Fatty Acid Biosynthesis - Rose-Hulman Institute of …brandt/Chem331/Lipid_synthesis... · of...
Transcript of Fatty Acid Biosynthesis - Rose-Hulman Institute of …brandt/Chem331/Lipid_synthesis... · of...
Fatty Acid Biosynthesis
Acetyl-CoA Acetyl-CoAcarboxylase
CO2+
ATP
Pi+
ADP
Malonyl-CoAN
NHHN
S H
HH
O
O
H
Lys-Enzyme
Carboxylaseprosthetic group
H3C C
O
S CoA
H2C C
O
S CoA
CO O
O
CH2
C CH3H3C
CHHO
CO
NH
H2C CH2 C
OHN
O P
O
CH2O
Phosphopantetheine groupof Acyl-Carrier Protein
CH2 CH2 SH
O
CH2
C CH3H3C
CHHO
CO
NH
H2C CH2 C
OHN
O P
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
O
Coenzyme A(CoA-SH)
CH2 CH2 SH
ACP
KR MAT DH ER KR ACP TE
KRMATDHERKRACPTE
Acetyl-CoA
CoA-SH
ACP-SH
H3C C
O
S CoA
H3C C
O
S ACP
Malonyl/acetyl-CoA-ACPtransacetylase (MAT)
H3C (CH2)n C
O
S ACP
Malonyl-CoA
H2C C
O
S CoA
CO O
KS-SH ACP-SH
-Ketoacyl-ACPSynthase (KS)
H3C (CH2)n C
O
S KS
CoA-SH
Malonyl-ACP
H2C C
O
S ACP
CO O
Malonyl/acetyl-CoA-ACPtransacetylase (MAT)
KS-SH+CO2
H3C (CH2)n C CH2 C
O
S ACP
O
-Ketoacyl-ACPSynthase (KS)
H3C (CH2)n C CH2 C
O
S ACP
OH
NADPH
NADP
H
-Ketoacyl-ACPReductase (KR)H3C (CH2)n C C C
O
S ACP
HH2O
-Hydroxyacyl-ACPDehydrase (DH)
H
NADP
NADPH
Enoyl-ACPReductase (ER)
H3C (CH2)n+2 C
O
S ACP
trans- 2-Enoyl-ACP
-Hydroxyacyl-ACP
-Ketoacyl-ACP
Acyl-ACP
Acyl-ACP(longer by2 carbons)
H3C C
O
S ACP(CH2)14
Palmitoyl-ACP
ACP-SHH2O
Thioesterase (TE)H3C C
O
O(CH2)14
Palmitate
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Polyketide Synthesis
O
OHO
O
OH
OH
6-Deoxyerythronolide B
O
OO
O
OH
O
Erythromycin A
OH OH
O
O
HON
H3CCH3
CH3
CH3
OH
O
CH3
CH3
Elongation
H3C C
O
S CoA
Acetyl-CoA
H3C (CH2)n CH2 CH2 C
O
S CoA
Acyl-CoA
NAD
NADHNADH
H3C (CH2)n C C C
O
S CoA
H
Htrans- 2-Enoyl-CoA
Enoyl-CoAHydratase
H3C (CH2)n C CH2 C
O
S CoA
H
OH
H3C (CH2)n C CH2 C
O
S CoA
O
H3C (CH2)n+2CH2 CH2 C
O
S CoA
Acyl-CoA(longer by two carbons)
CoA-SH
Thiolase
-Hydroxyacyl-CoA
-Ketoacyl-CoA
H2O
3-L-hydroxyacyl-CoAdehydrogenase
Enoyl-CoAReductase
NADPH
NADP
Desaturation
SC
O
Oleyl-CoA(18:1 9)
CS
O
Stearyl-CoA(18:0)
CoACoA
O2
2 H2 H2O+
NADH +
+ NAD
9-fatty-acyl-CoAdesaturase
Arachidonic Acid Synthesis
CS
OLinoleyl-CoA(18:2 9,12)
O2
2 H
NADH +
+
6-fatty-acyl-CoAdesaturase
-Linolenyl-CoA(18:3 6,9,12)
CS
O
Elongasesystem
Malonyl-CoA+ 2 NADPH
CoA-SH + CO2+ H2O + 2 NADP
CoA
CoA
CS
O
8,11,14-Eicosatrienyl-CoA(20:3 8,11,14)
CS
O
Arachidonyl-CoA(20:4 5,8,11,14)
O2
2 H2 H2O+ NAD
NADH +
+
5-fatty-acyl-CoAdesaturase
2 H2O+ NAD
CoA
CoA
Prostaglandin Synthesis
CO
O
H
OH
H
H
O
H
OH
H
OH
OH
H
OH
P OO
O
CH2 CH CH2
OC
O
Phosphatidylinositol
Phospholipase A2
COH
OC
OH
O
OOH
O
O
COH
O
OH
O
O
PGH2
PGG2Cyclooxygenase
Peroxidase
Prostaglandinsynthase
Prostaglandinsynthase
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 5,8,11,14)
COH
O
OH
O
O
PGH2
Prostacyclinsynthase
Thromboxanesynthase
PGE isomerase
PGFsynthase
Non-enzymatic
OHHO
OC
HO
O
PGI2(Prostacyclin)
COH
O
OH
O
OTXA2 TXB2
COH
O
OH
O
OH
HO
COH
O
OH
O
HO
PGE2
COH
O
OH
HO
HO
PGF2
Leukotrienes
COH
O
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 5,8,11,14)
5-lipoxygenase
OH
O
O 5-Hydroperoxy-ecosatetraenoicacid (5-HPETE)
HO
OH
OOH
OH
OH
OO
OH
OOH
S
H2N
O
HN
OH
O
OH
OOH
S
H2N
O
OH
O OH
OH
OOH
S
HN
O
HN
OH
O
OH2N
-glutamyltransferaseGlutamate
peptidase
Glycine
LeukotrieneA4 hydrolase
Glutathione
5-lipoxygenase
LTC4synthase
(glutathione S-transferase)
LTA4 LTB4
LTD4
LTC4
LTE4
Lipoxins
OH
OOH
OH
HO
OH
O
OH
15-lipoxygenase (15S)-HETE hydrolase
Aspirin-acetylatedcyclooxygenase-2
OH
O
OH
(15R)-HETE OH
OOH
OH
HO
5-lipoxygenase LXA4
COH
O
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 5,8,11,14)
hydrolase5-lipoxygenase
15-epi-LXA4
Anti-inflammatory Drugs
O
O
HO OH
OH
Cortisol
O
O
O OH
OH
Cortisone
11 -hydroxysteroiddehydrogenase
NAD(P) NAD(P)H
OHO
OH
OHO
O CH3
O
Salicylic acid[2-hydroxybenzoic acid]
Aspirin[acetyl salicylic acid]
[2-acetoxybenzoic acid]
H3CCH3
CH3
OHO
O
CH3
OH
O
H3C
Naproxen[2-(6-methoxynaphthyl)
propionic acid]
N
Cl
O
CH3
O
OHO
CH3
Indomethacin
Ibuprofen[2-(4-isobutylphenyl)propionic acid]
NS
O
O
H2NN CF3
CH3
S
O
O
H3CO
O
Rofecoxib[Vioxx]
Celecoxib[Celebrex]
S
O
O
H2N N
O
H3C
Valdecoxib[Bextra]
Acetaminophen Metabolism
UDP-Glucuronic acid
O H
H
OH
OH
H
H
OH
C
H
O
O N
NH
O
O
P
O
OO
OHHO
CH2OP
O
O
O
O
O H
H
OH
OH
H
H
OH
C
H
O
O
O
NHCH3
O
NHCH3
O
HO
Acetaminophen
N
NH
O
O
P
O
OO
OHHO
CH2OP
O
O
OO
O P
O
O
O
O S
O
OO
OH
CH2O
N
N N
N
NH2
P
O
O
O
3´-phosphoadenosine5´-phosphosulfate (PAPS)
glucuronyltransferase
sulfotransferase
NHCH3
O
HO
Acetaminophen
O S
O
O
O NHCH3
O
O P
O
O
O
O
OH
CH2O
N
N N
N
NH2
P
O
O
O
UDP
adenosine3´,5´-bisphosphate
NHCH3
O
HO
Acetaminophen cytochrome P450(CYP2E1)
NH3C
O
OHHO
NH3C
O
O
Acetimidoquinone
SpontaneousH2O
HN
O
HN
O
O
OH3N
O O
HS
-Glu
Cys Gly
Glutathione(reduced form)HN
O
HN
O
O
OH3N
O O
S
HNH3C
O
OH
Cys-Protein
S
HNH3C
O
OHProtein-Cys-SH
Spontaneous
Spontaneous
Cytochrome P450 Enzymes
R C
H
R
RCytochrome P450 R C
O
R
R
H
+ H2O+ O2
Fe3+
NN
NN
O O O O
Iron-Protoporphyrin IX
Fe3+N NN N
CysCH2S
6th axial ligand
B"/+(+<=#;
1C>)$C"<*+
B"/+(+<=#; Classes of Cytochromes P450 Soluble Mitochondrial �“Microsomal�” Ferredoxin Reductase Ferredoxin Cytochrome P450 Reductase
Cholesterol Biosynthesis
CH3 C
O
S CoAThiolase
CH3 C
O
CH2 C
O
S CoA
Acetyl CoA Acetoacetyl CoA
Acetyl CoA
HMG-CoAsynthase
CH3 C
OH
CH2 C
O
S CoA
CH2 C
O
O
Acetyl CoA
-Hydroxy- -methylglutaryl-CoA(HMG-CoA)CoA-SH CoA-SH
HMG-CoAReductase
CH3 C
OH
CH2 CH2 OH
CH2 C
O
O
2 NADPH
2 NADP+ CoA-SH
Mevalonate
ATPADP
Mevalonate-5-phosphotransferase
ATPADP
Phosphomevalonatekinase
CH3 C
OH
CH2 CH2 O
CH2 C
O
O
5-Pyrophospho-mevalonate
P
O
O
O P
O
O
O
5-Pyrophospho-mevalonate
decarboxylase
ATP
ADP + Pi + CO2
CH3 C CH2 CH2 O
CH2
Isopentenylpyrophosphate
P
O
O
O P
O
O
O
CH3 C CH CH2 O
CH3
Dimethylallylpyrophosphate
P
O
O
O P
O
O
OIsopentenyl
pyrophosphateisomerase
P
O
O
O P
O
O
O
OP
O
O
O P
O
O
O
O
Isopentenylpyrophosphate
Dimethylallylpyrophosphate
P
O
O
O P
O
O
O
O
Geranylpyrophosphate
PPi
Prenyltransferase
P
O
O
O P
O
O
O
O
Farnesylpyrophosphate
Prenyltransferase
Isopentenylpyrophosphate
PPiNADPH+ Farnesyl-
pyrophosphate
NADP+
2 PPi
Squalenesynthase
Squalene
+
O
HO
HH
H
H
HHO Lanosterol
Protosterolcation
2,3-OxidosqualeneSqualene
NADPH+ O2
NADP+ H2O
Squaleneepoxidase
Oxidosqualenecyclase
O 2,3-Oxidosqualene
HO CholesterolH
HO Lanosterol
19 steps
HHO Cycloartenol HO Sitosterol
Mammals
Many stepsPlants
HO Ergosterol
FungiProtozoa12 steps
(�–)
(+)SRE Transcribed region
bHLH
Endoplasmic ReticulumHO
WDbHLH
SREBPSCAP
HO
GolgiHO
WDbHLH
SREBPSCAP
Protease
O
O
OHO
O
SimvastatinN OH
OOHOH
NH
O
F
Atorvastatin
N
Terbinafine
F
F
HON
N
N
NN
N
Fluconazole
HO HO HO
dehydrogenase h
Cholesterol
7-Dehydrocholesterol
Pre-Vitamin D
h
HO
Cholecalciferol(Vitamin D3)HO
1 ,25-Dihydroxy-vitamin D3
1) 25-hydroxylase
2) 1 -hydroxylase
OH
OH
HO Cholesterol
1
2
34
56
7
8
9
10
11
12
13
14 15
O
HO Pregnenolone
1617
18
19
20
2122
23
24
25
26
27
O
O
O
O
O
O
O
O
OH
OH
OH
HO
HO
O
O
O
O
O
O
O
OH
OH
HO
O
HO
OH
OH
OH
OH
O
HO
O
O
HO
O
O
OH
O
OH
HO
OH
O
O
S
O
O
O
P450scc (cholesterol side-chain cleavage enzyme)
P45017 (17 -hydroxylase/lyase)
P45021 (21-hydroxylase)
P45011 (11 -hydroxylase)
P45018 (18-hydroxylase)
P450arom (aromatase)
P450scc
P45011
3 -Hydroxysteroid Dehydrogenase/ 5- 4-isomerase
P45
0 17
P45
0 17
P45021
P45018
P45018
P45
0 aro
m
17 -Hydroxysteroid Dehydrogenase
5 -Reductase
17 -Hydroxy-Pregnenolone
17 -Hydroxy-ProgesteroneProgesterone
Deoxycorticosterone
Corticosterone
Aldosterone
Dehydroepiandrosterone(DHEA)
DHEA-Sulfate
Deoxycortisol
Cortisol
Androstenedione
Testosterone
Dihydrotestosterone(DHT)
Estradiol
Estrone
Sulfotransferase
*
*
*
*
Steroid Biosynthetic Pathways
Glucocorticoid effects Liver
Gluconeogenesis and glucose release Glycogen synthesis Amino acid uptake
Phosphoenolpyruvate carboxykinase Fructose-bisphosphatase Glucose-6-phosphatase Glycogen synthase
Skeletal muscle
Glucose uptake Amino acid uptake Protein synthesis
Protein breakdown
Adipose Tissue
Glucose uptake Hormone sensitive lipase expression Lipid mobilization and redistribution
Immune System
Number and activity of lymphocytes Capillary permeability Inflammation
Susceptibility to infection
General Permissive effects
Maintenance of blood pressure Kidney function Survival of stress
Other effects
Insulin release Insulin action
Short-term memory formation
Phenylethanolamine-N-
methyltransferase (Adrenal medulla)
Lung surfactant formation
Wound healing
Mineralocorticoid Effects Sodium excretion Potassium excretion Blood pressure
Estrogen effects Maturation of internal sex organs in
female Breast development Uterine lining growth
Skin structure Blood vessel structure Coagulation Lipid profiles Bone resorption
Progesterone receptor
Effects in brain
Progestin effects
Breast development Uterine lining differentiation
Insulin levels
Effects in brain Androgen effects
Internal male sex organs External male sex organs Sperm production
Skeletal muscle
Bone formation
Libido
Psychological effects
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Causes of Congenital Adrenal Hyperplasia
Disorder 21-
Hydroxylase deficiency
11 -Hydroxylase
deficiency
Aldosterone synthase
deficiency
17 -Hydroxylase
deficiency
3 -Hydroxysteroid dehydrogenase/ 5-
4 isomerase deficiency
Lipoid hyperplasia
Defective gene CYP21 CYP11B1 CYP11B2 CYP17 HSD3B2 STAR
Ambiguous genitalia
Addison�’s Yes rare loss of Na+ No Yes Yes
Incidence
Classical 1:10,000
Non-classical 1:100
1:100,000
Glucocorticoids Normal Corticosterone
Aldosterone
Androgens Normal
Blood pressure
Na+ levels
K+ levels
O
O
OH
HO
O
Aldosterone
O
O
OH
O
HO
Aldosterone
O
O
OH
HO OH
Dexamethasone
CH3
F
O
O
OH
O OH
Prednisone
O
O
OH
HO OH
9 -FluorocortisolF
HOEquilin
O
HOEthinylestradiol
OH
O
OOH
HO
OH
Genistein
O
O
OH
O
HOCoumestrol