Oxidarea AG

Oxidarea glicerolului
Sinteza corpilor
cetonici
obiectivele
Oxidarea 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:
1. Activarea AG (citoplasm)
2. Transferul lui Acil CoA n mitocondrii
3. b oxidarea propriu zis (mitocondrii)
Activarea AG:
R-COOH + ATP R-COO-AMP + PP
i
aciladenilat

PP
i
2 P
i

R-COO-AMP + HS-CoA R-CO~SCoA + AMP
acil-CoA

Sumar:
R-COOH + ATP + HS-CoA R-CO~SCoA + AMP + PP
i

R-COOH + ATP + HS-CoA +H2O R-CO~SCoA + AMP + 2 P
i
E- acil Co A sintetaza
Activatori: K; Mg
Inhibitori: Na ; Li


Transferul lui Acil CoA n
mitocondrii
Acil CoA nu poate penetra membrana intern a
MC
Este 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 MC
repetarea a 4 reacii:
1. Dehidrogenarea lui acil Co A (FAD)
2. hidratare
3. a doua dehidrogenare (NAD)
4. reacie tiolazic
n rezultat - se formeaz acetil CoA i acil CoA cu
doi atomi de carbon mai puin


Bilanul energetic
Stoichiometria unui ciclu de oxidare:
CH3- (CH2)n-CH2 CH2-COSCoA +FAD+
H2O+NAD+HSCoA
Acil CoA (Cn-2) +FADH2+NADH+H+ Acetil
CoA
Stoichiometria oxidrii a. palmitic (C16):
n/2 -1 numrul de cicluri pn la oxidarea
complet
n numrul atomilor de C
Stoichiometria oxidrii a. palmitic
16/2 -1 = 7 cicluri
7FADH2-------- 7 X 2=14ATP
7NADH+H ----- 7X3=21 ATP
8 CH3COSCoA--- 8X12= 96 ATP
Sumar: 131 mol de ATP
Deoarece 2 legturi macroergice sunt irosite la
activarea acidului beneficiul net este de 129

Oxidarea AG nesaturai
b-oxidarea AG nesaturai se desfoar normal
pn n vecintatea legturii duble (cis
configuraie)

Dup trei cicluri normale de b-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 b-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 C
Se 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 C
E- propionil CoA carboxilaza
Co- vitamina H (biotin dependent)
E- Metilmalonil-mutaza
Co- vitamina B12
Lipsa acestei E acidemie metilmalonic (n
snge i urin apare acidul metilmalonic,
micornd pH sngelui (administrat vitamina
B12)
Oxidarea AG n peroxisomi
Caracteristic AG C20-C26
Produsul 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 ATP
E- acid gras peroxidaza (necesit H2O2, ce rezult prin
autooxidarea flavinenzimelor)
Au loc concomitent 2 procese:
1. eliminarea carboxilului sub form de CO2
2. oxidarea lui C la aldehid
Aldehida poate fi redus la alcool sau oxidat la acidul
corespunztor
Nu are loc degradarea total a AG, deoarece E este activ numai
la AG C13-C18.

Oxidarea
Are loc n microsomi
Necesit: O2, NADPH, citocromul P450
E monooxigenaza hepatic
AG se degradeaz n final prin beta oxidare
Metabolismul TG
n plasm exist 2 fluxuri de TG:
1. CM transport TG exogene de la intestin la esuturi
2. VLDL 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:
1. se supun b oxidrii ( pentru a obine ATP) sau acetil-CoA (rezultat
prin b-oxidare) poate fi utilizat la sinteza Col, corpilor cetonici.
2. Se activeaz i particip la sinteza TG, depozitate n esutul adipos
3. Difuzeaz 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 energie
Glicerolul:
1. Sinteza de TG i FL
2. Gluconeogenez
3. Oxideaz pn la CO2 i H2O






Oxidarea glicerolului
E1 glicerolkinaza
E2 glicerolfosfatDH
Trigliceridlipaza
Enzima 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 glucidelor
n lipsa glucidelor; inaniie, diabet - OA se utilizeaz pentru
generarea Gl.
n lipsa OA, Acetil Co A recurge la formarea corpilor cetonici:
acetoacetatul, -hidrohibutiratul i acetona
Sinteza lor are loc n ficat, dar se utilizeaz de esuturile periferice
Au rol energetic (muchiul cardiac, stratul cortical al rinichilor)


Utilizarea corpilor cetonici
Acetoacetatul 2 mol de acetil
CoA, utilizate ulterior n ciclul
Krebs (23 ATP)
A doua cale de activare a
acetoacetatului poate fi:
Acetona:
1. pn la propandiol (CH3-CHOH-
CH2OH) , scindat la fragmente acetil i
formil
2. Transformat n piruvat (prin hidroxilare
dubl)
Cetonemie, cetonurie
Cetonemie- mrirea c% de corpi cetonici n snge
Cetonurie apariia CC n urin
Diete bogate n lipide, srace n glucide; inaniie, diabet,
dereglri gastrointestinale la copii sau gravide;
glucozurie renal
Eliminarea hidroxibutiratului i acetoacetatului din
organism (fiind anioni la excreie) conduce la pierderea
de cationi Na- rezult cetoacidoza
Pierderea 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.

H
3
C C SCoA
O
CH
2
C SCoA
O

OOC
acetyl-CoA
malonyl-CoA
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-

H
3
C C SCoA
O
CH
2
C SCoA
O

OOC
acetyl-CoA
malonyl-CoA
ATP + HCO
3

ADP + P
i

Acetyl-CoA
Carboxylase
(inhibited by
AMP-Activated
Kinase)
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.

C
C
C
H
C
C
H
C
N
C
C
N
N
C
NH
C
H
3
C
H
3
C
O
O
CH
2
HC
HC
HC
H
2
C
OH
O P O P O
O
O-
O
O-
Ribose
OH
OH
Adenine
C
C
C
H
C
C
H
C
N
C
C
H
N
N
H
C
NH
C
H
3
C
H
3
C
O
O
CH
2
HC
HC
HC
H
2
C
OH
O P O P O
O
O-
O
O-
Ribose
OH
OH
Adenine
FAD FADH
2

2 e

+ 2 H
+

dimethylisoalloxazine
Human genetic diseases have been identified that
involve mutations in:
the plasma membrane fatty acid transporter CD36
Carnitine Palmitoyltransferases I & II (required for
transfer of fatty acids into mitochondria)
Acyl-CoA Dehydrogenases for various chain lengths of
fatty acids
Hydroxyacyl-CoA Dehydrogenases for medium & short
chain length fatty acids
Medium Chain b-Ketothiolase
the trifunctional protein complex
Electron 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 fasting
fatty degeneration of the liver
heart and/or skeletal muscle defects
maternal complications of pregnancy
sudden 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 B
12
(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.

Glucose-6-phosphatase
glucose-6-P glucose
Gluconeogenesis Glycolysis
pyruvate
fatty acids
acetyl CoA ketone bodies
cholesterol
oxaloacetate citrate

Krebs Cycle
During fasting
or carbohydrate
starvation,
oxaloacetate is
depleted in liver
due to
gluconeogenesis.