Eicosanoid, nitric oxide and inflammatory reactions Flashcards
Prostaglandins & related compounds:
“local hormones” synthesized from the _________________.
They have specific effects on target cells close to their site of formation.
They are (slowly or rapidly?) degraded, so they are _________________
polyunsaturated fatty acid arachidonate
Rapidly
not transported to distal sites within the body.
Prostaglandins & related compounds
Examples: list 5
prostaglandins, prostacyclins, thromboxanes, leukotrienes, epoxyeicosatrienoic acids (EETs).
Prostaglandins & related compounds:
Has Roles in _________, _________, regulation of __________ , blood ________, ____________ modulation, control of reproductive processes & tissue growth, ___________ cycle regulation.
inflammation
fever
blood pressure
clotting
immune system
sleep/wake cycle regulation.
Prostaglandins & related compounds are collectively known as ____________.
They are produced from ___________, a ___-C poly- unsaturated fatty acid
eicosanoids
arachidonic acid
20
20-C poly- unsaturated fatty acid
=
__,____,____,____,- ___________ acid).
5,8,11,14
eicosatetraenoic
PGE2 (_________________)
is an example of a prostaglandin.
prostaglandin E2
Prostaglandins
•all have a ________ ring.
A letter code is based on __________ (e.g., ______ or _____ groups).
A subscript refers to the ___________________
cyclopentane
ring modifications; hydroxyl or keto
number of double bonds in the two side-chains.
Thromboxanes are similar to Prostaglandins but have instead a _________________ ring.
6-member
Prostaglandins & related compounds are transported out of the cells that synthesize them.
Most affect other cells by interacting with plasma membrane _____________________.
Depending on the cell type, the activated _________ may stimulate or inhibit formation of ______, or may activate a _________ signal pathway leading to intracellular __________
G-protein coupled receptors
G-protein; cAMP; phosphatidylinositol
Ca++ release.
Prostaglandins & related compounds
Another prostaglandin receptor, designated ______, is related to a family of ______ receptors with transcription factor activity.
PPARg
nuclear
Prostaglandin receptors are specified by the same letter code. E.g.:
Receptors for E-class prostaglandins are ______.
Thromboxane receptors are designated _____.
EP
TP
Multiple receptors for a prostaglandin are specified by subscripts (E.g., _____,______,_____ , etc.).
EP1, EP2, EP3
Different receptors for a particular prostaglandin may activate different signal cascades.
T/F
T
The fatty acid arachidonate is often ______ to ____ on C2 of ________- lipids, especially _______________
esterified
OH
glycerophospho
phosphatidyl inositol.
Arachidonate is released from _______ by _______ catalyzed by _______________
phospholipids; hydrolysis
Phospholipase A2.
Phospholipase A2.
This enzyme hydrolyzes the ______ linkage between a ________ and the ____________ of the ______ backbone, releasing the ___________ & a _________ as products.
ester; fatty acid
OH at C2
glycerol
fatty acid; lysophospholipid
Corticosteroids are anti-inflammatory because they prevent inducible ________ expression, reducing _________ release.
Phospholipase A2
arachidonate
There are multiple Phospholipase A2 enzymes, subject to activation via different signal cascades.
The inflammatory signal , ___________ is involved in activating some Phospholipase A2 variants.
platelet activating factor
Attempts have been made to develop drugs that ________________________, for treating inflammatory diseases.
Success has been limited by the __________________, and the fact that arachidonate may give rise to _________ or _____________ eicosanoids in different tissues.
inhibit particular isoforms of Phospholipase A2
diversity of Phospholipase A2 enzymes
inflammatory or anti-inflammatory
Phosphatidyl inositol signal cascades may lead to release of __________.
arachidonate
After Phosphatidyl inositol is phosphorylated to ________, cleavage via ___________ yields __________ and _________
PIP2; Phospholipase C
diacylglycerol (and IP3).
Arachidonate release from diacylglycerol is then catalyzed by ___________
Diacylglycerol Lipase.
______ major pathways of eicosanoid metabolism.
Two
Cyclic pathway:
•_____________ catalyzes the committed step in the “cyclic pathway” that leads to production of ________,_______, and _____________.
Different cell types convert PGH2 to different compounds.
Prostaglandin H2 Synthase
prostaglandins, prostacyclins, & thromboxanes
PGH2 Synthase is a _____-containing _______, bound to _____ membranes.
heme
dioxygenase
ER
A dioxygenase incorporates ____ into a substrate
O2
PGH2 Synthase exhibits 2 activities:
_____________ and ___________
cyclooxygenase &peroxidase.
PGH2 Synthase is sometimes referred to as ____________, abbreviated ______.
Cyclooxygenase
COX
The interacting cyclooxygenase and peroxidase reaction pathways are complex.
T/F
T
A peroxide job is to _______ the _______
The product (________) accepts an electron from a nearby _____________
The resulting ____________ is proposed to extract a ___ atom from _______, generating a radical species that reacts with _____.
oxidizes; heme iron.
oxidized heme; tyrosine residue (Tyr385).
tyrosine radical ; H; arachidonate
O2
The signal molecule ·NO (nitric oxide) may initiate prostaglandin synthesis by reacting with ___________ to produce ____________, which —————— enabling electron transfer from the active site ________.
superoxide anion (O2·)
peroxynitrite
oxidizes the heme iron
tyrosine
Prostaglandin synthesis in response to some inflammatory stimuli is diminished by inhibitors of Nitric Oxide Synthase.
T/F
T
Membrane- binding domain:
____ (short or long?) ________ -______ that insert into one leaflet of the bilayer, facing the ____________.
4 short amphipathic -helices
ER lumen
Arachidonate, derived from membrane lipids, approaches the heme via a _______ channel extending from the ____________
In the image above, the channel is occupied by an inhibitor, an ibuprofen analog.
hydrophobic
membrane-binding domain.
Non-steroidal anti-inflammatory drugs (NSAIDs), such as ______ and derivatives of _________, inhibit _______ activity of ________
aspirin
ibuprofen
cyclooxygenase
PGH2 Synthase.
Non-steroidal anti-inflammatory drugs (NSAIDs)
They inhibit formation of prostaglandins involved in ______,_______, and ———-
They inhibit blood clotting by blocking _________ formation in blood platelets.
fever, pain, & inflammation.
thromboxane
Non-steroidal anti-inflammatory drugs (NSAIDs)
Ibuprofen and related compounds block the ______________ by which _________ enters the cyclooxygenase active site.
hydrophobic channel
arachidonate
Aspirin ________ a ________ group near the active site, preventing arachidonate binding.
The inhibition by aspirin is (reversible or irreversible?) .
However, in most body cells _________________ would restore cyclooxygenase activity.
acetylates
serine hydroxyl
irreversible
re-synthesis of PGH2 Synthase
Many people take a daily aspirin for its _________ effect, attributed to inhibition of __________ in blood platelets.
anti-clotting
thromboxane formation
Thromboxane A2 stimulates blood platelet _________, essential to the role of platelets in ___________
aggregation; blood clotting.
This effect of aspirin is (short or long?) -lived because ______________________________________________.
Long
platelets lack a nucleus and do not make new enzyme
Two isoforms of PGH2 Synthase are ______ and ______ (_________________________)
COX-1 & COX-2 (Cyclooxygenase 1 & 2)
Two isoforms of PGH2 Synthase are COX-1 & COX-2
COX-1 is constitutively expressed at (low or high?) levels in many cell types.
COX-2 expression is stimulated by _____,________, and ________
Low
growth factors, cytokines, and endotoxins.
COX-1 is essential for ________ formation in blood platelets, and for maintaining ——— of the gastrointestinal epithelium.
thromboxane
integrity
COX-2 levels _____ease in inflammatory diseases such as arthritis. Inflammation is associated with ___-regulation of COX-2 & ____eased amounts of particular prostaglandins.
incr
up
incr
COX-2 expression is increased in some cancer cells.
_________, which is essential to tumor growth, requires COX-2.
Overexpression of COX-2 leads to increased expression of _____
Regular use of NSAIDs has been shown to decrease the risk of developing ______ cancer.
Angiogenesis
VEGF
colorectal
Most NSAIDs inhibit both COX I & COX II.
T/F
T
Selective COX-2 inhibitors have been developed,
e.g., _______ and ______
Celebrex and Vioxx.
COX-2 inhibitors are anti-inflammatory & block pain, but are (more or less?) likely to cause gastric toxicity associated with chronic use of NSAIDs that block COX-1.
Less
A tendency to develop blood clots when taking some of these drugs has been attributed to:
•decreased production of an anti-thrombotic (clot blocking) prostaglandin (________) by endothelial cells lining small blood vessels
•lack of inhibition of COX-__-mediated formation of _________________________________ in platelets.
PGI2
1
pro-thrombotic thromboxanes
Some evidence suggests the existence of a third isoform of PGH2 Synthase, designated COX-3, with roles in _____________________, and subject to inhibition by ___________________
mediating pain and fever
acetaminophen (Tylenol).
Acetaminophen has (little or major?) effect on COX-1 or COX-2, and thus lacks _________ activity.
Little ; anti-inflammatory
The 1st step of the Linear Pathway for synthesis of leukotrienes is catalyzed by __________.
Lipoxygenase
Mammals have a family of Lipoxygenase enzymes that catalyze _______________________________________________ at different sites.
Many of the products have signal roles.
oxygenation of various polyunsaturated fatty acid
5-Lipoxygenase, found in __________, catalyzes conversion of _________ to __________ , which is converted to _______________, which in turn may be converted to various other leukotrienes.
leukocytes
arachidonate to 5-HPETE
leukotriene-A4
5-HPETE
=
???
5-hydroperoxy- eicosatetraenoic acid
A ___________ is the prosthetic group of Lipoxygenase enzymes.
non-heme iron
Lipoxygenase enzymes
Ligands to the Fe include 3 _____ atoms & the _______________.
The arachidonate substrate binds in a _________ pocket, adjacent to the ________________
O2 is thought to approach from the ___________ of the substrate than the iron, for a ________ reaction.
His N
C-terminal carboxylate O
hydrophobic ; catalytic iron atom.
opposite side ; stereospecific
Lipoxygenase reaction starts with extraction of ____ from ________, with transfer of the electron to the iron, reducing it from ______ to ______
The resulting fatty acid radical reacts with ______ to form a __________ group.
H; arachidonate
Fe3+ Fe2+.
O2; hydroperoxy
Leukotrienes have roles in inflammation and induce asthmatic _______________________
Some leukotrienes act via specific G-protein coupled receptors (GPCRs) in the plasma membrane.
constriction of the bronchioles.
Anti-asthma medications include:
inhibitors of 5-Lipoxygenase, e.g., _______(____________)
drugs that block leukotriene-receptor interactions.
E.g., ____________(_______) , _______(________)
Zyflo (zileuton)
Singulair (montelukast) & Accolate (zafirlukast)
Anti-asthma medications include:
_____________________, e.g., Zyflo (zileuton)
drugs that ______________________
E.g., Singulair (montelukast) & Accolate (zafirlukast)
inhibitors of 5-Lipoxygenase
block leukotriene-receptor interactions.
5-Lipoxygenase requires the membrane protein ________ (______________).
This membrane protein binds _________, facilitating its interaction with the enzyme.
FLAP
5-lipoxygenase-activating protein
arachidonate
A complex including ____________, FLAP, & ______________ forms in association with the ______________ during leukotriene synthesis in leukocytes.
5-Lipoxygenase
Phospholipase A2
nuclear envelope
A beta- barrel domain at the ____-terminus of _________ enzymes has a role in membrane binding.
N
Lipoxygenase
Cytochrome P450 epoxygenase pathways:
_______________(EETs) and _____________ acids are formed from arachidonate by enzymes of the ___________ family.
Epoxyeicosatrienoic acids
hydroxyeicosatrienoic
cytochrome P450
EETs are modified by additional enzyme-catalyzed reactions to produce many distinct compounds.
T/F
T
EETs
They may be incorporated into ________, and released by action of __________.
phospholipids; phospholipases
EETs have roles in regulating cellular ________, _________ , ________ secretion, & various signal pathways relevant to cardiovascular and renal functions.
proliferation
inflammation
peptide hormone
Eicosanoids
(Localized or Generalized ?)
(short or long?) -lived hormone-like activities
Duration =_______
Very (low or high?) cellular concentrations
Action initiated by signal transduction
Like hormones
Localized
Short ; a few seconds
Low
Prostaglandin synthase = _____
Has _______ and ———- activity
Forms ____-membered cyclic structure
COX
Oxygenase and peroxidase
five
PG____ and PG____: in sleep center in brain
PG___: promotes sleep
PG_____: induces wakefulness
E2; D2
D2
E2
Painkillers
Nonsteroidal anti-inflammatory drug = NSAID
Inhibition of ______ and ______
Acetaminophen: inhibits ____
Side effects: _____ problems
COX-1 and COX-2
COX-3
gastric
COX inhibitors
More selective for COX-____, not on COX-____
Rheumatoid arthritis, osteoarthritis, and acute pain
May increase risk of ———- and ____
2; 1
heart attack and stroke
Leukotrienes
Cause ______ of smooth muscle
Especially in ______
contraction
lungs
Leukotrienes
Asthma attack and allergic reaction
May be caused by ______________
overproduction of leukotriene
What is Nitric Oxide?
First described in 1979 as a potent _______ of peripheral vascular smooth muscle.
Used by the body as a _________
Serves different functions depending on body system. i.e. ________,______,______
relaxant
signaling molecule.
neurotransmitter, vasodilator, bactericide.
First gas known to act as a biological messenger is???
Nitric Oxide
Nitric Oxide is an Environmental Pollutant
T/F
T
Nitric oxide is (Short or Long?) lived, usually degraded or reacted within ____________
Short
a few seconds
The natural form of nitric oxide is a _____
gas
This reaction is catalyzed by ____________, a 1,294 aa enzyme
nitric oxide synthase
Activation of NOS
Glutamate neurotransmitter binds to ______ receptors
_______ channels open causing ________ into cell
Activation of _________, which activates NOS
Mechanism for start of synthesis dependent on body system
NO synthesis takes place in endothelial cells, lung cells, and neuronal cells
NMDA
Ca++; Ca influx
calmodulin
Types of NOS
NOS I
Central and peripheral neuronal cells
Ca+2 (dependent or independent?) , used for __________
NOS II
Most ______ cells, particularly ________
(dependent or independent?) of intracellular Ca+2
Inducible in presence of inflammatory cytokines
dependent ; neuronal communication
nucleated; macrophages
independent
Types of NOS
NOS III
Vascular endothelial cells
Ca+2 (dependent or independent ?) Vascular regulation
dependent
What is the role of Nitric Oxide in the human body?
Nitric Oxide in the human body has many uses which are best summarized under five categories.
NO in the ___________ system
NO in the ___________ system
NO in the ___________ system
NO in the ___________ system
NO in the ___________ system
NO in the nervous system
NO in the circulatory system
NO in the muscular system
NO in the immune system
NO in the digestive system
