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48 Cards in this Set
- Front
- Back
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What are eicosanoids derived from?
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Arachidonic acid
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What is the major storehouse for arachidonic acid?
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Phosphatidylinositol (AA is esterified at the C2 position)
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How are phospholipids different than triglycerides?
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They have a phosphate group (or modifications, thereof) esterified to C3 instead of a fatty acid.
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What is the initial precursor to a phospholipid that is derived from glycerol?
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DHAP reduction (via NADH) leads to the production of glycerol-3-phosphate.
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Where does de novo synthesis of phosphatidic acid occur?
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In endoplasmic reticulum and outer mitochondrial membrane.
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How is phosphatidic acid formed?
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It's formed by the addition of two fatty acids (from acyl CoA derivatives) onto glycerol-3-phosphate.
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What is typical about the fatty acid components of phosphatidic acid?
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C1 has saturated fatty acid esterified. C2 typically has an unsaturated fatty acid.
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How is lysophosphatidic acid formed and what is its significance?
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The most basic mechanism by which it is formed is by the addition of a fatty acid to the C1 (typical) or C2 position of glycerol-3-P via a fatty acyl CoA. Besides being a precursor to phosphatidic acid, it is an important signalling molecule for PPARgamma receptors (upregulates adipogenesis and lipid storage genes) and cell surface LPAR receptors (affect cytoskeleton reorganization).
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Describe phosphatidates and name some important classes.
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Phosphatidates are phospholipids that are derivatives of phophatidic acid that have polar groups esterified to the phosphate moiety. Important classes include phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.
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How is phosphatidate synthesis generated from phosphatidic acid?
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It occurs via a multi-step process starting with cytosine triphosphate (CTP) (CTP also serves an important role in nucleic acid biosynthesis).
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(What's the major source of phophatidylserine?)
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Phosphatidylethanolamine
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How are ether phospholipids characterized and which important ether phospholipid plays a role in inducing platelet aggregation, smooth muscle contraction, and immune cell activation?
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Ether phospholipids are characterized by an ether moiety at C1. Platelet activating factor (PAF) has the distinctive feature of an acetyl group (rather than a long fatty acid) at the C2 position which increases its hydrophilicity. PAF is an important mediator in anaphylactic shock.
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What are plasmalogens and what is their significance?
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Plasmalogens are ether phospholipids with an unsaturated ether at C1. Plasmalogen derivatives are important for myelin and cardiac muscle. Because plasmalogens are synthesized in peroxisomes, their levels are low in Zellweger's syndrome, making this an important consideration in the differential diagnosis of Down's syndrome (which also has low plasmalogen levels).
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Which proteins engage in phospholipid remodeling by cleaving fatty acid chains or phosphate derivatives?
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Phospholipases
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Which phospholipase cleaves the fatty acid chain of a phosophlipid at the C1 position of the glycerol backbone?
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Phospholipase A1
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Which phospholipase cleaves the fatty acid chain of a phosophlipid at the C2 position of the glycerol backbone?
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Phospholipase A2
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Which phospholipase cleaves the fatty acid chain of a phosophlipid at the C3 position producing diacylglycerol in the process?
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Phospholipase C
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Which phospholipase cleaves the fatty acid chain of a phosophlipid at the C3 position producing phosphatidic acid in the process?
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Phospholipase D
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What is the effect of Phospholipase C acting upon PIP2?
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It produces diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3)
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What is the importance of PIP2 with respect to signal cascades?
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After PIP2 is cleaved by Phospholipase C to produce DAG and IP3, IP3 diffuses to the ER stimulating the release of Ca2+ ions. These interact with DAG in the cell membrane to activate protein kinase C (PKC) which has a number of downstream phosphorylation targets.
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What is the importance of phospholipids with respect to some membrane associated proteins?
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Phospholipids can serve as anchors for membrane associated proteins. For instance proteins like lipoprotein lipase or acetylchoine esterase are anchored to the plasma membrane by a glycosyl phosphatidylinositol (GPI) anchor and are released into the extracellular environment by the cleavage of phospholipase C under the appropriate signalling conditions.
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What are some common covalent lipid modifications of proteins that promote membrane association (review)?
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Myristoylation (C14), Palmitoylation (C16), Farnesylation (C15), and Geranylgeranylation (C20)
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Which children's disease is associated with farnesylation of prelamin A (review)?
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Hutchinson-Gilford Progeria Syndrome (HGPS), a disease in which children age prematurely at an exceptional rate.
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What enzyme releases arachidonic acid from phosphatidylinositol?
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Phospholipase A2
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What are the essential precursors of eicosanoids?
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Linoleic acid (an essential fatty acid), a precursor to arachidonic acid
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What type of hormones are eicosanoids?
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Paracrine hormones (localized action with short half-lives)
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How do eicosanoids elicit a cellular response?
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Via their action on G-protein-couple receptors
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What are the three classes of eicosanoids?
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Prostaglandins, thromboxanes, and leukotrienes
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What are the two main pathways for synthesizing the three classes of eicosanoids?
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Cyclooxygenase and lipoxygenase
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What is the basic structure of arachidonic acid?
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It is a 20 carbon unsaturated fatty acid with 4 double bonds
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What stimulates PLA2 to deacylate arachidonic acid from phosphatidylinositol?
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Ca2+ and phosphorylation by downstream effectors of PKC (it is known as Ca2+-dependent cytosolic PLA2)
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What is the central structural feature of prostaglandins?
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A cyclopentane ring formed from C8-C12 of arachidonic acid
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How is prostaglandin H formed?
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From prostaglandin G/H synthase (PGS) which containes both cyclooxygenase (COX) and glutathione-dependent peroxidase (PG hydroxidase) activities. Note: arachidonic acid is dioxygenated
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Other than different prostaglandins, what other important molecules can be generated from prostaglandin H2?
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Thromboxanes (principally thromboxane A2--TXA2) and prostacyclin
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What is the key structural feature of thromboxanes?
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A six-membered oxygen-containing ring in place of the cyclopentane ring of Prostaglandin H2.
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Which form of prostaglandin G/H synthase (PGS) is inducible?
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PGS-2
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What are some of the key effects of prostaglandins?
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1. Stimulate uterine smooth muscle contraction 2. Elevate body temperature 3. Cause inflammation and pain
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What are some of the key effects of prostacyclins?
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Inhibit platelet aggregation
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What are some key effects of thromboxanes?
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1. Promote clotting 2. Reduce blood flow to clot site
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When and how is PGS-2 induced?
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PGS-2 is only induced in activated macrophages and monocytes. It can be expressed in response to platelet activating factor (PAF). It can be inhibited by glucocorticoids.
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Why are corticosteroids effective anti-inflammatory agents?
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They inhibit phospholipase A2 (cPLA2), reducing arachidonic acid production.
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Why are NSAIDs effective anti-inflammatory agents, and what is the mechanism of aspirin?
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NSAIDS inhibit the COX activity of PGS. Aspirin, specifically, acetylates COX, blocking the active site.
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How are the key leukotrienes synthesized?
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Leukotrienes are synthesized by the monooxygenation of arachidonic acid via 5-lipoxygenases. Leukotriene A4 (LTA4) is one of the more common derivatives formed in two catalytic steps. LTB4 is formed from LTA4 by adding water across the C11-12 double bond. LTC4, LTD4, and LTE4 are all glutathione bonded derivatives of LTA4.
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How are lipoxins related to leukotrienes?
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They are derived from leukotrienes by a different lipoxygenase. (Hydroxyl groups are added to C5 & C6 with these.) They oppose most leukotrienes in that most are anti-inflammatory.
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What functional relationship due 5-LO and cPLA2 share?
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They both reside in the cytosol at rest and are regulated by divalent cations (Ca2+) and phosphorylation which leads to their actiavtion and association with the nuclear membrane. (fMLP) and PAF activate both of these enzymes.
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Which membrane associated protein is functionally located near 5-LO and is a topic of active research for leukotriene inhibitors?
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FLAP
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What are the slow reacting substances of anaphylaxis (SRS-A)?
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LTC4, LTD4, AND LTE4 (cause bronchoconstriction and gastroconstriction)
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What are some medications for asthma related to leukotrienes?
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Montelukast (singulair) and zafirlukast (accolate) block leukotriene binding to lung smooth muscle receptors.
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