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

Oxidarea AG saturai cu numr

par de atomi de carbon

1.
2.

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 mitocondrii
xidarea propriu zis (mitocondrii)

Activarea AG:

R-COOH + ATP R-COO-AMP + PPi

aciladenilat
PPi 2 Pi

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

acil-CoA

Sumar:
R-COOH + ATP + HS-CoA R-CO~SCoA + AMP + PPi
R-COOH + ATP + HS-CoA +H2O R-CO~SCoA + AMP
+ 2 Pi
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

xidarea propriu zis

1.
2.
3.
4.

Localizat n MC
repetarea a 4 reacii:
Dehidrogenarea lui acil Co A (FAD)
hidratare
a doua dehidrogenare (NAD)
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

-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 Dizomer-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

1.
2.

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:
eliminarea carboxilului sub form de CO2
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

1.

2.

n plasm exist 2 fluxuri de TG:

CM transport TG exogene de la intestin la
esuturi
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 oxidrii ( pentru a obine ATP) sau acetil-CoA
(rezultat prin -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)

1.

2.

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:
pn la propandiol (CH3-CHOHCH2OH) , scindat la fragmente
acetil i formil
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

O
H3C

SCoA

acetyl-CoA
O

OOC

CH2

SCoA

malonyl-CoA
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.

AMP-Activated Kinase,
H3C C SCoA
a sensor of cellular
acetyl-CoA
energy levels, is
Acetyl-CoA

allosterically activated by ATP + HCO

Carboxylase
3
AMP, which is high in
(inhibited by
concentration when
AMP-Activated
ADP
+
P
i
[ATP] is low.
Kinase)
Acetyl-CoA Carboxylase
is inhibited when
phosphorylated by AMP-

OOC

CH2

SCoA

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 acetylCoA, for entry into Krebs cycle with associated ATP
production.

dimethylisoalloxazine
H3 C

H3 C

H
C

C
H

FAD

C
C

C
C

O
C

2e +2H

NH
C

CH2
HC

OH

HC

OH

HC

OH O

H2C

P
O-

Adenine

O
O

P
O-

Ribose

H3C

H3C

H
C

C
H

C
C

FADH2

H
N

O
C
C

CH2

N
H

HC

OH

HC

OH

HC

OH O

H2C

P
O-

NH
C

Adenine

O
O

O-

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 -proton.

Ribose

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 -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 -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 -oxidation
pathway are summarized in the textbook.

Glucose-6-phosphatase
glucose-6-P
glucose
Gluconeogenesis

Glycolysis
pyruvate
fatty acids

During fasting
acetyl CoA
ketone bodies
or carbohydrate
cholesterol
starvation,
citrate
oxaloacetate is oxaloacetate
depleted in
liver due to
Krebs Cycle
gluconeogenesis
.
This impedes entry of acetyl-CoA into Krebs cycle.
Acetyl-CoA in liver mitochondria is converted then to
ketone bodies, acetoacetate & -hydroxybutyrate.