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
