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LIPIDELEROLUL STRUCTURA CHIMICPROPRIETI
Funciile biologice ale lipidelor.Clasificarea lipidelor( structural, funcional, dup proprietile fizico-chimice ).Lipidele de rezerv acilgliceridele, reprezentanii, structura, proprietile fizico-chimice, rolul biologic.Lipidele protoplasmatice fosfogliceridele, sfingolipidele, glicolipidele, colesterolul- structura, proprietilefizico-chimice, rolul biologic.Eicosanoizii- prostaglandinele, leucotrienele, tromboxanele- structura i rolul biologic.Vitaminele liposolubile A,D,E, K structura i rolul biologic.Membranele biologice: Funciile i structura modelul S.G.Snger i G.L.Nicolson;Proprietile fundamentale fluiditatea, molilitatea, permeabilitatea selectiv, asimetria, autoasamblarea i autorapararea;Diversitatea i specificitatea structurilor i funciilor diferitor membrane biologice.
LIPIDESubstane organice, greu solubile n ap dar solubile n solveni nepolari (eter, benzen, cloroform).Rolulprincipala form de depozitare i de transport a rezervelor energetice ale organusmuluiConstituieni structurali ai membranelor celulare i intracelularerol n procesul de comunicare i recunoatere intercelularIzolator: termo; mecano-; electroizolatorPot avea efecte biologice: sunt vitamine, hormoni, prostaglandine
ClasificareaSaponifiabile prin hidroliz se descompun n substanele componente (acilglicerolii, fosfogliceride, sfingolipide, cerurile, glicolipidele)Nesaponifiabile nu se scindeaz hidrolitic n compui simpli (hidrocarburile, alcoolii, aldehidele, acizi cu schelete alifatice sau ciclice cu structur poliizoprenic: terpenele, steroizii, carotenoizii)
Structural:Lipide monocomponente (monomeri lipidici) lipide nesaponifiabileLipidele policomponenteSimple: cerurile, gliceridele, sterideleConjugate (mixte): fosfolipidele, sfingolipidele, glicolipidele
Dup proprietile fizico-chimice: Polare (FL, AG)Nepolare TgDup importana fiziologic:Lipide de rezerv - TgStructurale FL, Col, SfingolipideleLipidele sngelui: Tg, Col, LPLipidele constituie 10-20% din masa corpului.10-12 kg lipide (2-3 kg lipide structurale; 98% - concentrate n esutul adipos)
AG structura, proprietiAG- derivaii hidrocarburilor alifatice ce conin druparea carboxilClasificare:Dup nr atomilor de C- AG cu nr par i imparDup gradul de saturare saturai i nesaturaiDup rolul fiziologic: eseniali i neeseniali(linoleic i linolenic)
Structura chimicCH3-COOH aceticCH3-(CH2)2-COOH butiric CH3-(CH2)4-COOH caproic CH3-(CH2)6-COOH caprilicCH3-(CH2)8-COOH capricCH3-(CH2)10-COOH lauricCH3-(CH2)12-COOH miristicCH3-(CH2)14-COOH palmiticCH3-(CH2)16-COOH stearic
AG mononesaturai i polinesaturaiAG nesaturai conin una sau mai multe legturi duble etilenice care de regul sunt ntre poziia C9 i C10 -cisCH3- (CH2)5- CH=CH-(CH2)7-COOH -a. palmitooleic (C16:1)CH3-(CH2)7-CH=CH-(CH2)7-COOH a. oleic (C18:1)CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)7- COOH a.linoleic (C18:2 cis9, 12)CH3-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH-(CH2)7-COOH a. linolenic (C18:3 cis9,12,15)CH3-(CH2)4-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH-(CH2)3-COOH - a.arahidonic (C20:4, cis5,8,11,14)
Proprietile AGAG saturai pn la C8 sunt lichizi; mai sus de C8- solizi. AG nesaturai sunt lichizin cristale catenele hidrocarburilor saturate au configuraia de zig-zagAG nesaturai prezint izomerie cis-trans ns formele naturale ale acestor sunt izomerii cisAG puin solubili n ap, solubilitatea scznd odat cu lungimea cateneiAG nu se afl n stare liber n celule i esuturi ci sunt legai covalentAG nesaturai au t de topire mai joas comparativ cu cei saturai--- lungimea i prezena legturilor duble amplific fluiditatea
Proprietile chimiceAG saturai i nesaturai pot forma:Esteri (gliceride, fosfogliceride)Sruri (spunuri cu proprieti tensioactive)Amide (sfingolipide)AG nesaturai adiioneaz la nivelul dublei legturi halogeni (Br2; Cl2), tiocianatul (SCN)2, gruparea hidroxilAG nesaturai sufer procesul de peroxidare, la care se altereaz gustul i mirosul (rncezire)
GLICERIDE ( acilgliceroli, grsimi neutre)Sunt esteri ai glicerolului cu AGDup nr gruprilor alcoolice esterificate din glicerol deosebim: mono-; di- i tri gliceride
Rolul TgConstituie grsimea de rezerv din esuturiRol energeticSe gsesc n LP plasmaticeIzolatorLa oxidarea 1g se elimin 9kcalTg din esutul uman cuprind urmtorii AG:Oleic-45%, palmitic-25%, linoleic 8%, palmitooleic 7%, stearic- 7% i alii -7%
Proprietile TgSunt determinate de natura i numrul de AG constituieniInsolubile n ap, solubile n solveni organiciTg ce conin AG saturai solide(grsimi, unt)- de origine animalTg ce conin AG nesaturai consisten lichid (uleiurile vegetale)Prin hidroliza enzimatic (se produce n intestin sub aciunea lipazei) se scindeaz n glicerol i 3AGPrin hidroliza alcalin (KOH, NaOH) glicerol+spunuriPrezena AG nesaturai proprietatea de a adiiona halogenii la dublele legturiSub aciunea luminii, cldurii se autooxideaz
FosfatideleDerivai ai acidului fosfatidicReprezentanii: fosfatidilcolina (lecitina)Fosfatidiletanolamina (cefalina)Fosfatidilserina FosfatidilinozitolRolul:StructuralFosfatidilcolina cu 2 resturi de palmitil este componentul principal al surfactantului pulmonar, ce acoper alveolele i mpedic colapsul la expiraieFosfatidiletanolamina sunt abundente n esutul nervosFosfatidilinozitolul- rol n procesul de transmitere a semnalelor extracelulare
ProprietileCaracter amfipatic (lecitinile i cefalinele au structur bipolar: prezena resturilor acil hidrofobe i a sarcinilor electrice: sarcina negativ restul a fosforic; sarcin pozitiv gr alcool)
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phosphatidylcholine
_1020453292.cdx
_1033410619.cdx
_1033410831.cdx
_1020453481.cdx
_997970231.cdx
Proprietile FL2. Proprieti tensioactive puternice3. n ap se dizolv formnd agregate micelii, alctuite din 2 straturi bilipidice4. Sunt neutre la electricitate5. Fosfatidilserina i fosfatidilinozitolul au sarcin negativ
SfingolipideleDerivai ai sfingozineiSe gsesc cu predelecie n esutul cerebral, splin i eritrociteRolul:Sunt surse energetice (datorit AG)Componente ale membranei celulare (nervoas)Particip la coagularea sngeluiSunt transportori de e i componente ale mitocondriilor, unde au loc procesele de O/RRol n fiziologia SNCProprieti; amfioni, au caracter amfipatic2 categorii: sfingomielina i glicosfingolipidele
SfingomielinaSfingozina +AG = ceramidCeramida+ rest de fosforilcolin = sfingomielina
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sphingosine
_970259667.cdx
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ceramide
_970259667.cdx
_992176078.cdx
Glicolipide (Glicosfingolipidele) - includ ceramida legat glicozidic de monozaharide sau oligozaharide (nu cuprind fosfor)Cerebrozide se afl abudent n substana alb a creierului; n nervi. Proprieti:nu au sarcin electric; au caracter amfipaticStructur: ceramida (AG-24C)+gGal (mai rarGl)
2. Gangliozide sunt prezente n toate esuturile n cantiti mici, mai abudent n substana alb a creierului; n nerviStructur: ceramida (AG-stearic)+oligozaharid (Gal+Gl+Nacetilglucozamin)+ 1,2sau3 resturi de a sialic acetilneuraminic mono-; di-; tri- sialogangliozidProprieti: la PH=7 au sarcin negativ
SteroiziiSunt derivai a ciclului pentanperhidrofenantren (steranului C17)
ColesterolulC27Origine animal (lipsete n plante)Rol structuralSolid, alb, insolubil n apPrecursorul tuturor compuilor steroidici (provitaminei D, acizilor biliari, hormonilor steroizi)2 forme: esterificat i neesterificat
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Acizii biliariSunt componeni ai bileiStructur: steroizi C24: colic, chenodezoxicolic, dezoxicolicRolul: proprieti de solubilitate (micele n ap i au capacitatea de a solubiliza alte lipide)Transport (AG)EmulgatoriActiveaz lipaza pancreaticLa PH alcaln se gsesc sub form de sruri biliare (conjugai cu glicina sau taurina
Membranele biologiceStructuri superorganizate, posednd constituienii de baz - proteinele i lipidele.despart celula de mediul estern i separ mediul ei intern n compartimentereprezint o barier de permeabilitate selectivConin pompe moleculare specifice i canale (sisteme de transport)Sunt flexibile, labile, permanent se rennoiescsunt elastice i dure la deformare
Funciile biologice ale membranelor: de separare (de barier)de integrare sau asociere asociaz procesele biochimice izolate n structuri integrede transport (pasiv, activ);Osmotic de concentrarea a substanelor ntre spaiile intra- i extracelulareElectric repartizarea neuniform a sarcinilor pe ambele pri ce duce la apariia diferenei de potenial electric;de transformare a energiei asigur transformarea energiei electrice, osmotice n energia chimic -ATP;de recepie prin intermediul receptorilor ele regleaz schimbul de informaie ntre celule i mediul extern;reglatoare; metabolic particip la formarea AMPc; GMPc; enzimele membranare n diverse transformri metabolice;Antigenic glicoproteinele membranare determin capacitatea de formare a anticorpilor;
Structura MBComponeni de baz: lipidele i proteinele (1:4 pn la 4:1)GlucideleLipidele: conin grupe hidrofobe (nepolar) i hidrofile (polar) n soluii apoase formeaz stratul bilipidicFosfolipidele i glicolipidele constituienii cheie ai membranelor ndeplinesc funcia de barier a permeabilitii i asigur crearea compartimentelor unice
polar
non-polar
"kink" due to double bond
Bilayer Spherical Micelle
Proteinele asigur transportul, transmiterea informaiei, transformrile de energie.Deosebim: proteine periferice i integraleProteinele periferice sunt legate de membrane prin fore electrostatice i de hidrogenProteinele integrale - amfipatice, conin AA nepolari formeaz cu lipidele membranei legturi hidrofobe
Glucidele sub form de glicolipide i glicoproteineSunt situate pe suprafaa membranei, dar nu n faza hidrocarbonatFavorizeaz meninerea asimetriei membranelor biologiceAu funcia de identificare intercelular, de detectare a celulelor strine sistemului imunDetermin transportul proteinelor membranare n locusurile necesare
Proprietile membranelor biologice.fluiditatea. Starea n care se afl lipidele membranare se numete fluidcristalin, deoarece ptura lipidic este lichid, ns n ea se conin sectoare compacte. Reglatorul fluiditii ColSitundu-se ntre catenele acil, Col evit cristalizarea i fuziunea lor, dar blocheaz mobilitatea catenelor acil, micorndu-le i fluiditatea -- Col menine fluiditatea la un nivel mediu
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Cholesterol
in membrane
Proprietile membranelor biologice.Asimetria:repartizarea neuniform a lipidelor i proteinelor pe suprafaa intern i extern a MBLa suprafaa extern este prezent componenta glucidic (glicocalixul), pe cnd pe partea intern ele practic lipsesc.
Proprietile membranelor biologice.mobilitatea. Moleculele lipidelor membranei se afl n micare continu. Snt posibile 2 tipuri de micare a moleculelor: rostogolire i difuziune lateral. Proteinele membranare tot posed mobilitate. Ele parc plutesc n ptura lipidic, deplasndu se n procesul difuziunii laterale.
Lateral Mobility
Flip Flop
Proprietile membranelor biologice.permeabilitatea selectiv. Membrana biologic este permeabil pentru substanele lipofile (steroizi .a.) i moleculele nepolare mici. Substanele polare (ionii, aminoacizii, glucoza etc.) nu pot trece membrana prin difuziune simpl, ele necesit anumite sisteme de transport.
Digestia i absorbia grsimilor n tractul digestiv Digestia lipidelor decurge n intestinul subire cu participarea enzimelor lipolitice pancreatice i intestinale. Pentru digestia normal este necesar prezent acizilor biliari, care ndeplinesc urmtoarele funcii:activeaz lipaza pancreatic,emulsioneaz lipidele,paticip la absorbia lipidelor.Trigliceridele snt scindate dup urmtoarea schem pn la glicerol i acizi grai:
Fosfolipidele snt scindate de fosfolipazele pancreatice (A1, A2, C, D) pn la glicerol, acizi grai, acid fosforic i compui azotai
Absorbia decurge n intestinul subire sub form de micele (picturi lipidice mici), la formarea crora particip acizii biliari. Componentele lipidice snt utilizate n epiteliul intestinal pentru resinteza lipidelor. Acizii biliari prin sistemul portal ajung la ficat de unde iari snt excretai n duoden (circulaia entero-hepatic a acizilor biliari).
Transportul lipidelor sanguine se face n form de lipoproteine. Lipoproteinele snt complexe lipoproteice alctuite din trigliceride, fosfolipide, colesterol i colesteride, proteine. Lipidele nepolare formeaz miezul hidrofob, (trigliceridele i colesteridele). La suprafaa particulei lipoproteice snt situate lipidele amfifile (fosfolipidele i colesterolul) i proteinele.Lipoproteinele se mpart n:chilomicroni,pre- - lipoproteine (pre--LP), - lipoproteine (-LP) - lipoproteine (- LP)
Chilomicronii transport lipidele resintetizate n epiteliul intestinal spre esuturi. Snt alctuite din 80% trigliceride, 7-8 % fosfolipide, 7% colesteride i doar 2% proteine.Pre--LP se formeaz n ficat din lipidele sintetizate aici i ndeplinesc funcia de transport a trigliceridelor din ficat spre esuturi. Snt LP bogate n trigliceride.n snge pre--LP snt transformate n -LP (prin cedarea trigliceridelor esuturilor i nbogirea cu colesterol). ndeplinesc funcia de transport a colesterolului spre esuturi.-LP se formeaz n ficat, au un coninut nalt de proteine i fosfolipide. Funcia lor principal este transportul colesterolului de la esuturi spre ficat.
Digestia i absorbia lipidelorMetabolismul lipoproteinelor
ObiectiveleImportana lipidelor n alimentaie.Digestia i absorbia lipidelor n tractul gastrointestinal.Acizii biliari clasificarea, structura, funciile lor. Metabolismul acizilor biliari ( noiuni generale).Resintaza lipidelor n enterocite. Soarta lipidelor resintetizate. Metabolismul LPP.
Importana lipidelor n alimentaie.
Aportul alimentar de lipide necesar zilnis este n mediu de 80g, incluznd grsimi att de origine animal ct i de origine vegetal.Principalele lipide ale raiei alimentare sunt: Tg; FL; Col liber i esterificat.Lipidele alimentare snt sursa acizilor grai indespensabili linolic i linolenic.Funcionarea normal a organismului necesit un consum minim obligatoriu de vitamine liposolubile ( A,D,E,K )
Digestia grsimilor n TGI Digestia i absorbia lipidelor alimentare necesit: prezena bilei , sucului pancreatic enzimelor lipolitice.Acizii biliari (compuii majori ai bilei) contribuie la:emulsionarea lipidelor alimentare, activizarea enzimelor lipolitice; absorbia produselor finale ale digestiei. Bicarbonaii sucului pancreatic creaz pH-ul optim pentru enzimele lipolitice. Principalele E lipolitice sunt: lipaza, fosfolipazele, colesterolesteraza, sfingomielinaza i ceramidaza.
Digestia grsimilor n TGIla aduli are loc n intestinul subire.Prezena E lipoliticeCondiii pentru emulsionarea lipidelorPH optim pentru aciunea E (neutru sau slab alcalin)
n cavitatea bucal Tg nu se supun modificrilor deoarece saliva nu conine E digestiei lorExcepie: sugari, lipaza lingval digesteaz Tg n poziia 3 1,2 digliceridn stomac digestia are loc doar la copiii sugari (PH sucului gastric = 5) sub aciunea lipazei gastrice se digesteaz Tg din lapte
n intestin - chimul din stomac este neutralizat de bicarbonaii sucului pancreatic i intestinal. Grsimile se supun emulsionrii sub aciunea srurilor AB i E lipolitice. AB se amplaseaz la suprafaa grsime-ap mpedic separarea acestor 2 faze. Peristaltismul intestinului ajut la frmiarea picturilor mici de grsime, iar srurile AB le menin n stare suspendat, mpedicnd contopirea picturilor mici de grsime
Digestia TGlipaza pancreatic:Este o glicoproteidSe activeaz sub aciunea colipazei i AB PH=8-9are specificitate pentru legturile 1,3.
sub aciunea izomerazei (transfer restul acil din poziia 2 n 1) - 1/3 din 2 monoglicerid trece n 1 monoglicerid 1 monogliceridul sub aciunea lipazei se scindeaz la AG i glicerol
Digestia fosfogliceridelor fosfolipazele pancreatice (A1, A2, C, D) pn la glicerol, acizi grai, acid fosforic i compui azotai
Digestia fosfogliceridelorCea mai activ este fosfolipaza A2 (se activeaz de tripsin, Ca; AB)fosfatidilcolina-------lizolecitina (proprieti detergente puternice; particip la solubilizarea lipidelor n intestin)
Sub aciunea lizofosfolipazei - lizolecitina se scindeaz n glicerolfosfocolin i AG
Digestia sfingomielinelorSfingomielinaza: singozin+AG+fosforilcolinCeramidaza degradeaz legtura N acilic
Digestia ColColesterolesteraza pancreatic (activat de AB) scindeaz Col esterificat n Col i AG
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Absorbia lipidelorProdusele finale ale digestiei lipidelor sunt: 2 monogliceridul; glicerolul; AG; sfingozina; a. fosforic, colina, etanolamina; Col. sunt absorbite la nivelul intestinului subire prin difuzie simpl sau pinocitoz micelar (sub form de micele (picturi lipidice mici), la formarea crora particip AB). Prin difuzie simpl sunt transportai: AG cu catena scurt; glicerolul, colina, etanolaminaAcidul fosforic sub form de sare de Na sau KAG cu catena lung, monoacilglicerolul, Col se absorb cu ajutorul AB
Ciclul entero-hepaticAG +AB formeaz o soluie micelar i ptrund n spaiile intervilozitare de la nivelul jejunului proximal unde AG se absorb. Srurile AB rmn n lumen, participnd la solubilizarea i transportul altor lipide. Abia n poriunea distal a ileonului srurile AB se absorb printr-un mecanism activ.Prin sistemul portal trec n ficat (se rennoiesc) bila --- intestin - circulaia entero-hepatic a acizilor biliari.
Resinteza lipidelorDin substanele ce se absorb din lumenul intestinului n eterocite are loc resinteza lipidelor specifice organismului uman: Tg, FL, Col esterificatRolul: lipidele digestive se deosebesc dup structur, proprietile fizico-chimice de lipidele specifice. n enterocite se formeaz lipide specifice organismului uman.Moleculele lipidelor reconstituite mpreun cu cantiti mici de protein sunt ncorporate n chilomicroni (CM)CM sunt secretai n vasele limfatice ce dreneaz intestinul i la nivelul canalului toracic trec n plasm.
LIPOPROTEINELE (LP)LP- snt complexe lipoproteice, alctuite din componente lipidice i proteice. Componentele lipidice: Tg, FL, Col, colesteride Componentele proteice snt denumite apolipoproteine (Apo).Rolul LPTransportul lipidelor exogene i endogeneParticip la pstrarea compoziiei lipidice a membranelorRegleaz procese metabolice celulareRolul Apo: componente amfipatice a LPOfer situsuri de recunoatere pentru R de pe suprafaa celulelorSunt activatori sau inhibitori ai E ce particip la metabolismul lor
Structura LPLP au o structur comun, lipidele nepolare (TG i esterii Col) formeaz un miez hidrofob, iar lipidele amfipatice (FL, Col) i Apo alctuesc nveliul hidrofil. LP cuprind i cantiti mici de glucide (sub form de glicoproteine).
Metodele de separareLP plasmatice pot fi separate prin ultracentrifugare i prin electroforez.Prin centrifugare au fost obinute 4 fraciunichilomicroniiLP cu densitate foarte mic (VLDL, very low density lipoproteins)LP cu densitate mic (LDL, low density lipoproteins)LP cu densitate mare (HDL, high density lipoproteins)
prin electroforez: separarea se efectueaz la pH alcalin (8,6) pe geluri de agaroz, de poliacrilamid. Prin aceast tehnic snt separate 4 fraciuni:chilomicronii care nu migreazpre - - LP (corespund VLDL) - LP (corespund LDL) - LP (corespund HDL)
Chilomicroniisunt LP cu un coninut mare de lipide (98-99% - Tg) i puine proteine (1-2%). Sunt sintetizai n celulele mucoasei intestinale i ncorporeaz lipidele alimentare absorbite. Sunt secretai n vasele limfatice care dreneaz intestinul i la nivelul canalului toracic trec n plasm. Particulile primare cuprind apo-B48 i apoA. n plasm are loc transferul pe CM a Apo C i E de la -LP CM snt prezeni n plasm dup ngerare de alimente bogate n grsimi. Dup 6-7 ore de la ngestia de grsimi chilomicronii dispar din snge.
Catabolismul chilomicronilorare loc n dou etape. n prima etap TG snt hidrolizate sub aciunea lipoproteidlipazei. (2monogliceridul AG+glicerol). AG se depoziteaz n esutul adipos; se oxideaz n esutul muscular; pe cnd Col, FL, Apo C sunt transferate pe HDL. CM devin resturi CM A dou etap const n captarea resturilor de CM de ctre ficat, facilitat de apo E (interacioneaz cu E-receptorii din hepatocit). Pe aceast cale ajunge la ficat o parte din Col exogen i cel intestinal.
PatologiaDeficitul nscut de LPL- hiperchilomicronemieMrirea concentraiei CM, Tg, depunerea Tg n esuturi (xantoame)Anomalia sintezei de Apo B-48 imposibilitatea formrii CM i transportului lipidelor exogeneTg se acumuleaz n celulele intestinale; este perturbat absorbia lor; ele fiind eliminate prin masele fecale steatoreen snge: micorarea lipidelor totale; Tg; Col
Pre--LP (VLDL)sintetizate n ficat au un coninut ridicat de lipide (90-93%): 55-65% TG, 12-18% FL, Col esterificat 12-14% i Col liber 6-8%. cuprind apo B-100 , n plasm primesc apo C i apo E de la -LP.Funcia principal- transportul Tg sintetizate n ficat spre esuturile extrahepatice. VLDL snt prezente n plasm dup ngerare de raii bogate n glucide
Catabolismul VLDLVLDL , mbogite n apo C-II, sunt supuse aciunii LP-lipazei care hidrolizeaz Tg. Odat cu scderea Tg are loc i pierderea de apo C-II care trece pe HDL. particulele se mbogesc cu Col, prin 2 moduri:Sub aciunea acil-Col-ester-transferazei - Col esterificat - este transferat din HDL pe VLDL.Sub aciunea lecitin-Col-acil-transferazei (LCAT) E plasmatic. Apo C-I, component al VLDL, activeaz aceast E. LCAT catalizeaz reacia:Lecitin + Col ----2-lizolecitin + AcilcolesterolParalel cu pierderea Tg i mbogirea cu Col - apo C trec la HDL, astefl VLDL sunt transformate n IDL. 50% sunt catabolizate n ficat prin interaciunea cu E-R, iar 50% sunt transformate n LDL.
PatologiaSteatoza (infiltraia gras a ficatului) acumularea grsimilor n ficatCauza: amplificarea sintezei Tg n ficat sau perturbarea cilor de sintez i transport (export) de VLDLAciune protectoare o au factorii lipotropi: Met; proteine bogate n Met; grsimile nesaturate; vitamina E ele favorizeaz exportul Tg hepatice
-LPse formeaz n plasm din VLDL dup ndeprtarea Tg (sub aciunea LPL, TGL) i mbogire cu Col.au un coninut lipidic de 75-86%, componenta major fiind Col: 35-40% - Col esterificat, 3-10% -Col liber; 20-25% - FL i 8-12% - Tg. Apo majoritar este B-100.sunt prezente n sngele recoltat dimineaa dup un post de 8-10 ore i cuprinde 70% din Col total plasmatic.au rol de a furniza Col diverselor esuturi.
Catabolismul LDLLDL plasmatice prin intermediul apo B-100 i apo E interacioneaz cu R specifici de pe suprafaa celulelorLP LDL fixate pe R snt translocate n interiorul celulei i fuzioneaz cu lizozomii (endocitoz).n lizozomi sub aciunea E lizozomale LDL sunt hidrolizate n: proteine, FL, Col esterificat, Tg. Col liber: o parte este utilizat pentru nevoile proprii ale celulei (construcia membranelor, sinteza de hormoni steroidici, acizi biliari) iar surplusul este esterificat i depozitat n celul. Esterificarea Col e catalizat de E - acil-CoA- Col-aciltransferaza (ACAT), rezultnd esteri ai Col cu acizii palmitic, palmitooleic, oleic.
Colesterolul liber: inhib HMG-CoA-reductaza, ca rezultat sinteza Col n esuturile extrahepatice este meninut la un nivel sczut;inhib sinteza R- B,E, astefl determin micorarea numrului lor pe membran i diminuarea captrii LDLactiveaz E microzomial ACAT
PatologiaHiperlipoproteinemia de tip II deficien calitativ i cantitativ a R membranari pentru LDLIIa mrirea Col LDL xantomatozIIb mrirea Col LDL+VLDL (Tg)- obezitate (lipsesc xantomele)Risc de aterogenez nalt
-LP HDLconinut lipidic de 45-55%, predominnd FL 20-30%, Col 17-23% i Tg 3-6%.Componena proteic - apo A (AI, AII) dar conin cantiti mici de apo C, D, E. Nu cuprind apo B.HDL snt secretate i sintetizate de hepatocite i enterocite sub forma unor particule nscnde de form discoidal, alctuite dintr-un strat dublu lipidic (FL; Col) i apo A, apo E. Particulele nscnde din intestin nu conin apo E. particulele nscnde prin schimburi cu celelalte LP plasmatice se transform n HDL mature. Sub aciunea LCAT - Col este esterificat i migreaz n interiorul particulei. Stratul superficial al HDL este ocupat de Col preluat din esuturi i din alte LP plasmatice (CM).
Catabolismul HDLHDL snt catabolizai la nivelul ficatului: Prin intermediul apo E particulele interacioneaz cu R de pe suprafaa hepatocitelor, sunt internalizai i componentele degradate. Rolul principal al HDL este transportul Col din celulele extrahepatice n ficat, sediul catabolismului Col (transformare n AB i excreie prin bil).
PatologiaHipolipoproteinemia familiar deficit de HDL Cauza: deficit al sintezei de apoA Caracteristic: micorarea HDL; Col HDL; FLSplenomegalie, hipotrofie amigdalian; anomalii neurologice
Oxidarea AGOxidarea gliceroluluiSinteza corpilor cetonici
obiectiveleOxidarea acizilor grai: a) saturai cu numr par de atomi de carbon; b) nesaturai cu numr par de atomi de carbon; c) saturai cu numr impar de atomi de carbon; d) n peroxizomi. Reaciile pariale, enzimele, coenzimele, reglarea, randamentul energetic.Catabolismul triacilglicerolilor reaciile pariale, enzimele, reglarea.Oxidarea glicerolului reaciile pariale, enzimele, coenzimale, reglarea, randamentul energetic al oxidrii anaerobe i aerobe.Oxidarea fosfo-, sfingo- i glicolipidelor.Metabolismul corpilor cetonici. Cile biosintezei i utilizrii lor reaciile pariale, enzimele, coenzimele, reglarea. Rolul biologic al corpilor cetonici.
Oxidarea AG saturai cu numr par de atomi de carbon oxidarea AG (degradarea, scindarea, catabolizarea oxidativ a AG) moleculele de AG sufer un atac oxidativ n poziia , urmat de desprinderea unui fragment cu 2C (Acetil Co A)3 etape:Activarea AG (citoplasm) Transferul lui Acil CoA n mitocondriib oxidarea propriu zis (mitocondrii)
Activarea AG:R-COOH + ATP R-COO-AMP + PPi aciladenilatPPi 2 PiR-COO-AMP + HS-CoA R-CO~SCoA + AMP acil-CoASumar: R-COOH + ATP + HS-CoA R-CO~SCoA + AMP + PPiR-COOH + ATP + HS-CoA +H2O R-CO~SCoA + AMP + 2 PiE- acil Co A sintetazaActivatori: K; MgInhibitori: Na ; Li
Transferul lui Acil CoA n mitocondriiAcil CoA nu poate penetra membrana intern a MCEste transportat cu ajutorul carnitinei (-hidroxi--trimetilaminobutirat), ce se formeaz din Lyz i Met activ cu participarea vitaminei C, B6, NAD
Transferul lui Acil CoA n mitocondrii
b oxidarea propriu zis
Localizat n MCrepetarea a 4 reacii:Dehidrogenarea lui acil Co A (FAD)hidratarea doua dehidrogenare (NAD)reacie tiolazicn rezultat - se formeaz acetil CoA i acil CoA cu doi atomi de carbon mai puin
Bilanul energeticStoichiometria unui ciclu de oxidare:CH3- (CH2)n-CH2 CH2-COSCoA +FAD+H2O+NAD+HSCoA Acil CoA (Cn-2) +FADH2+NADH+H+ Acetil CoAStoichiometria oxidrii a. palmitic (C16): n/2 -1 numrul de cicluri pn la oxidarea complet n numrul atomilor de C
Stoichiometria oxidrii a. palmitic16/2 -1 = 7 cicluri 7FADH2-------- 7 X 2=14ATP7NADH+H ----- 7X3=21 ATP8 CH3COSCoA--- 8X12= 96 ATPSumar: 131 mol de ATPDeoarece 2 legturi macroergice sunt irosite la activarea acidului beneficiul net este de 129
Oxidarea AG nesaturai-oxidarea AG nesaturai se desfoar normal pn n vecintatea legturii duble (cis configuraie)
Dup trei cicluri normale de -oxidare se ajunge la un cis 3 enoil CoA.
Sub aciunea izomerazei legtura dubl din cis 3 trece n trans- 2 se formeaz trans 2 enoil CoA, intermediar normal al -oxidrii.
Exemplu: oxidarea acidului oleic (C18:19)CH3-(CH2)7-CH=CH-(CH2)7-COOH
Pentru AG polienici e necesar i o alt enzim epimeraza, care modific configuraia grupei OH la C3. Aceast E e rezultat din hidratarea legturii duble D-izomer-3 hidroxiacil CoA, ce nu poate fi substrat al enzimei de tipul L
Oxidarea AG cu numr inpar de atomi de CSe oxideaz n acelai mod ca AG saturai, dar n ultima etap se formeaz o molecul de propionil CoA i una de Acetil CoA.
Oxidarea AG cu numr inpar de atomi de CE- propionil CoA carboxilazaCo- vitamina H (biotin dependent)E- Metilmalonil-mutazaCo- vitamina B12Lipsa acestei E acidemie metilmalonic (n snge i urin apare acidul metilmalonic, micornd pH sngelui (administrat vitamina B12)
Oxidarea AG n peroxisomiCaracteristic AG C20-C26Produsul final este Acetil CoA, dar nu este asociat cu sinteza de ATP (acetil CoA trece n mitocondrii unde este oxidat la CO2 i H2O)Difer de oxidarea mitocondrial prin reacia de oxidare a acil-CoA la enoil-CoA (E- oxidaz)R-(CH2)n-COSCoA+O2 R-(CH2)-CH=CH-COSCoA + H2O2 ( sub aciunea catalazei 2H2O2 2H2O+O2)Amploarea acestui proces variaz n dependen de factorii nutriionali, hormonali, medicamentoi. Numrul peroxisomilor crete n diabet, inaniie, la administrarea unor medicamente (aspirina, preparate hipolemiante)Absena peroxisomilor- sindromul Zellweger: creterea AG cu catena lung i deces n primele luni de via
Oxidarea Predomin n esutul nervos (creier)Se formeaz hidroxiacizii grai superiori, proprii lipidelor SNC Necesit: NAD, Vitamina C, ATP, O2, Fe2+Nu intervine CoA i nu se formeaz ATPE- acid gras peroxidaza (necesit H2O2, ce rezult prin autooxidarea flavinenzimelor)Au loc concomitent 2 procese:eliminarea carboxilului sub form de CO2 oxidarea lui C la aldehidAldehida poate fi redus la alcool sau oxidat la acidul corespunztorNu are loc degradarea total a AG, deoarece E este activ numai la AG C13-C18.
Oxidarea Are loc n microsomiNecesit: O2, NADPH, citocromul P450E monooxigenaza hepaticAG se degradeaz n final prin beta oxidare
Metabolismul TGn plasm exist 2 fluxuri de TG:CM transport TG exogene de la intestin la esuturiVLDL transport TG endogene- de la ficat spre esuturi Mobilizarea TG din esutul adipos are loc n etape, pn la glicerol i AG, sub aciunea lipazelor (mono-; di- , triacilglicerollipaza).
Soarta AG i glicerolului:AG sunt transportai spre esuturi de albumina seric, unde:se supun oxidrii ( pentru a obine ATP) sau acetil-CoA (rezultat prin -oxidare) poate fi utilizat la sinteza Col, corpilor cetonici.Se activeaz i particip la sinteza TG, depozitate n esutul adiposDifuzeaz n plasm i circul sub form de AG liberi (sunt captai de esuturile periferice: muchii scheletici, miocard, rinichi, ficat)Eritrocitele i creierul nu pot utiliza AG ca surs de energieGlicerolul:Sinteza de TG i FLGluconeogenezOxideaz pn la CO2 i H2O
Oxidarea gliceroluluiE1 glicerolkinaza E2 glicerolfosfatDH
TrigliceridlipazaEnzima cheie a lipolizei - trigliceridlipaza adipocitar, cunoscut ca lipaza hormonsensibil.Enzima este convertibil prin fosforilare defosforilare. Forma fosforilat este activ. Catecolaminele (adrenalina, noradrenalina) snt factori majori lipolitici. Glucagonul are acela efect. Insulina, prostoglandina E snt factori antilipolitici, ei favorizeaz sinteza de TG n esutul adipos.
Sinteza corpilor cetonici(cetogeneza)Principala cale de metabolizare a acetil CoA includerea n ciclul Krebs (n condiiile n care scindarea lipidelor i a glucidelor este echilibrat)- lipidele ard n flacra glucidelorn lipsa glucidelor; inaniie, diabet - OA se utilizeaz pentru generarea Gl.n lipsa OA, Acetil Co A recurge la formarea corpilor cetonici: acetoacetatul, -hidrohibutiratul i acetonaSinteza lor are loc n ficat, dar se utilizeaz de esuturile perifericeAu rol energetic (muchiul cardiac, stratul cortical al rinichilor)
Utilizarea corpilor cetoniciAcetoacetatul 2 mol de acetil CoA, utilizate ulterior n ciclul Krebs (23 ATP)A doua cale de activare a acetoacetatului poate fi:Acetona: pn la propandiol (CH3-CHOH-CH2OH) , scindat la fragmente acetil i formilTransformat n piruvat (prin hidroxilare dubl)
Cetonemie, cetonurieCetonemie- mrirea c% de corpi cetonici n sngeCetonurie apariia CC n urinDiete bogate n lipide, srace n glucide; inaniie, diabet, dereglri gastrointestinale la copii sau gravide; glucozurie renalEliminarea hidroxibutiratului i acetoacetatului din organism (fiind anioni la excreie) conduce la pierderea de cationi Na- rezult cetoacidozaPierderea H2O dehidratarea organismului
Sinteza corpilor cetonici(cetogeneza)Principala cale de metabolizare a acetil CoA includerea n ciclul Krebs (n condiiile n care scindarea lipidelor i a glucidelor este echilibrat) - lipidele ard n flacra glucidelorn lipsa glucidelor; inaniie, diabet - OA se utilizeaz pentru generarea Gl.n lipsa OA, Acetil Co A recurge la formarea corpilor cetonici: acetoacetatul, -hidrohibutiratul i acetonaSinteza lor are loc n ficat, dar se utilizeaz de esuturile perifericeAu rol energetic (muchiul cardiac, stratul cortical al rinichilor)
cetogeneza
Utilizarea corpilor cetoniciAcetoacetatul 2 mol de acetil CoA, utilizate ulterior n ciclul Krebs (23 ATP)A doua cale de activare a acetoacetatului poate fi:Acetona: pn la propandiol (CH3-CHOH-CH2OH) , scindat la fragmente acetil i formilTransformat n piruvat (prin hidroxilare dubl)
Cetonemie, cetonurieCetonemie- mrirea c% de corpi cetonici n sngeCetonurie apariia CC n urinDiete bogate n lipide, srace n glucide; inaniie, diabet, dereglri gastrointestinale la copii sau gravide; glucozurie renalEliminarea hidroxibutiratului i acetoacetatului din organism (fiind anioni la excreie) conduce la pierderea de cationi Na- rezult cetoacidozaPierderea H2O dehidratarea organismului
Biosinteza lipidelor
Obiectivele:Biosintaza acizilor grai:saturai cu numr par de atomi de carbon;nesaturai cu numr par de atomi de carbon;saturai cu numr impar de atomi de carbon. Enzimele, coenzimele, reglarea.Biosinteza TAG: substanele iniiale, enzimele i coenzimele, reglarea.Biosinteza fosfogliceridelor: substratele, reaciile pariale ale I i a II ci; Biosinteza sfingolipidelor: precursorii, reaciile principale, enzimele, reglarea.Metabolismul colesterolului. Biosinteza colesterolului substratele, etapele, reaciile pariale ale I etape (pn la acidul mevalonic), enzimele, coenzimele, reglarea. Cile de utilizare i eliminare ale colesterolului.
Sinteza AGSinteza AG i ncorporarea lor n Tg constituie mecanismul principal de stocare a excesului de glucide alimentare (Gl nu se mai transform n glicogen dar n Tg)Etapele:Sinteza de novo cu formarea acidului palmiticElongarea acidului palmiticIntroducerea de legturi duble n AG
Particularitile sintezei AGAre loc n citozolE acid gras sintetaza alctuit din 8 proteine (domenii)- 7 sunt enzime, a 8-a proteina (purttoare) transportatoare de acil -ACP.ACP cuprinde 2 grupe SH: SH furnizat de un rest de cisteinil: SH-Cis- SH - fosfopanteteina, ataat prin legtura fosfat-Ser: SH-PantCa iniiator este acetil CoA (rezultat din glicoliz), pe cnd sursa major malonil CoA rolul reductor i revine NADPH+H
Sinteza de novo cu formarea acidului palmiticEtapele: transferul lui Acetil CoA din mitocondrii n citozolSinteza de malonil CoASinteza acidului palmitic
Transferul lui Acetil CoA din mitocondrii n citozol
Sinteza de malonil CoAacetil-CoA + HCO3- + ATP ADP + Pi + malonil-CoA E- acetil CoACarboxilazacitrat, Insulina palmitoil CoAGlucagonul
Sinteza acidului palmitic
Sinteza acidului palmitic
Sinteza acidului palmiticCiclu de reacii este reluat: butiril+ACP se condenseaz cu malonil+ACP- formnd n final C6-acil ACP.Catena AG crete pn la formarea palmitil-S-ACP
Reacia sumar: Acetil-ACP+7 malonil-CoA +14 NADPH+H Palmitat +7CO2+14NADP + + 8HSCoA+6H2Odeoarece malonil CoA se sintetizeaz din acetil CoA:8 acetil-CoA + 14 NADPH +H + + 7 ATP palmitate+ 14 NADP+ + 8HSCoA + 7 ADP + 7 Pi
Elongarea AGLocalizat: reticulul endoplasmaticAG este activat La acidul preexistent (palmitil CoA) se ataeaz malonil CoA
Biosinteza AG nesaturaiPot fi sintetizai AC mononesaturai. Introducerea unei duble legturi are loc prin aciunea unei monooxigenaze (introduce gruparea hidroxil), urmat de deshidratare
Acidul linoleic i linolenic sunt eseniali (exogen)Acidul linoleic se transform n acidul arahidonic conform reaciilor
Sinteza TAG2 ci:calea monoacilglicerolului: are loc n peretele intestinal (enterocite)din produi absorbii (resinteza lipidelor).calea glicerolfosfatului: n toate esuturile (activ: esutul adipos i ficat)AG sunt incorporai n TAG sub form activ de acilCoA:R-COOH + ATP + HS-CoA +H2O R-CO~SCoA + AMP + 2 Pi E- acil Co A sintetaza
1. calea monoacilglicerolului
TG mpreun cu FL,Col, proteine sunt incorparate n CM i secretai mai departe n vasele limfatice.
calea glicerolfosfatului
originea glicerol fosfatului n ficat:n esut adipos, ficat
Sinteza glicerofosfolipidelor2 c de sintez:Sinteza de novo - utilizeaz ca intermediar comun acidul fosfatidicCalea de rezerv o sintez din produse formateParticularitatea biosintezei FL este participarea precursorilor n forme active de derivai ai citidin fosfatului (CDP) ca CDP-colina, CDP-etanolamina, CDP-diglicerid.
Sinteza de novo
2. sinteza din produse formate
Sinteza sfingolipidelorSe formeaz din palmitoil CoA i SerSfingozina liber se formeaz din ceramid Sinteza are loc pe suprafaa citozolic a membranelor reticulului endoplasmatic
Sinteza sfingolipidelor
Sinteza ColesteroluluiSe sintetizeaz din Acetil-CoANecesit 18 moli de Acetil-CoA i 18 de ATPPrincipalul organ de metabolizare este ficatul, dar are loc i n intestin, suprarenale, tegumenteAre loc n 3 etape:Sinteza acidului mevalonicmevalonatul prin mai multe reacii - 3-izopentenil pirofosfat. 6 molecule de 3-izopentenil pirofosfat scualenScualenul se supuine ciclizrii lanosterol -- Col
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mevalonate
5-pyrophosphomevalonate
(2 steps)
isopentenyl pyrophosphate
_1010603910.cdx
_1010640906.cdx
_1010641069.cdx
_1010604570.cdx
_1010603109.cdx
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isopentenyl
pyrophosphate
dimethylallyl
pyrophosphate
_1010640402.cdx
_1010640820.cdx
_1010605428.cdx
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2 farnesyl pyrophosphate
squalene 2,3-oxidosqualene lanosterol
_1033415813.cdx
_1033416539.cdx
_1033416972.cdx
_1033414730.cdx
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squalene 2,3-oxidosqualene lanosterol
_1066650397.cdx
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lanosterol cholesterol
19 steps
_1033472530.cdx
_1033472583.cdx
REGLAREA I PATOLOGIA METABOLISMULUI LIPIDIC
ObiectiveleMetabolismul eicosanoizilor. Cile ciclooxigenazic i lipooxigenazic ale biosintezei lor. Inactivarea.Metabolismul vitaminelor liposolubile: sursele alimentare, necesitile diurne, transformrileReglarea metabolismului lipidelor la nivelul celulei.Reglarea neurohormonal a metabolismului lipidelor. Rolul lipotropinelor, ACTH, hormonilor tiroizi, insulinei, glucagonului, glucocorticoizilor i catecolaminelor.Relaiile reciproce dintre metabolismul energetic, glucidic i lipidic.Dereglrile digestiei i absorbiei lipidelor. Steatoreea pancreatic, hepatic i intestinal.Dislipidemiile:a) hipolipoproteinemiile familiale afeciunea Tangier, - i -lipoproteinemia familial; b) hiperlipoproteinemiile primare i familiale; c) hiperlipoproteinemiile secundare (dobndite) n diabet zaharat, alcoolism, afeciuni ale glandelor endocrine. Cauze, mecanismele dereglrii metabolismului lipidelor, manifestrile biochimice.6. Lipidozele tiszlare: a) ereditare Neimann-Pick, Tay-Sachs, Krabbe, Gaucher, Farber, leucodistrofia metacromatic, gangliozidoza GM1; b) dobndite obezitate, ateroscleroz, alcoolism. Cauze, mecanismele dereglrii metabolismului lipidelor, manifestrile biochimice.7. A-, hipo- i hipervitaminozele A, D, E, K cauze, manifestri metabolice.8. Rolul eicosanoizilor n procesele inflamatorii, reaciile alergice, dereglrile fluiditii sanguine.
Metabolismul eicosanoizilor
ATP-dependent carboxylation provides energy input. The CO2 is lost later during condensation with the growing fatty acid. The spontaneous decarboxylation drives the condensation reaction. The input to fatty acid synthesis is acetyl-CoA, which is carboxylated to malonyl-CoA.
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acetyl-CoA
malonyl-CoA
_1033147502.cdx
HCO3- + ATP + acetyl-CoA ADP + Pi + malonyl-CoA
Enzyme-biotin
HCO3- + ATP
ADP + Pi
Enzyme-biotin-CO2-
O
CH3-C-SCoA
acetyl-CoA
O
-O2C-CH2-C-SCoA
malonyl-CoA
ll
ll
Enzyme-biotin
1
2
Biotin is linked to the enzyme by an amide bond between the terminal carboxyl of the biotin side chain and the e-amino group of a lysine residue. The combined biotin and lysine side chains act as a long flexible arm that allows the biotin ring to translocate between the 2 active sites.
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Carboxybiotin
lysine residue
_972241744.cdx
_977422854.cdx
_977422990.cdx
_968414373.cdx
Acetyl-CoA Carboxylase, which converts acetyl-CoA to malonyl-CoA, is the committed step of the fatty acid synthesis pathway. The mammalian enzyme is regulated, by phosphorylationallosteric control by local metabolites.Conformational changes associated with regulation:In the active conformation, Acetyl-CoA Carboxylase associates to form multimeric filamentous complexes. Transition to the inactive conformation is associated with dissociation to yield the monomeric form of the enzyme (protomer).
The decreased production of malonyl-CoA prevents energy-utilizing fatty acid synthesis when cellular energy stores are depleted. (AMP is abundant only when ATP has been extensively dephosphorylated.)AMP-Activated Kinase catalyzes phosphorylation of Acetyl-CoA Carboxylase, causing inhibition.
Phosphorylated protomer of
Acetyl-CoA Carboxylase (inactive)
Dephosphorylated Polymer of
Acetyl-CoA Carboxylase (active)
Citrate
Dephosphorylated, e.g., by insulin-activated Protein Phosphatase
Palmitoyl-CoA
Phosphorylated, e.g., via AMP-activated Kinase when cellular stress or exercise depletes ATP.
Regulation of Acetyl-CoA Carboxylase
When AMP is high (ATP low), malonyl-CoA production is diminished, releasing fatty acid oxidation from inhibition. This will lead to increased ATP production.AMP-Activated Kinase has a significant role even in tissues (e.g., cardiac muscle) that do not significantly synthesize fatty acids. In such tissues malonyl-CoA, produced via one isoform of Acetyl-CoA Carboxylase, functions mainly as an inhibitor of fatty acid oxidation.
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acetyl-CoA
malonyl-CoA
ATP + HCO3
ADP + Pi
Acetyl-CoA Carboxylase
(inhibited by AMP-Activated Kinase)
_1155582881.cdx
A cAMP cascade, activated by glucagon & epinephrine when blood glucose is low, may also result in phosphorylation of Acetyl-CoA Carboxylase via cAMP-Dependent Protein Kinase.With Acetyl-CoA Carboxylase inhibited, acetyl-CoA remains available for synthesis of ketone bodies, the alternative metabolic fuel used when blood glucose is low.
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acetyl-CoA
malonyl-CoA
_1033147502.cdx
The antagonistic effect of insulin, produced when blood glucose is high, is attributed to activation of Protein Phosphatase.
Phosphorylated protomer of
Acetyl-CoA Carboxylase (inactive)
Dephosphorylated Polymer of
Acetyl-CoA Carboxylase (active)
Citrate
Dephosphorylated, e.g., by insulin-activated Protein Phosphatase
Palmitoyl-CoA
Phosphorylated, e.g., via AMP-activated Kinase when cellular stress or exercise depletes ATP.
Regulation of Acetyl-CoA Carboxylase
Palmitoyl-CoA (product of Fatty Acid Synthase) promotes the inactive conformation, diminishing production of malonyl-CoA, the precursor of fatty acid synthesis. This is an example of feedback inhibition.Regulation of Acetyl-CoA Carboxylase by local metabolites:
Phosphorylated protomer of
Acetyl-CoA Carboxylase (inactive)
Dephosphorylated Polymer of
Acetyl-CoA Carboxylase (active)
Citrate
Dephosphorylated, e.g., by insulin-activated Protein Phosphatase
Palmitoyl-CoA
Phosphorylated, e.g., via AMP-activated Kinase when cellular stress or exercise depletes ATP.
Regulation of Acetyl-CoA Carboxylase
[Citrate] is high when there is adequate acetyl-CoA entering Krebs Cycle. Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage. Citrate allosterically activates Acetyl-CoA Carboxylase.
Glucose-6-phosphatase
glucose-6-P glucose
Gluconeogenesis Glycolysis
pyruvate
fatty acids
acetyl CoA ketone bodies
cholesterol
oxaloacetate citrate
Krebs Cycle
Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are:in bacteria catalyzed by 6 different enzymes plus a separate acyl carrier protein (ACP) in mammals catalyzed by individual domains of a very large polypeptide that includes an ACP domain.Evolution of the mammalian Fatty Acid Synthase apparently has involved gene fusion. NADPH serves as electron donor in the two reactions involving substrate reduction. The NADPH is produced mainly by the Pentose Phosphate Pathway.
Fatty AcidSynthase prosthetic groups: the thiol of the side-chain of a cysteine residue of Condensing Enzyme domain.the thiol of phosphopantetheine, equivalent in structure to part of coenzyme A.
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-mercaptoethylamine
pantothenate
ADP-3'-
phosphate
Coenzyme A
phosphopantetheine
_1021578728.cdx
_1021578976.cdx
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cysteine
_1123783145.unknown
Phosphopantetheine (Pant) is covalently linked via a phosphate ester to a serine OH of the acyl carrier protein domain of Fatty Acid Synthase.The long flexible arm of phosphopantetheine helps its thiol to move from one active site to another within the complex.
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-mercaptoethylamine
pantothenate
serine
residue
phosphopantetheine
of acyl carrier protein
phosphate
_1128866047.cdx
As each of the substrates acetyl-CoA & malonyl-CoA bind to the complex, the initial attacking group is the oxygen of a serine hydroxyl group of the Malonyl/acetyl-CoA Transacylase enzyme domain. Each acetyl or malonyl moiety is transiently in ester linkage to this serine hydroxyl, before being transferred into thioester linkage with the phosphopantetheine thiol of the acyl carrier protein (ACP) domain. Acetate is subsequently transferred to a cysteine thiol of the Condensing Enzyme domain.
Condensing Malonyl/acetyl-CoA Dehydratase Enoyl -Ketoacyl ACP Thioesterase
Enzyme (Cys) Transacylase (Ser) Reductase Reductase (Pant)
N-
-C
Order of domains in primary structure of mammalian Fatty Acid Synthase
The condensation reaction (step 3) involves decarboxylation of the malonyl moiety, followed by attack of the resultant carbanion on the carbonyl carbon of the acetyl (or acyl) moiety.
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1
2
3
1 Malonyl/acetyl-CoA-ACP Transacylase
2 Malonyl/acetyl-CoA-ACP Transacylase
3 Condensing Enzyme (-Ketoacyl Synthase)
_1009269396.cdx
The b-ketone is reduced to an alcohol by e- transfer from NADPH. Dehydration yields a trans double bond. Reduction by NADPH yields a saturated chain.
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4
5
6
4 -Ketoacyl-ACP Reductase
5 -Hydroxyacyl-ACP Dehydratase
6 Enoyl-ACP Reductase
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Following transfer of the growing fatty acid from phosphopantetheine to the Condensing Enzyme's cysteine sulfhydryl, the cycle begins again, with another malonyl-CoA.
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7
2
7 Condensing Enzyme
2 Malonyl/acetyl-CoA-ACP Transacylase (repeat).
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Product release: When the fatty acid is 16 carbon atoms long, a Thioesterase domain catalyzes hydrolysis of the thioester linking the fatty acid to phosphopantetheine. The 16-C saturated fatty acid palmitate is the final product of the Fatty Acid Synthase complex.
The primary structure of the mammalian Fatty Acid Synthase protein is summarized above.Fatty Acid Synthase in mammals is a homo-dimer. X-Ray crystallographic analysis at 4.5 resolution shows the dimeric Fatty Acid Synthase to have an X-shape, with domains arranged as summarized at right.
Condensing Malonyl/acetyl-CoA Dehydratase Enoyl -Ketoacyl ACP Thioesterase
Enzyme (Cys) Transacylase (Ser) Reductase Reductase (Pant)
N-
-C
Order of domains in primary structure of mammalian Fatty Acid Synthase
KR KR
DH DH
KS KS
MAT MAT
ER ER
Arrangement of domains
in Fatty Acid Synthase
arm
leg
The solved structure does not resolve the position of ACP & Thioesterase domains, predicted from primary structure to be near b-Ketoacyl Reductase (KR) domains of lateral "arms" of the complex. These domains may be too flexible to be resolved. KR = b-Ketoacyl Reductase; ER = Enoyl Reductase; DH = Dehydratase; KS = b-Ketoacyl Synthase (Condensing Enzyme); MAT = Malonyl/Acetyl-CoA Transacylase.
Condensing Malonyl/acetyl-CoA Dehydratase Enoyl -Ketoacyl ACP Thioesterase
Enzyme (Cys) Transacylase (Ser) Reductase Reductase (Pant)
N-
-C
Order of domains in primary structure of mammalian Fatty Acid Synthase
KR KR
DH DH
KS KS
MAT MAT
ER ER
Arrangement of domains
in Fatty Acid Synthase
arm
leg
Fatty Acid Synthase complex is somewhat asymmetric.There is evidence for conformational changes relating to catalysis. Protein flexibility may facilitate transfer of ACP-attached reaction intermediates among the several active sites in each half of the complex. For images see:website (ETH Zurich)website (Asturias lab, Scripps) article (Maier, Jenni & Ban; requires subscription to Science).
KR KR
DH DH
KS KS
MAT MAT
ER ER
Arrangement of domains
in Fatty Acid Synthase
arm
leg
Explore with Chime the structure of the E. coli b-Ketoacyl-ACP Synthase III, equivalent to the domains of the mammalian Fatty Acid Synthase that catalyze the initial acetylation and condensation reactions.
b-Oxidation & Fatty Acid SynthesisCompared
Oxidation Pathway
Fatty Acid Synthesis
pathway location
mitochondrial matrix
cytosol
acyl carriers (thiols)
Coenzyme-A
phosphopantetheine (ACP) & cysteine
e acceptors/donor
FAD & NAD+
NADPH
-OH intermediate
L
D
2-C product/donor
acetyl-CoA
malonyl-CoA
(& acetyl-CoA)
Fatty Acid Synthase is transcriptionally regulated. In liver:Insulin, a hormone produced when blood glucose is high, stimulates Fatty Acid Synthase expression.Thus excess glucose is stored as fat.Transcription factors that that mediate the stimulatory effect of insulin include USFs (upstream stimulatory factors) and SREBP-1. SREBPs (sterol response element binding proteins) were first identified for their regulation of cholesterol synthesis.Polyunsaturated fatty acids diminish transcription of the Fatty Acid Synthase gene in liver cells, by suppressing production of SREBPs.
In fat cells:Expression of SREBP-1 and of Fatty Acid Synthase is inhibited by leptin, a hormone that has a role in regulating food intake and fat metabolism. Leptin is produced by fat cells in response to excess fat storage. Leptin regulates body weight by decreasing food intake, increasing energy expenditure, and inhibiting fatty acid synthesis.
Elongation beyond the 16-C length of the palmitate product of Fatty Acid Synthase occurs in mitochondria and endoplasmic reticulum (ER). Fatty acid elongation within mitochondria involves the b-oxidation pathway running in reverse, but NADPH serves as electron donor for the final reduction step. Polyunsaturated fatty acids esterified to CoA are substrates for the ER elongation machinery, which uses malonyl-CoA as donor of 2-carbon units. The reaction sequence is similar to Fatty Acid Synthase but individual steps are catalyzed by separate proteins. A family of enzymes designated Fatty Acid Elongases catalyze the initial condensation step for elongation of saturated or polyunsaturated fatty acids.
Desaturases introduce double bonds at specific positions in a fatty acid chain.Mammalian cells are unable to produce double bonds at certain locations, e.g., D12. Thus some polyunsaturated fatty acids are dietary essentials, e.g., linoleic acid, 18:2 cis D9,12 (18 C atoms long, with cis double bonds at carbons 9-10 & 12-13).
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oleate 18:1 cis 9
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Formation of a double bond in a fatty acid involves the following endoplasmic reticulum membrane proteins in mammalian cells:NADH-cyt b5 Reductase, a flavoprotein with FAD as prosthetic group. Cytochrome b5, which may be a separate protein or a domain at one end of the desaturase. Desaturase, with an active site that contains two iron atoms complexed by histidine residues.
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oleate 18:1 cis 9
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The desaturase catalyzes a mixed function oxidation reaction. There is a 4-electron reduction of O2 2 H2O as a fatty acid is oxidized to form a double bond. 2e- pass from NADH to the desaturase via the FAD-containing reductase & cytochrome b5, the order of electron transfer being: NADH FAD cyt b5 desaturase2e- are extracted from the fatty acid as the double bond is formed.E.g., the overall reaction for desaturation of stearate (18:0) to form oleate (18:1 cis D9) is:stearate + NADH + H+ + O2 oleate + NAD+ + 2H2O
Control of fatty acid oxidation is exerted mainly at the step of fatty acid entry into mitochondria. Malonyl-CoA (which is also a precursor for fatty acid synthesis) inhibits Carnitine Palmitoyl Transferase I. Malonyl-CoA is produced from acetyl-CoA by the enzyme Acetyl-CoA Carboxylase.
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acetyl-CoA
malonyl-CoA
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Activated Kinase, leading to decreased malonyl-CoA. The decrease in malonyl-CoA concentration leads to increased activity of Carnitine Palmitoyl Transferase I. Increased fatty acid oxidation then generates acetyl-CoA, for entry into Krebs cycle with associated ATP production.AMP-Activated Kinase, a sensor of cellular energy levels, is allosterically activated by AMP, which is high in concentration when [ATP] is low.Acetyl-CoA Carboxylase is inhibited when phosphorylated by AMP-
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acetyl-CoA
malonyl-CoA
ATP + HCO3
ADP + Pi
Acetyl-CoA Carboxylase
(inhibited by AMP-Activated Kinase)
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The carbonyl O of the thioester substrate is hydrogen bonded to the 2'-OH of the ribitol moiety of FAD, giving the sugar alcohol a role in positioning the substrate and increasing acidity of the substrate a-proton.
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FAD
FADH2
2 e + 2 H+
dimethylisoalloxazine
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Human genetic diseases have been identified that involve mutations in:the plasma membrane fatty acid transporter CD36Carnitine Palmitoyltransferases I & II (required for transfer of fatty acids into mitochondria) Acyl-CoA Dehydrogenases for various chain lengths of fatty acidsHydroxyacyl-CoA Dehydrogenases for medium & short chain length fatty acidsMedium Chain b-Ketothiolasethe trifunctional protein complexElectron Transfer Flavoprotein (ETF).
Human genetic diseases:Symptoms vary depending on the specific genetic defect but may include:hypoglycemia and failure to increase ketone body production during fastingfatty degeneration of the liverheart and/or skeletal muscle defectsmaternal complications of pregnancysudden infant death (SIDS). Hereditary deficiency of Medium Chain Acyl-CoA Dehydrogenase (MCAD), the most common genetic disease relating to fatty acid catabolism, has been linked to SIDS.
The reactions presented accomplish catabolism of a fatty acid with an even number of C atoms & no double bonds. Additional enzymes deal with catabolism of fatty acids with an odd number of C atoms or with double bonds.The final round of b-oxidation of a fatty acid with an odd number of C atoms yields acetyl-CoA & propionyl-CoA. Propionyl-CoA is converted to the Krebs cycle intermediate succinyl-CoA, by a pathway involving vitamin B12 (to be presented later).
Most double bonds of naturally occurring fatty acids have the cis configuration. As C atoms are removed two at a time, a double bond may end up in the wrong position or wrong configuration to be the correct substrate for Enoyl-CoA Hydratase. The reactions that allow unsaturated fatty acids to be fully catabolized by the b-oxidation pathway are summarized in the textbook.
This impedes entry of acetyl-CoA into Krebs cycle. Acetyl-CoA in liver mitochondria is converted then to ketone bodies, acetoacetate & b-hydroxybutyrate. During fasting or carbohydrate starvation, oxaloacetate is depleted in liver due to gluconeogenesis.
Glucose-6-phosphatase
glucose-6-P glucose
Gluconeogenesis Glycolysis
pyruvate
fatty acids
acetyl CoA ketone bodies
cholesterol
oxaloacetate citrate
Krebs Cycle
Chilomicronii transport lipidele resintetizate n epiteliul intestinal spre esuturi. Snt alctuite din 80% trigliceride, 7-8 % fosfolipide, 7% colesteride i doar 2% proteine.Pre--LP se formeaz n ficat din lipidele sintetizate aici i ndeplinesc funcia de transport a trigliceridelor din ficat spre esuturi. Snt LP bogate n trigliceride.n snge pre--LP snt transformate n -LP (prin cedarea trigliceridelor esuturilor i nbogirea cu colesterol). ndeplinesc funcia de transport a colesterolului spre esuturi.-LP se formeaz n ficat, au un coninut nalt de proteine i fosfolipide. Funcia lor principal este transportul colesterolului de la esuturi spre ficat.
Cell layers adjacent to the lumen of arterial blood vessel. Development of an atherosclerotic plaque: Various conditions can initiate formation of a lesion in the endothelium lining the arterial lumen. Inflammatory response, including cytokine production that may be activated by oxidized lipids present in LDL. Risk factors include elevated circulating LDL, high blood pressure, exposure to nicotine, etc.
blood vessel lumen
smooth muscle cells
endothelial cells
elastic
lamina
Lipoproteins (e.g., LDL) leak across the endothelium and accumulate in the subendothelial space. They accumulate in part through binding to proteoglycans.Macrophages accumulate at the lesion and enter the subendothelial space. They ingest lipoproteins and appear as foam cells due to cytoplasmic lipid droplets.
blood vessel lumen
smooth muscle cells
endothelial
cells
(
(
foam cell
LDL
( ( (
( ( (
(
( (
Smooth muscle cells may also migrate into the subendothelial space & become foam cells.As foam cells eventually die, they may release harmful cellular contents that can contribute to rupturing of the plaque and development of blood clots.
blood vessel lumen
smooth muscle cells
endothelial
cells
(
(
foam cell
LDL
( ( (
( ( (
(
( (