Fatty Acid Synthesis

Biosintesis Asam lemak
Input untuk biosintesis
asam lemak :
acetyl-CoA, yg
dikarboksilasi menjadi
malonyl-CoA.
O
H3C
C
SCoA
acetyl-CoA
O
−
OOC
CH2
C
SCoA
malonyl-CoA
Input energi: ATP.
CO2 dilepaskan selama pertumbuhan asam lemak.
Acetyl-CoA
Carboxylase
mengkatalsis
reaksi 2-langkah
dimana acetylCoA
dikarboksilasi
membentuk
malonyl-CoA.
Enzyme-biotin
HCO3 + ATP
1
ADP + Pi
Enzyme-biotin-CO2
O
ll
CH3-C-SCoA
acetyl-CoA
2
Enzyme-biotin
O
-
ll
O2C-CH2-C-SCoA
malonyl-CoA
Gugus prostetik enzim: biotin.
Reaksi keseluruhan: spontan,:
HCO3− + ATP + acetyl-CoA  ADP + Pi + malonyl-CoA
O
O−
C
C
O
N
NH
CH CH
H2C
CH
S
Carboxybiotin
O
O
(CH2)4 C
NH
C
(CH2)4 CH
lysine NH
residue
Biotin diikat ke enzim dg ikatan amida antara ujung
karboksil biotin dan gugus ε-amino residu lysine.
Rantai samping gabungan biotin dan lysine bertindak
sbg lengan panjang yg fleksibel
SH
Coenzyme A
CH2
CH2
β -mercaptoethylamine
NH
C
O
CH2
CH2
pantothenate
NH
cysteine
C
NH2
O
ADP-3'phosphate
HO
C
H
H3C
C
CH3 O
H2C
O
P
N
N
O
O
O−
P
O
CH2
O−
H
phosphopantetheine
N
N
−
O
O
H
H
O
H
OH
P
O
O−
SH
CH2
Phosphopantetheine
(Pant) terikat kovalen
via ester fosfat ke OH
serin dalam acyl carrier
protein domain sintase
asam lemak.
Lengan fleksible yg
panjang dari
phosphopantetheine
membantu thiol nya
untuk bergerak dari sisi
aktif satu ke yg lain
dalam kompleks enzim.
phosphopantetheine
of acyl carrier protein
CH2
β -mercaptoethylamine
NH
C
O
CH2
CH2
pantothenate
NH
C
O
HO
C
H
H3C
C
CH3 O
H2C
O
P
NH
O
O−
phosphate
CH2
CH
C
serine
residue
O
acetyl-S-CoA HS-CoA
Pant
SH
Cys
SH
Pant
1
SH
CO2
malonyl-S-CoA HS-CoA
Cys
2
S
C
CH3
O
Pant
Cys
S
S
C
O C
CH2
1 Malonyl/acetyl-CoA-ACP Transacylase COO−
2 Malonyl/acetyl-CoA-ACP Transacylase
3 Condensing Enzyme (β-Ketoacyl Synthase)
CH3
3
O
Pant
Cys
S
SH
C
O
CH2
C
CH3
Reaksi kondensasi (langkah ke 3) menyangkut
dekarboksilasi malonyl, diikuti dg serangan yg
dihasilkan carbanion pada karbon karbonil acetyl
(atau acyl).
O
NADPH NADP+
Pant
Cys
S
SH
C
O
O
CH3
Pant
Cys
S
SH
C
O
HC
5
Pant
Cys
S
SH
C
CH
CH2
CH2
C
4
NADPH NADP+
H2O
OH
CH3
HC
CH3
O
6
Pant
Cys
S
SH
C
O
CH2
CH2
CH3
4 β-Ketoacyl-ACP Reductase
5 β-Hydroxyacyl-ACP Dehydratase
6 Enoyl-ACP Reductase
4. β-keton direduksi mjd alkohol dg transfer e− transfer
dari NADPH.
5. Dehidrasi menghasilkan ikatan rangkap trans
6. Reduksi dg NADPH menghasilkan rantai jenuh.
Malonyl-S-CoA HS-CoA
Pant
Cys
S
SH
C
O
7
Pant
Cys
SH
S
C
2
O
Pant
Cys
S
S
C
O
C
CH2
CH2
CH2
CH2
CH2
CH2
COO−
CH2
CH3
CH3
O
CH3
7 Condensing Enzyme
2 Malonyl/acetyl-CoA-ACP Transacylase (repeat).
transfer asam lemak yg sdg tumbuh dari
phosphopantetheine ke sulfhidril sistein Condensing
enzyme, siklus mulai lagi dg malonyl-CoA yg lain.
Product release:
Jika asam lemak telah mencapai 16 atom karbon,
Thioesterase mengkatalisis hidrolisis ikatan tioester
asam lemak - phosphopantetheine.
Asam lemak jenuh 16-C ( palmitate) adalah produk
akhir kompleks sintase asam lemak.
Overall Reactions
Acetyl-CoA + 7 malonyl-CoA + 14NADPH
7H+ + 14H+
Palmitate + 7CO2 + 14NADP+ + 8 HSCoA +
6H2O
7 Acetyl-CoA + 7CO2 + 7ATP
7 malonyl-CoA +7ADP + 7Pi + 7H+
8 Acetyl-CoA + 14NADPH + 7H+ + 7ATP
Palmitate + 14NADP+ + 8 HSCoA + 6H2O +
7ADP + 7Pi
Pemanjangan rantai
R-CH2CH2CH2C~SCoA
Malonyl-CoA*
O
HS-CoA
OOC-CH2C~SCoA
CH3C~SCoA
O
O
CO2
Acetyl-CoA
R-CH2CH2CH2CCH2C~SCoA
O
O
1 NADPH
Sistem pemanjangan
NADH
di dalam smooth ER
2 - H2O
3 NADPH
R-CH2CH2CH2CH2CH2C~SCoA
O
Modifikasi:
1.Pemanjangan
2.Desaturasi menghasilkan ikatan
rangkap
Rule:
NADH
2
Desaturase System memerlukan O2 dan
terkait dg sistem transport elektron
Cyt b5
reductase
O2
Cyt b5
3
(FAD)
Saturated FA-CoA
1
2
NOTE:
1. Sistem dalam membran ER
2. NADH dan asam lemak menyokong elektron
3. Fatty acyl desaturase memp fungsi
oksidase campuran
Sistem
SistemDesaturasi
Desaturasi Asam
Asam Lemak
Lemak
C18-stearoly-CoA
C18 ∆9-oleyl-CoA
+ O2 + 2H+
+ 2H2O
Desaturase
2 cyt b5 Fe2+
2 cyt b5 Fe2+
2H+ + cyt b5 reductase cyt b5 reductase
FAD
FADH2
NADH + H+
NAD+
Desaturase
Cyt
b5
Cyt b5
reductase
Desaturase
Palmitoleat
16:1(∆9)
Asam lemak
esensial
Desaturase
α-Linolenat
18:3(∆9,12,15)
Lipid lain
Palmitat
16:0
Stearat
18:0
Elongase
Batas diijinkan
Dalam mamalia
Desaturase
Oleat
18:1(∆9)
Desaturase
Linoleat
18:2(∆9,12)
Desaturase
Elongase
γ-Linolenat
18:3(∆6,9,12)
Eicosatrienoat
20:3(∆8,11,14)
Desaturase
Arachidonat
20:4(∆5,8,11,14)
Biosintesis Asam Lemak
Synthesis
Beta Oxidation
•
•
•
•
Kloroplas
Memerlukan NADPH
Acyl carrier protein
D-isomer
• aktivasi dg CO2
• peroksisom
• NADH, FADH2
• Keto → jenuh
• Jenuh → keto
• CoA
• L-isomer
• CO2
Pemanjangan palmitat dilakukan di endoplasmic
reticulum (ER).
Substrat : Asam lemak terseterifikasi dg coenzyme A
Malonyl-CoA : donor 2 C.
10 9
O
C
OH
oleate 18:1 cis ∆9
Desaturasi menghasilkan ikatan rangkap pada posisi
spesifik rantai asam lemak
Fatty
FattyAcid
AcidSynthase
Synthase
β-Ketoacyl
β-Ketoacyl
-ACP
-ACPsynthase
synthase
O
CH3-CH2-CH2-C-S
O
S-C-CH2-CH2-CH3
KS
HS
Acetyl-CoA
CoA-SH
NADP+
Enoyl-ACP
Enoyl-ACP
NADPH
reductase
reductase
H+
O
CH3-CH=CH-C-S
β-Hydroxyacyl-ACP
β-Hydroxyacyl-ACP H2O
KS
ACP
CoA-SH
O
S -C-CH2-COO-
CH3-CH -CH2-C-S
β-Ketoacyl
β-Ketoacyl
-ACP
-ACPreductase
reductase
O
S-C-CH3
SH
Malonyl-CoA
O
NADP+
NADPH
H+
Initiation or
priming
O
S -C-CH3
KS -SH
dehydrase
dehydrase
OH
Acetyl-CoAAcetyl-CoAACP
ACPtransacylase
transacylase
KS
S
C=O
CH2
C=O
CH3
CO2
KS -SH
Malonyl-CoAMalonyl-CoAACP
ACPtransacylase
transacylase
β-Keto-ACP
β-Keto-ACP
synthase
synthase(condensing
(condensingenzyme)
enzyme)
Elongation
Struktur Membran Plasma