid secretion in stomach
218
how does cimetidine block acid secretion in the stomach?
competitive antagonist of the Gs coupled H2 receptor
