Chapter 25 LIPID METABOLISM
Transcript of Chapter 25 LIPID METABOLISM
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Chapter 25LIPID METABOLISM
1) Lipid digestion, absorption and transport2) Fatty acid oxidation3) Keton bodies4) Fatty acid biosynthesis5) Regulation of fatty acid metabolism6) Cholesterol metabolism7) Eicasonoid metabolism8) Phospholipid and glycolipid metabolism
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Lipid Digestion, Absorption andTransport
Major form of energy: triacylglycerol/fat/triglycerideso 90% of dietary lipido oxidized to CO2 and H2Oo 6 times more energy/weight of glycogeno water insolubleo digestion at lipid/water interfaceo emulsified by bile salts/bile acids in small intestineo cut at pos 1 and 3 by lipase (triacylglycerol lipase)
TAG -> 1,2-diacylglycerol -> 2 acylglycerolo + Na+, K+ salts -> fatty acid salts/soap bind to I-FABP
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Energy Content of FoodConstituents
Fat storage: anhydrous !
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Mechanism of interfacial activation oftriacylglycerol lipase in complex with
procolipase
• Pancreas Lipase = TAG lipase• Lipase activation by colipase• Interfacial activation• Activity depends on surface area• Alpha/beta hydrolase fold• 25 AS lid structure• catalytic triad, asp ser his• hydrolysis similar to peptidase
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Catalytic action of phospholipase A2
o Generates a lysophospholipid ! Which are detergentso Cobra and bee venomo Interfacial activation without conformational change ≠TAG lipase, but hydrophobic channel
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Substrate binding to phospholipase A2
No conformational changeUpon interfacial binding
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The X-ray structure of porcinephospholipase A2
• Catalytic diad, His, Asp• Ca2+ / 2x H2O instead of Ser• no acyl-enzyme intermediate, as in TAG lipases
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X-Ray structure of rat intestinalfatty acid–binding protein
As micelles with bile saltsand PC (lecithin) Or lipid-protein complexes
also for Vit A,D,E, K
Inside the cell:o I-FABP, increases solubilityof FAs in the cytosol ofenterocyteso Protect cells from their detergent effecto β-clam structure (Muschel)
LIPID ABSORBTION by enterocytes
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Lipid transport
• Hydrolyzed lipids are absorbed by the intestinal mucosa• Converted back to triglycerides !• Packed into lipoprotein particles, chylomicrons• Released into lymph/blood -> delivered to tissue• Triglyceride made by liver is packaged into VLDL part. -> Released into blood• TAG hydrolyzed in periphery by lipoprotein lipase ->• FA uptake but glycerol back transport to liver and kidney• TAG in adipose tissue is mobilized by hormone-sensitive lipase -> free FA enter blood, bound to serum albumin
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Conversion of glycerol to the glycolyticintermediate dihydroxyacetone
phosphate
o Glycerol release by lipoprotein lipaseo Taken up by liver and kidneyo Converted into glycolytic intermediate, DAHP
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X-Ray structure of human serum albumin incomplex with 7 molecules of palmitic acid
o Increased solubility of free FAs in blood from µM to mMo FAs would form micelles, -> detergents, toxic !o Analbuminemia, low levels of albumin but no severe phenotype -> other FA- binding proteinso Albumins comprise 50% ofserum proteins !
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Lipases overview
1) Pancreas lipase, TAG2) Phospholipase A2, A1, C, D3) Lipoprotein lipase4) Hormone-sensitive, adipocytes
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Fatty acid oxidation
o degradation of fatty acid through oxidation ofCβ = β-oxidationo mitochondriao FA need to cross 2 membranes to reach matrixo not as CoAs but as acyl-carnitineo CPT-I, cytosol; CPT-II, matrixo separate pools of mitoch/cytosol.
•CoAs•ATPs•NAD+
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Franz Knoop’s classic experiment indicatingthat fatty acids are metabolically oxidized at
their β-carbon atom
o Phenyl-labelled even- or odd-numbered fatty acidso Feed to dogs -> what product appears in urine ?
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Mechanism of fatty acid activationcatalyzed by acyl-CoA synthetase
1) Activation of acyl chains toacyl-CoAs in cytosol
2) Requires ATP -> acyl-adenylate intermediated
3) Transesterification to CoA4) Driven by inorganic
pyrophosphatase PPi ->H2O+2Pi
5) 18O-labels AMP and Acyl-CoA
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Acylation of carnitine catalyzed bycarnitine palmitoyltransferase
2nd step: preparation for mitochondrial importo Transesterification of acyl-CoA to carnitine
(no AMP intermediate !)o catalyzed by CPTI (equilibrium close to 1)
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Transport of fatty acids into themitochondrion
as: acyl-carnitine, through carnitine carrier protein IMM
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β-oxidation
• Chemically resembles the cytric acid cycle: Decarboxylation of succinate via fumarate and malate to oxaloacetate
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β-oxidation, 4 steps
1. Formation of trans-α,β double bond, by FAD-dependent acyl-CoA dehydrogenase (AD)
2. Hydration of the double bonds by enoyl-CoAhydratase (EH) to form 3-L-hydroxyacyl-CoA
3. NAD+-dependent dehydrogenation by 3-L-hydroxyacyl-CoA dehydrogenase (HAD) to form β-ketoacyl-CoA
4. Cα–Cβ cleavage by β-ketoacyl-CoA thiolase (KT,thiolase) -> acetyl-CoA and C2 shortened acyl-CoA
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The β-oxidationpathway of fatty
acyl-CoA
Long chain versions of EH, HAD and KTs in α4β4ocatmeric protein, mitochobdrial trifunctionalprotein -> chanelling, no detectable intermediates
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acyl-CoA dehydrogenases
• VLCAD (C12-C18), LCAD (C8-C12)• MCAD (C6-C10)• SCAD (C4-C6)
• MCAD deficiency linked to sudden infant death syndrome• Jamaican vomiting sickness, ackee fruit with hypoglycin A• FADH2 is reoxidized via the electron transport chain• generates acetyl-CoA and C2 shortened acyl-CoA
• 1st step: acyl-CoA dehydrogenases (AD)• mitos contain 4 such dehydrogenases with different chain length specificities
MCAD, homo-tetramerFAD green
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Metabolic conversions of hypoglycinA to yield a product that inactivates
acyl-CoA dehydrogenase
Jamaican vomiting sickness, lethal !Ingestion of unripe ackee fruits -> mechanism based inhibition ofMCAD -> covalent modification of FAD
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Mitochondrial trifunctionalprotein
2-enoyl-CoA are further processed by chain length-specific:• Enoyl-CoA hydratase (EHs)• Hydroxyacyl-CoA dehydrogenase (HADs)• β-ketoacyl-CoA thiolase (KTs)
• Long chain version contained α4β4 octameric protein = mitochondrial trifunctional protein
• α chain contains LCEH and LCHAD• β chain LCKT(multifunctional protein, more than one enzyme on pp)Multienzyme complexChanneling of intermediates
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Mechanism of actionof β-ketoacyl-CoA
thiolase
o Final step in β-oxidationo Via an enzyme thioester
bound intermediate to the substratesoxidized β carbon,displaced by CoA
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Energy balance of β-oxidation
o for C16 palmitic acid: 7 rounds of β-oxidation -> 8 x acetyl-CoA
o Each round of β-oxidation produces:o 1 NADH -> 3 ATPo 1 FADH2 -> 2 ATPo 1 acetyl-CoA -> TCA (1 GTP, 3 NADH, 1
FADH2) (respiration only !)
OVERALL:o 129 ATP per C16
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Oxidation of unsaturated fattyacids
Structures of two common unsaturated fatty acids,Usually, cis double bond at C9Additional double bond in C3 intervals, i.e. next at C12-> odd, even numbered C atoms
Problems for β-oxidation
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Problems for β-oxidation ofunsaturated fatty acids
1) Generation of a β, γ double bond2) A ∆4 double bond inhibits hydratase action3) Isomerization of 2,5-enoyl-CoA by 3,2-enoyl-CoA
isomerase
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Problem 1:Generation of a β, γ
double bond
No substrate for hydroxylase
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No substrate for hydroxylase
Stabilityof DB
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Oxidation of odd chainfatty acids
o Most naturally FA are even numberedo Odd numbered FA are rare, some plants and marine organismso Final round of b-oxidation yields propionyl-CoAo Propionyl-CoA is converted to succinyl-CoA -> TCAo Propionate is also produced by oxidation of Ile, Val, Meto Ruminant animals, most caloric intake from acetate and propionate produced by microbial fermentation of carbohydrates in their stomach
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Propionyl-CoA-> succinyl-CoA
3-step reaction:1) Propionyl-CoA carboxylase,
tetrameric enzyme with biotinas prosthetic group, C3->C4
2) Methylmalonyl-CoA racemase3) Methylmalonyl-CoA mutase,
B12 containing
Direct conversion would involve anextremely unstable carbanionat C3
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The propionyl-CoAcarboxylase reaction
See also pyruvate carboxylase1) Carboxylation of biotin by
bicarbonate, ATP req.2) Stereospecific transfer of
carboxyl group
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The rearrangement catalyzedby methylmalonyl-CoA mutase
Vit B12-dependentHighly stereospecific (R-methylmalonyl-CoA) -> racemase
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Coenzyme B125'-deoxyadenosylcobalamin1. Heme-like corrin ring
2. 4 pyrrol N coordinate 6 foldcoordinated Co
3. 5,6 coordination bydimethylbenzimidazole anddeoxyadenosyl (C-Co bond ! )
4. In carbon-carbonrearrangements
5. Methyl group transfer6. About 12 known B12-
dependent enzymes7. Only 2 in mammals
a. Methylmalonyl mutase,homolytic cleavage, freeradical mechanism
b. Methionine synthase8. B12 acts as a reversible free
radical generator, hydrogenrearrangement or methyl grouptransfer by homolytic cleavage
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X-Ray structure of P. shermanii methylmalonyl-CoA mutase in complex with 2-carboxypropyl-CoA
and AdoCblα/β-barrel class of enzymes
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Proposed mechanism ofmethylmalonyl-CoA
mutase
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Vit B12 deficiency
Pernicious anemiao in elderlyo decreased number of red blood cellso treated by daily consumption of raw liver (1926) -> (1948)o only few bacteria synthesize B12, plants and mammals noto human obtain it from meato Vit. B12 is specifically bound in intestine by intrinsic factoro complex absorbed in intestinal mucosa -> bloodo bound to transcobalamins in blood for uptake by tissueo not usually a dietary disease but result from insufficient secretion of intrinsic factor
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The fate of Succinyl-CoA
•Succinyl-CoA is not consumed in TCA cycle buthas a catalytic function•To consume it, it must first be converted topyruvate or acetyl-CoA
•Conversion to malate (TCA)•Export of malate to cytosol, if conc. are high•Conversion to pyruvate by malic enzyme
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Peroxisomal β oxidation
• β-oxidation occurs both in mitochondria and in peroxisomes• Peroxisomes: Shortening of very-long chain fatty acids (VLCFA) for subsequent transport and oxidation in mitochondria• ALD protein to transport VLCFA into peroxisomes, no carnitine required, VLCFA-CoA synthetase• X-adrenoleukodystrophy caused by defects in ALD, lethal in young boys, 13% reduced efficiency of lignoceric acid (C24:0) to lignoceryl-CoA conversion• first step in perox. oxid. Acyl-CoA oxidase generates H2O2 -> name ! Catalase• carnitine for transport of chain shortened FAs out of perox. and into mito.
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Peroxisomal β-oxidation
First step:Fatty acyl-CoA + O2 -> enoyl-CoA + H2O2
FAD dependent but direct transfer of electrons to O2
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• β-oxidation is blocked by methyl group at Cβ
• Phytanic acid, breakdown product of Chlorophyll’s phytyl side chain• Degraded by α-oxidation• generates formyl-CoA• and propionyl-CoA• C-end will give 2-methyl-propionyl-CoA• Refsum disease/phytanic acid storage d.• omega oxidation in the ER, Cyt P450
Pathway of α oxidationof branched chain fatty
acids
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Ketone bodies• Fate of acetyl-CoAgenerated by β-oxidation:
1. TCA cycle2. Ketogenesis in livermitoch.
• Keton bodies, fuel for peripheral tissue (brain !)• where they are again converted into acetyl-CoA• water soluble equivalent of fatty acids
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Ketogenesis 3 step reaction:1. Condesation of 2 acetyl-
CoA -> acetoacetyl-CoA(reversal of thiolase rxt)
2. Addition of third acetyl-CoA
3. cleavage by HMG-CoA lyase
Ketosis:spontaneous decarboxylationof acetoacetate to CO2 andacetone breath (more fuelthan used)
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The metabolic conversion of ketone bodies toacetyl-CoA in the periphery
Liver lacks ketoacyl-CoA transferase -> export of acetoacetyl/hydroxybutyrate
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Proposed mechanism of 3-ketoacyl-CoAtransferase involving an enzyme–CoA
thioester intermediate
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Fatty acid SynthesisSynthesis of FA through condensation of C2 units ->reversal of β-oxidationCytosolic, NADPH <-> mitochondrial, FAD, NADDifference in stereochemistryC3 unit for growth (malonyl-CoA) <-> C2 for oxidation(acetyl-CoA)
Growing chain esterified to acyl-carrier protein (ACP)Esterified to phosphopantetheine group as in CoA whichitself is bound to a Ser on ACPACP synthase transfers phosphopantetheine to apo-ACPto form a holo-ACP
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A comparison of fatty acid β oxidationand fatty acid biosynthesis
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The phosphopantetheine group inacyl-carrier protein (ACP) and in CoA
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Acetyl-CoA carboxylase• Catalyzes first and committed step of FA synthesis• Biotin-dependent (see propionyl-CoA carboxylase)• Hormonally regulated• Glucagon -> cAMP up -> PKA -> ACC is phosphorylated -> inactive, inhibited by palmitate• AMPK, AMP-dependent kinase activates ACC• ACC undergoes polymerization during activation• Mammals two isoforms:
α-ACC, adipose tissue β-ACC, tissue that oxidize FA, heart muscle, regulates β-ox. as malonyl-CoA inhibits CPT-I
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Association of acetyl-CoA carboxylaseprotomers
• Multifunctional protein ineukaryotes (1 polypeptide chain)• Composed of 3 proteins inbacteria:
• Biotin carboxylase• Transcarboxylase• Biotin carboxyl-carrier
• Polymerizes upon activation
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Fatty acid synthaseo Synthesis of FA from acetyl-CoA (starter) and malonyl-CoA (elongation) requires 7 enzymatic reactionso 7 proteins in E. coli + ACPo α6β6 complex in yeasto homodimer in mammals, 272 kD
EM-based image of the human FASdimer as viewed along its 2-foldaxis, each monomer has 4 50 Å
diameter lobs -> functional domainsantiparallel orientation
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Schematic diagram of the order of the enzymaticactivities along the polypeptide chain of a monomer
of fatty acid synthase (FAS)
Multifunctional protein with 7 catalytic activitiesHead to tail interaction of monomer in the dimer(KS close to ACP)
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The mechanism of carbon–carbon bondformation in fatty acid biosynthesis
CO2 that has beenincorporated into malonyl-CoA is not found in thefinal FA
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An example of polyketide biosynthesis: thesynthesis of erythromycin A
• 2000kD• α2β2γ2 complex
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Transfer of acetyl-CoA from mitochondrionto cytosol via the tricarboxylate transport
system•Acetyl-CoA: produced bypyruvate dehydrogenase,beta-oxidaion in mito•Acetyl-CoA enters thecytosol in form of citrate viathe tricarboxylatetransporter• In the cytosol:• Citrate + CoA +ATP <->acetyl-CoA + OXA + ADP + Pi(cytrate lyase)• citrate export balanced byanion import (malate,pyruvate, or Pi)
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Fatty acid elongationand desaturation
Mitochondrial fatty acid elongation
Elongation at carboxy terminus:o mitochondria (reversal of β-ox)o ER (malonyl-CoA)
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FA desaturation
The electron-transfer reactions mediated by the ∆9-fatty acyl-CoA desaturase complex
Properties:o Cis, ∆9 first, not conjugatedo membrane-bound, nonheme iron enzymes, cyt b5-dependento mammals front end desaturation (∆9, 6, 5/4)o essential FA, linoleic (C18:2n-6, ∆9,12), linolenic (C18:3n-3, ∆9,12,15)o some made by combination of desaturation and elongationo PUFAs, fish oil, n-3, n-6 (omega)o vision, cognitive functions
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The reactions oftriacylglycerol biosynthesis
o Glycerol-3-phosphateacyltransferase in ER andmitochondriao DHP acyltransferase in ER andperoxisomes
Glyceroneogenesis in liverPartial gluconeogenesis fromoxalacetate
TAG are synthesized from fatty acyl-CoAs and glycerol-3-phosphate or dihydroxyacetone phosphate
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Metabolic controlDifferences in energy needs:
o between resting and activated muscle 100xo feed <-> fasting
o Breakdown of glycogen and fatty acids concern the whole organismo organs and tissues connected by blood stream
o Blood glucose levels sensed by pancreatic α cells, glucosedown -> secrete glucagono β cells, glucose up -> insulin
o These hormones also control fatty acid synthesis <-> β oxidation
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Short term regulationregulates catalytic activities of key enzymes inminutes or less:
substrate availabilityallosteric interactionsCovalent modification
-> ACC
Long term regulationamount of enzyme present, within hours or days-> ACC
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Sites of regulation offatty acid metabolism
Synthesis or oxidation of FA?Short-term, hormonalLong-term
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Cholesterol metabolism
All of cholesterol’s carbon atoms are derived from acetate
o Vital constituent of cell membraneso precursor to:
o steroidso bile salts
o Cardiovascular disease, delicate balance !
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Cholesterol is made by cyclization ofsqualene
Squalene from 6 isopren units (C30), polyisoprenPart of a branched pathway that uses isoprens
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The branched pathway ofisoprenoid metabolism in
mammalian cells
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Formation of isopentenylpyrophosphate from HMG-CoA
HMG-CoA is rate-limitingER membrane enzyme, 888 Aa1. Reduction to OH2. Phosphorylation3. Pyrophosphate4. Decarboxylation/
Dehydration
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Action of pyrophosphomevalonatedecarboxylase
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Mechanism of isopentenylpyrophosphate isomerase
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Formation of squalene fromisopentenyl pyrophosphate
and dimethylallylpyrophosphate
C5
C10
C15
C30
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Two possible mechanisms forthe prenyltransferase reaction
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Action of squalene synthase
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Proposed mechanism forthe formation of
presqualene pyrophosphatefrom two farnesyl
pyrophosphate molecules bysqualene synthase
Via cyclopropyl intermediate
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Mechanism ofrearrangement and
reduction ofpresqualene
pyrophosphate tosqualene as catalyzedby squalene synthase
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Squalene synthase
o ER anchoredo Monomer single domain
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The squalene epoxidase reaction
o Preperation for cyclization o Oxygen required for cholesterol synthesis
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The oxidosqualenecyclase reaction
Lanosterol synthaseFolding of oxidosqualene on the enzyme !
Related reaction in bacteria:O2-independnetSqualene-hopene cyclase
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Squalene–hopene cyclase
α/α barrel
monotopicmembrane protein
Active as homodimer
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Squalene–hopene cyclase with itsmembrane-bound region yellow
Hydrophobic channelfrom active site tomembrane
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The 19-reactionconversion of lanosterol to
cholesterol
Lanosterol -> cholsterol• 19 steps• Loss of 3 methyl groups• C30 -> C27• One oxidation• 9 O2 dependent• ER localized enzymes
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CholesterolLiver synthesized cholesterol is:
o converted to bile saltso esterified to cholesteryl ester, ACAT
which are then packaged into lipoprotein complexes, VLDLand taken up by the tissue by LDL receptor mediatedendocytosis
Mammalian cells thus have 2 ways to acquire cholesterol:de novo synthesis or via LDL uptake
Dietary sterols are absorbed in small intestine andtransported as chylomicrons in lymph to tissue/liver
HDL transports cholesterol from the peripheral tissue tothe liver
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LDL receptor-mediated endocytosis inmammalian cells
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Regulation of cholesterol levels
Sterol Homeostasis:1. HMG-CoA reductase, i.e. de novo synthesis
short-term: competitive inhib., allosteric, cov. mod.long-term, rate of enzyme synthesis and degradation
=> SREBP PATHWAY !!2. Regulation of LDL Receptor3. Regulating esterification, ACAT
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Model for thecholesterol-mediatedproteolytic activation
of SREBP
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The SREBP PathwaySREBP, membrane anchored transcription factor (1160 Aa)
480 Aa N-term, basic helix-loop-helix/leucine zipper dom. => binds SRE elementcentral 2 TMD, loop590 Aa C-term regulatory domain
SCAP, integral membrane protein, ER, 1276 AaN-term 8 TMDs (730 Aa), Sterol-sensing domainC-term, WD40 repeat => protein interaction (546 Aa)
1) Long term regulation of HMG-CoA reductase2) Short term by phosphorylation via AMPK (see ACC1),
P-form less active3) LDL receptor
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Control of plasma LDL production and uptake byliver LDL receptors. (a) Normal human subjects
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Control of plasma LDL production anduptake by liver LDL receptors
d) Overexpression of LDL receptor prevents diet-inducedhypercholesterolemia
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Competitive inhibitors of HMG-CoAreductase used for the treatment of
hypercholesterolemia
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COMBINATORIAL THERAPHY
1) Anion exchanger,cholestyramine, reduced uptake of dietary cholesterol => 15-20% drop
2) HMG-CoA inhibitorstatins
Combined => 50-60% reduction of bloodcholesterol levels
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Simplified scheme ofsteroid biosynthesis
•Progestins•Glucocorticoids•Mineralocorticoids•Androgens•Estrogens
Side-chain cleavagein mitochondria !!
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Bile acids and their glycine and taurineconjugates
o Only route for cholesterol excretion, < 1 g/dayo Cholesterol 7α-hydroxylase is rate-limiting, ERo Detergent properties
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Prostaglandins (PGs)o 1930, Ulf von Euler: human semen extract
stimulates uteruscontraction and lower blood pressure
o Thought to originate in prostata -> name
o mid 50s, isolated from body fluids in etherextract (PGE)
o Made by all cells except RBC
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Eicosanoid metabolism:Prostaglandinsm prostacyclins,
thromboxanes, leukotriens, and lipoxins
o Collectively: eicosanoids, C20 compounds- profound physiological effects at very low conc.- hormone-like but paracrine- bind to G-coupled receptors, affect cAMP- signal as hormones do- arachidonic acid C20:4
o What you inhibit by aspirin !!NSAIDs, nonsteroidal anti-inflammatory drugs
o What you inhibit by cortisol !!
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Eicosanoids
Mediate:1) inflammation2) production of pain and fever3) regulate blood pressure4) induction of blood clotting5) reproductive functions6) sleep/wake cycle
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Prostaglandin structures. (a) The carbonskeleton of prostanoic acid, the prostaglandin
parent compound
Cyclopentane ringSynthesized from arachidonic acid, C20:4, ∆5,8,11,14(ω-6 FA)
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Prostaglandin structures. (b) Structures ofprostaglandins A through I.
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Prostaglandin structures. (c) Structures ofprostaglandins E1, E2, and F2α (the first
prostaglandins to be identified)
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Synthesis of prostaglandinprecursors, arachidonic acid
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Arachidonic acid is theprecursor to PGs
o Arachidonic acid: C20:4, n-6, ∆5,8,11,14
o AA is synthesized from the essential linoleic acid, C18:3, ∆6,9,12 by elongation and desaturation
o AA is phospholipid bound (sn2, PI) and released upon stimuli by: 1) phospholipase A2
2) phospholipase C ->DAG + P-Ins -> PA (DAG kinase) -> AA (PLA2)3) DAG hydrolysis by DAG lipase
o Corticosteroids inhibit PLA2 and thus act through PGs !!anti-inflammatory
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Release of arachidonic acidby phospholipid hydrolysis
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Pathways of arachidonic acidliberation from phospholipids
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The cyclic and linear pathways ofarachidonic acid metabolism
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The cyclic pathway of arachidonicacid metabolism
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The reactions catalyzedby PGH synthase
(PGHS)
o PGHS catalyzes first step inthe cyclic pathway
o cycloogynase (COX) +peroxidase activity
o heme activates Tyr radicalo Target of aspirino Monotopic membrane protein (see squalene-hopene cyclase)
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X-Ray structure of PGH synthase (PGHS)from sheep seminal vesicles in complex with
the NSAID flurbiprofen
Homodimeric monotopic ER membrane proteinHemeFluriprofenActive side Tyr
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X-Ray structure of PGH synthase (PGHS) from sheepseminal vesicles in complex with the NSAID flurbiprofen.
(b) A Cα diagram of a PGHS subunit (green)
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ASPIRIN
o Acetylsalicylic acido Inhibits cyclooxygenase activity of PGHSo Acetylates Ser 530o Flurbiprofen blocks channelo Low dose of aspirin reduce heart-attack
risk, inhibits platelet aggregation(enucleated cells, 10 days lifetime, cannotresynthesize enzyme
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Inactivation of PGH synthase byaspirin
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Some nonsteroidal anti-inflammatory drugs (NSAIDs)
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Vioxxo 2 PGH synthase isoforms, COX1, COX-2o COX-1 is constitutively expressed in most tissues, including the gastrointestinal mucosao COX-2 only in certain tissues expressed in response to inflammatory stimuli
Aspirin can induce gastrointestinal ulceration
⇒Search for selective COX-2 inhibitors (coxibs) forlong-term treatment, i.e. arthritis
COX-3 may be the target of acetaminophen, widelyused analgesic/antipyretic drug -> treat pain & fever
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COX-2 inhibitors
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•The 5-LO–catalyzed oxidation ofarachidonic acid to LTA4 via theintermediate 5-HPETE
The linear pathway:Leukotrienes and Lipoxinds
• Conversion of arachidonic acid todifferent hydroperoxyeicosatetraenoicacids (HPETEs) by lipoxygenase• Hepoxilins, hydroxy epoxy derivativesof 12-HEPTE, anti-inflammatory
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15-lipoxygenase (15-LO) in complexwith its competitive inhibitor RS75091
o N-term β-barrelo Fe
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Formation of the leukotrienes from LTA4
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Lipoxin biosynthesis
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ESKIMOS
o Low risk of cardiovascular diseasedespite the fact that they eat a lotof fat, why?
o Are healthy because they eat fish, PUFAs, n-3, n-6
o Reduce cholesterol, leukotriene and PG levels
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Phospholipid and glycerolipidmetabolism:
The glycerolipids and sphingolipids
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Membrane lipidsAmphipathic: hydrophobic tail / hydrophilic head• glycerol, 1,2-diacyl-sn-glycerol• N-acylsphingosine (ceramide)• Head:
• phosphate ester• carbohydrate
• 2 categories of phospholipids: Glycerophospholipids, sphingophospholipids
• 2 categories of glycolipids Glyceroglycolipids, sphingoglycolipids/glycosphingolipids
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Glycerophospholipidbiosynthesis
o sn-1: saturated FAo sn-2: unsaturated FA
o Biosynthesis of diacylglycerophospholipidso from DAG and PA as TAG synthesis
o Head group addition:o PC/PE
o P-activated Etn or Choo -> CDP-activated Etn or Cholo -> transfer on DAG
o PS, head-group exchange with PEo PI/PG, CDP-DAG
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o DAG and CDP-etn or CDP-chol
o methylation pathway in the liver PE -> PC, SAM-dependent
The biosynthesis of phosphatidylethanolamineand phosphatidylcholine
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Phosphatidylserine synthesis
Head group exchange with PE
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The biosynthesis ofphosphatidylinositol and
phosphatidylglycerol
CDP-DAG activated DAG+ inositol or glycerol-3P= PI or PG
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The formation ofcardiolipin
Mitochondrial phospholipid2x PG = CL + Glycerol
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FA Remodeling
Tissue and cell-type specific introduction of definedFA into lipids
Examples:o 80% of brain PI contains C18:0 in sn-1 and C20:4 in sn-2o 40% of lung PC has C16:0 in both positions, surfactant
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PlasmalogensAround 20% of mammalian PLs are plasmalogens
o Nervous tissueo Mainly PEs
1. Plasmalogens: vinyl ether linkage in C12. Alkylacylglycerophospholipids: ether linkage
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The biosynthesis of ethanolamine plasmalogenvia a pathway in which 1-alkyl-2-acyl-sn-
glycerolphosphoethanolamine is an intermediate
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Sphingolipids1. Cover the external surface of the plasma membrane,
biosynthesis in ER/Golgi lumen
2. Sphingomyelin is major phosphosphingolipid,phosphocholine head group, not from CDP-choline butfrom PC
3. Sphingoglycolipids1. Cerebrosides, ceramide monosaccharides2. Sulfatides, ceramide monosaccharides sulfates3. Globosides, neutral ceramide oligosaccharides4. Gangliosides, acidic, sialic acid-containing ceramide
oligosaccharides
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The biosynthesis ofceramide
1) Serine + palmitoyl-CoA = KS2) Reduction of KS to sphinganine (LCB)3) LCB + Acyl-CoA = ceramide (DHC)4) Oxidation of DHC to Cer
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The synthesis of sphingomyelin from N-acylsphingosine and phosphatidylcholine
o PC is head-group donorto convert Cer to SM
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Principal classes ofsphingoglycolipids
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The biosynthesis of cerebrosidesMost common:
galactosylceramideglucosylceramide
Ceramide + UDP-hexose
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The biosynthesis of sulfatidesAccount for 15% of lipids in white matter in the brainTransfer of activated sulfate group from PAPS to C3 OH of galactose on galactosylcerebroside
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The biosynthesis of globosides andgangliosides
o Globosides: neutral ceramide oligosaccharideso Gangliosides: acidic, sialic-acid containing ceramide oligosacharides
o made by a series of glycosyltransferases1) galactosyl transfer to glucocerebroside -> lactosyl ceramide, precursor to globosides andgangliosides (over 60 different gangliosides known)2) UDP activated sugar
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The biosynthesis of globosides andGM gangliosides
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Sphingoglycolipid degradationand lipid storage disease
o Degraded in lysosomes by series of enzyme-mediates hydrolytic stepso Catalyzed at lipid-water interface by soluble enzymeso Aid of SAPS, sphingolipid activator proteinso GM2-activator-GM2 complex binds hexosaminidase A that hydrolyzes N-acetylgalactosamine from GM2
o Enzymatic defect leads to sphingolipid storage disease,e.g., Tay-Sachs disease, deficiency in hexosaminidase A,neuronal accumulation of GM2 as shell like inclusions,In utero diagnosis possible with fluorescent substrate
o Substrate deprivation therapy, inhibition of glucosyl-ceramide synthase
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Cytoplasmic membranous body in aneuron affected by Tay–Sachs
diseaseMost common SL storage diseaseHexosaminidase deficiencyCytoplasmic membrane bodies in neurons
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Model for GM2-activator protein–stimulatedhydrolysis of ganglioside GM2 by
hexosaminidase
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The breakdown ofsphingolipids by
lysosomal enzymes
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Sphingolipid Storage Diseases