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

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

_1033147502.cdx

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)

_1155582881.cdx

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

_1001749585.cdx

_1066634605.cdx

_1066634638.cdx

_1001749759.cdx

_1001749458.cdx

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