Med Chem Part 1 Flashcards
true or false
inflammation is a normal process
true
it’s a normal response to noxious (harmful) stimuli that threaten the host
name the thing that initiates inflammation, and then the 4 steps that follow
-initial injury
1. histamine and prostaglandins released
- blood vessels dilate and clotting begins
- phagocytic cells attracted to the area by chemotactic factors
- phagocytes consume pathogen and cell debris
as mentioned, the initial injury is what triggers the first step of inflammation (histamine and prostaglandin release)
this initial injury can be what 5 stimuli?
physical stimuli
chemical stimuli
microbial stimuli
inflammatory stimuli
mitogenic stimuli
how are NSAIDS involved in preventing the inflammatory process?
they block the biosynthesis of prostaglandins from arachidonic acid
bc prostaglandins are the things responsible for pain, inflammation, and fever
the release of lysosomal enzymes during inflammation does what?
degrades the connective tissue
what catalyzes the conversion of arachidonic acid to prostaglandins?
COX (cyclooxygenase)
what is COX (cyclooxygenase)
an enzyme that catalyzes the formation of prostaglandins from arachidonic acid
what is the target for NSAIDS
COX
how many isoforms of COX are there?
3
COX-1
COX-2
COX-3
Where in the cell are COX enzymes located?
bound to the ER membrane
COX are ___ containing ___ enzymes
explain
heme containing bifunctional enzymes
bifunctional because COX possesses cyclooxygenase and peroxidase activity, BOTH of which are needed for the production of prostaglandins
what is the target of NSAIDS? how do they accomplish this?
the target of enzymes is COX activity.
they do this by competing with arachidonic acid for the COX active site
true or false
NSAIDS promote the synthesis of prostaglandins
FALSE - they inhibit.
these cause pain and inflammation and fever
how many active sites does COX have? what are they?
2
the cyclooxygenase active site and the peroxidase active site
explain the relationship between the 2 active sites of the COX enzyme
they are spacially distant but functionally intertwined
how is it that the cyclooxygenase active site and the peroxidase active site of COX are functionally intertwined?
because both pathways are needed for the production of prostaglandins
NSAIDS are useful for treating what?
acute pain and inflammation
osteoarthritis, rheumatoid arthritis
ankylosing spondylitis (arthritis that causes inflammation in spine and other areas)
painful shoulder
acute gouty arthritis
postoperative pain (in some scenarios)
what is the major pathway catalyzing the conversion of arachidonic acid into prostaglandins?
the COX (cyclooxygenase) enzyme system
_____ is converted into prostaglandins through the COX enzyme
arachidonic acid
explain the structure of prostaglandins. name 2 things
they contain a cyclopentane
they are lipophilic acids
where are prostaglandins produced?
locally - at the site of tissue damage
explain the half life of prostaglandins
very short - 1-5 mins
where is arachidonic acid located?
how is it released from this location for activity?
arachidonic acid is located as a component of the phospholipid cell membrane.
the enzyme PLA2 (phospholipase A2) hydrolyzes the phospholipid cell membrane, releasing arachidonic acid
as mentioned, PLA2 (phospholipase A2) is the enzyme that hydrolyzes the cell membrane to release arachidonic acid from it.
what process will increase the amount of PLA2?? What is the result of increased PLA2?
inflammatory cytokines like IL-1 will increase membrane bound PLA2 activity
this will in turn increase prostaglandin biosynthesis, through the increased release or arachidonic acid from the cell membrane
where is PLA2 located?
some is membrane bound, like arachidonic acid
explain the structure of a membrane phospholipid
glycerol + phosphatidic acid
glycerol has 3 hydroxyl groups
at 2nd hydroxyl group, arachidonic acid is attached
what is the chemical reaction catalyzed by PLA2 that releases arachidonic acid from the cell membrane?
hydrolysis
explain the structure of arachidonic acid
has 20 carbons
with 4 double bonds, all of which are CIS conformation
has terminal COOH (carboxylic acid group)
as mentioned, arachidonic acid contains 4 double bonds
at which positions are they and what conformations are they?
all are cis
5,8,11,14
give another name for arachidonic acid
eicosatetraenoic acid
arachidonic acid is a _____ acid
what is the relative half life?
lipophilic acid
very short half life
glycerol contains how many hydroxyl groups?
3
explain the full pathway of arachidonic acid metabolism by COX (after arachidonic acid is released from the cell membrane)
- Arachidonic acid is converted to Prostaglandin G2 through COX activity
- Prostaglandin G2 is converted to Prostaglandin H2 through PEROXIDASE activity
prostaglandin H2 is a MAJOR source of bioimportant prostaglandins
- Tissue-specific synthase enzymes convert prostaglandin H2 into 5 major bioactive prostaglandins
as mentioned, Prostaglandin H2 is a major source of bioimportant prostaglandins through tissue-specific synthase enzyme activity.
name these 5 makor bioactive prostaglandins.
PGE2
PGI2
PGD2
PGF2
TXA2
the 5 major bioactive prostaglandins are
PGD2
PGE2
PGF2
PGI2
TXA2
how do they exert their effects in the body?
by interacting with their respective prostaglandin receptors. they are G-protein coupled receptors (GPCRs)
PGE2 binds EP receptor
PGD2 binds DP receptor
PGF2 binds FP receptor
PGI2 binds IP receptor
TXA2 binds TP receptor
true or false
the 5 major bioactive prostaglandins exert their effects through binding to ligand gated ion channels
FALSE - through GPCRs
how is prostaglandin G2 produced
through COX1 and COX2 activity conversion of arachidonic acid to prostaglandin G2
explain in further detail the chemistry of the conversion of arachidonic acid to prostaglandin G2 (PGG2)
this occurs through COX1 and COX2 activity
needs 2 MOLECULAR OXYGEN**** (2O2)
Bis-oxygenation occurs to form the HIGHLY UNSTABLE PGG2
explain in further detail the chemistry of the conversion of PGG2 to PGH2 by Peroxidase activity
15-OOH, through the Peroxidase activity of COX, is reduced to 15-OH to produce PGH2
essentially peroxide (H2O2) becomes hydroxide (OH)
explain the difference between the target of NSAIDS vs acetaminophen
NSAIDS inhibit COX1 AND COX2 - the cyclooxygenase active site - prevents conversion of arachidonic acid to PGG2
acetaminophen inhibits the PEROXIDASE activity of COX - prevents conversion of PGG2to PGH2
true or false
NSAIDS inhibit the conversion of PGH2 to PGG2
false
inhibit conversion of arachidonic acid into PGG2
once PGG2 is converted to PGH2 through peroxidase activity, what happens to PGH2?
it’s converted into various major bioactive prostaglandins through different pathways
what enzyme converts PGH2 into PGE2?
PG endoperoxide E isomerase
what enzyme converts PGH2 into PGF2?
PG endoperoxide reductase
What enzyme converts PGH2 into PGD2
Glutathione-S-transferase
what major bioactive prostaglandin is responsible for uterine contraction
PGF2
what 2 major bioactive prostaglandins are responsible for being proinflammatory, swelling, and fever?
which additionally causes allergic reactions?
PGE2 and PGD2
PGD2 also responsible for allergic reactions
