Eicosanoid, nitric oxide and inflammatory reactions Flashcards by Iseoluwa Ojo

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.

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Prostaglandins & related compounds

Examples: list 5

prostaglandins, prostacyclins, thromboxanes, leukotrienes, epoxyeicosatrienoic acids (EETs).

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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.

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Prostaglandins & related compounds are collectively known as ____________.

They are produced from ___________, a ___-C poly- unsaturated fatty acid

eicosanoids

arachidonic acid

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20-C poly- unsaturated fatty acid

__,____,____,____,- ___________ acid).

5,8,11,14

eicosatetraenoic

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PGE2 (_________________)

is an example of a prostaglandin.

prostaglandin E2

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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.

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Thromboxanes are similar to Prostaglandins but have instead a _________________ ring.

6-member

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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.

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Prostaglandins & related compounds

Another prostaglandin receptor, designated ______, is related to a family of ______ receptors with transcription factor activity.

PPARg

nuclear

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Prostaglandin receptors are specified by the same letter code. E.g.:

Receptors for E-class prostaglandins are ______.

Thromboxane receptors are designated _____.

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Multiple receptors for a prostaglandin are specified by subscripts (E.g., _____,______,_____ , etc.).

EP1, EP2, EP3

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Different receptors for a particular prostaglandin may activate different signal cascades.

T/F

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The fatty acid arachidonate is often ______ to ____ on C2 of ________- lipids, especially _______________

esterified

glycerophospho

phosphatidyl inositol.

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Arachidonate is released from _______ by _______ catalyzed by _______________

phospholipids; hydrolysis

Phospholipase A2.

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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

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Corticosteroids are anti-inflammatory because they prevent inducible ________ expression, reducing _________ release.

Phospholipase A2

arachidonate

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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

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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

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Phosphatidyl inositol signal cascades may lead to release of __________.

arachidonate

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After Phosphatidyl inositol is phosphorylated to ________, cleavage via ___________ yields __________ and _________

PIP2; Phospholipase C

diacylglycerol (and IP3).

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Arachidonate release from diacylglycerol is then catalyzed by ___________

Diacylglycerol Lipase.

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______ major pathways of eicosanoid metabolism.

Two

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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

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PGH2 Synthase is a _____-containing _______, bound to _____ membranes.

heme dioxygenase ER

A dioxygenase incorporates ____ into a substrate

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

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

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

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

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

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