Download Fatty Acid Biosynthesis - Rose

Fatty Acid Biosynthesis
CO2
+
ATP
Pi
+
ADP
O
HN
H2C C S CoA
O
H3C C S CoA
O
Acetyl-CoA
carboxylase
Acetyl-CoA
Carboxylase
prosthetic group
O
NH
H
C
O
Malonyl-CoA
H
H
S
O
N
Lys-Enzyme
H
NH2
N
N
O
O
N
N
O
O P O CH2
O P O P O CH2 O
O
O
O
CH2
OH
H3C C CH3
CH2
OH
HO CH
H3C C CH3
Coenzyme A
(CoA-SH)
O C
NH
HO CH
NH
MAT
DH
TE
ACP
KR
ER
ER
O
H3C C S CoA
Acetyl-CoA
ACP-SH
Malonyl/acetyl-CoA-ACP
transacetylase (MAT)
CoA-SH
O
H3C C S ACP
O
H
H2C CH2 C N CH2 CH2 SH
H
C N CH2 CH2 SH
KR
Phosphopantetheine group
of Acyl-Carrier Protein
O C
O
H2C CH2
ACP
KR
ACP
TE
DH
MAT
KR
O
H2C C S CoA
O
KS-SH
Acyl-ACP
(CH2)n
H3C
ACP-SH
O
H3C
O
O
H
O
C
C S ACP
KS-SH
+
CO2
NADP
(CH2)14 C S ACP
Palmitoyl-ACP
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OH
H3C
H2O
O
!"("#+
O
H2O
-Hydroxyacyl-ACP
Dehydrase (DH)
,/
O
Malonyl-ACP
-Ketoacyl-ACP
Reductase (KR)
H
trans-2-Enoyl-ACP
H3C
C
O
H3C (CH2)n C CH2 C S ACP
-Ketoacyl-ACP
NADPH
NADPH
C
H2C C S ACP
-Ketoacyl-ACP
Synthase (KS)
Enoyl-ACP
Reductase (ER)
(CH2)n
Malonyl/acetyl-CoA-ACP
transacetylase (MAT)
C S KS
O
NADP
H3C
(CH2)n
CoA-SH
(CH2)n+2 C S ACP
H3C
O
Malonyl-CoA
O
C S ACP
-Ketoacyl-ACP
Synthase (KS)
Acyl-ACP
(longer by
2 carbons)
C
12,
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(CH2)n
O
C
CH2 C S ACP
H
-Hydroxyacyl-ACP
ACP-SH
O
Thioesterase (TE)
315,
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(CH2)14 C O
H3C
Palmitate
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Polyketide Synthesis
O
O
OH
OH
OH
O
OH
O
CH3
O
O CH3
O
O
6-Deoxyerythronolide B
N CH3
HO
O
OH
O
H3C
OH
CH3
OH
O
Erythromycin A
CH3
Elongation
O Acetyl-CoA
H3C C S CoA CoA-SH
Acyl-CoA
O
O
H3C
(CH2)n
CH2 CH2 C S CoA
H3C
(CH2)n
Thiolase
O
C
CH2 C S CoA
-Ketoacyl-CoA
NADH
Acyl-CoA
(longer by two carbons)
H3C
3-L-hydroxyacyl-CoA
dehydrogenase
O
NAD
(CH2)n+2 CH2 CH2 C S CoA
OH
H3C
Enoyl-CoA
Reductase
NADP
NADPH
H
H3C
C C
H
C
O
CH2 C S CoA
H
H2O
(CH2)n
(CH2)n
O
C S CoA
trans-2-Enoyl-CoA
-Hydroxyacyl-CoA
Enoyl-CoA
Hydratase
Desaturation
NADH + O2
+ 2H
2 H2O
+ NAD
O
O
C
C
S CoA
9-fatty-acyl-CoA
desaturase
Stearyl-CoA
(18:0)
S CoA
Oleyl-CoA
(18:1 9)
Arachidonic Acid Synthesis
NADH + O2
+ 2H
Linoleyl-CoA
(18:2 9,12)
2 H2O
+ NAD
-Linolenyl-CoA
(18:3 6,9,12)
O
C
S CoA
O
6-fatty-acyl-CoA
desaturase
C
Elongase
system
2 H2O
+ NAD
O
C
NADH + O2
+ 2H
S CoA
Malonyl-CoA
+ 2 NADPH
CoA-SH + CO2
+ H2O + 2 NADP
S CoA
Arachidonyl-CoA
(20:4 5,8,11,14)
8,11,14-Eicosatrienyl-CoA
(20:3 8,11,14)
5-fatty-acyl-CoA
desaturase
O
C
S
CoA
Prostaglandin Synthesis
OH
H
H OH
H
OH
O
H
OH
H
OH
O
H
C
O P O
Phosphatidyl
inositol
Phospholipase A2
O
O
Prostaglandin
synthase
OH Cyclooxygenase
C
O
OH
PGG2
CH2 CH CH2
O
O
C
O
O
C
O
OOH
Arachidonic acid
5,8,11,14-Eicosatetraenoic acid
(20:4 5,8,11,14)
Prostaglandin
synthase
Peroxidase
O
C
O
OH
PGH2
O
O
O
C
O
PGE
isomerase
OH
C
O
O
OH
Prostacyclin
synthase
C
HO
O
PGE2
O
HO
OH
OH
PGF
synthase
HO
OH
O
C
OH
O
OH
PGI2
(Prostacyclin)
Thromboxane
synthase
PGF2
HO
HO
PGH2
O
C
OH
O
OH
Non-enzymatic
TXA2
O
TXB2
HO
OH
C
OH
O
OH
OH
Leukotrienes
O
O
C
OH
OH
HO
5-lipoxygenase
O
5-Hydroperoxyecosatetraenoic
acid (5-HPETE)
Arachidonic acid
5,8,11,14-Eicosatetraenoic acid
(20:4 5,8,11,14)
5-lipoxygenase
O
OH
OH
Glutathione
OH
LTC4
S
HN
H2N
O
O
OH
O
OH
O
OH
O
O
OH
OH
Glycine
O
OH
O
OH
OH
OH
S
S
peptidase
O
H
N
H2N
LTB4
-glutamyl
transferase
Glutamate
LTD4
LTA4
LTC4
synthase
(glutathione
S-transferase)
O
H
N
Leukotriene
A4 hydrolase
LTE4
OH
H2N
O
OH
O
Lipoxins
O
O
C
OH
15-lipoxygenase
(15S)-HETE
5-lipoxygenase
OH
OH
hydrolase
HO
Arachidonic acid
5,8,11,14-Eicosatetraenoic acid
(20:4 5,8,11,14)
Aspirin-acetylated
cyclooxygenase-2
OH
O
OH
OH
(15R)-HETE
5-lipoxygenase
hydrolase
O
OH
OH
15-epi-LXA4
HO
OH
O
OH
OH
LXA4
Anti-inflammatory Drugs
OH
OH
O
HO
OH
Cortisol
O
O
O
11-hydroxysteroid
dehydrogenase
NAD(P)
OH
NAD(P)H
O
O
OH
Cortisone
O
OH
OH
CH3
O
O
Aspirin
[acetyl salicylic acid]
[2-acetoxybenzoic acid]
Salicylic acid
[2-hydroxybenzoic acid]
CH3
H3C
CH3
OH
O
Ibuprofen
[2-(4-isobutylphenyl)propionic acid]
O
CH3
CH3
O
OH
O
H3C
CH3
OH
O
N
Naproxen
[2-(6-methoxynaphthyl)
propionic acid]
O
Indomethacin
Cl
O
H2N S
N
N
CF3
O
H3C S
O
O
O
O
O
H2N S
O
Celecoxib
[Celebrex]
Rofecoxib
[Vioxx]
CH3
Valdecoxib
[Bextra]
H3C
O
N
Acetaminophen Metabolism
O
Acetaminophen
O
O H
H H
OH
OH
H
CH3
NH
HO
NH
O
H
OH
O
O P O P O CH2
O
N
O
O
O
O S O P O CH2
NH
O
UDP
O H
H H
OH
OH
H
O
NH
OH
O
CH3
H
NH
O
O
N
sulfotransferase
O
O
CH3
O S O
O
O
NH
O P O CH2
cytochrome P450
(CYP2E1)
O
OH
O
CH3
N
OH
HO
Spontaneous
H2O
O
O
H3C
Protein-Cys-SH
O
HN
OH
H
N
HN
H3N
O
O
O
N
O
O
Acetimidoquinone
Glutathione
(reduced form)
O
O
HS
-Glu
H
N
HN
H3N
O
Cys
O
O
O
H3C
HN
H3C
Spontaneous
S
N
O
OH
O P O adenosine
3´,5´-bisphosphate
O
H3C
NH
HO
N
O
O
O
O
N
N
O
O
OH
NH2
N
N
O
N
O
HO
O P O
Acetaminophen
O
O P O P O CH2
NH2
N
CH3
O
O
C O
OH
3´-phosphoadenosine
5´-phosphosulfate (PAPS)
Acetaminophen
O
glucuronyl
transferase
O
HO
HO
O
O
UDP-Glucuronic acid
C O
Gly
O
O
Spontaneous
OH
S
Cys-Protein
O
Cytochrome P450 Enzymes
H
H
R C R
+ O2
R
O
+ H2O
R C R
Cytochrome P450
R
N
N
6th axial ligand
Fe3+
N
N
N
3+
N Fe
N
N
S CH2 Cys
O
O
O
O
1C>)$C"<*+
Iron-Protoporphyrin IX
B"/+(+<=#;
B"/+(+<=#;
Classes of Cytochromes P450
Soluble
Mitochondrial
““Microsomal””
Ferredoxin Reductase
Ferredoxin
Cytochrome P450 Reductase
Cholesterol Biosynthesis
Acetyl CoA CoA-SH
O
O
Acetyl CoA
CH3 C CH2 C S CoA
CH3 C S CoA
Thiolase
Acetyl CoA
O
-Hydroxy--methylglutaryl-CoA
(HMG-CoA)
CoA-SH
OH
O
CH3 C CH2 C S CoA
HMG-CoA
synthase
Acetoacetyl CoA
CH2 C O
O
2 NADPH
HMG-CoA
Reductase
ADP
OH
O
O
2 NADP
+ CoA-SH
ATP
OH
O
O
5-Pyrophosphomevalonate
5-Pyrophosphomevalonate
decarboxylase
ADP
O
CH3 C CH2 CH2 O P O P O
CH2 C O
ATP
CH3 C CH2 CH2 OH
Phosphomevalonate Mevalonate-5CH2 C O
kinase
phosphotransferase
Mevalonate
O
ATP
ADP + Pi + CO2
Isopentenyl
pyrophosphate
O
Dimethylallyl
pyrophosphate
O
CH3 C CH2 CH2 O P O P O
CH2
O
O
Dimethylallyl
pyrophosphate
O
O
O P O P O +
O
O
Isopentenyl
pyrophosphate
isomerase
O
CH3
O
O P O P O
O
O
O
O
PPi
O
Prenyltransferase
Farnesyl
pyrophosphate
O
Squalene
synthase
O
O P O P O
Prenyltransferase
NADP
NADPH
+
+ Farnesyl2 PPi pyrophosphate
O
Geranyl
pyrophosphate
PPi
Isopentenyl
pyrophosphate
Squalene
O
CH3 C CH CH2 O P O P O
Isopentenyl
pyrophosphate
O
O
O
O P O P O
O
O
NADPH
+ O2
NADP
+ H2O
Squalene
epoxidase
Oxidosqualene
cyclase
Squalene
O
HO
2,3-Oxidosqualene
Protosterol
cation
H
H
Lanosterol
H
H
HO
H
Many steps
Plants
HO
O
2,3-Oxidosqualene
H
Cycloartenol
19 steps
Mammals
HO
H
12 steps
HO
Lanosterol
Fungi
Protozoa
Ergosterol
HO
Cholesterol
HO
Sitosterol
SCAP
WD
SREBP
bHLH
Endoplasmic Reticulum
HO
HO
SCAP
(––)
WD
SREBP
bHLH
Golgi
HO
Protease
bHLH
SRE
HO
(+)
Transcribed region
O
O
O
Simvastatin
OH
O
O
N
H
OH
O
N
OH
Atorvastatin
F
N
N
N
HO
N
N
N
Fluconazole
Terbinafine
F
N
F
Cholesterol
Pre-Vitamin D
h
dehydrogenase
HO
HO
HO
7-Dehydrocholesterol
h
OH
1,25-Dihydroxyvitamin D3
HO
1) 25-hydroxylase
2) 1-hydroxylase
OH
HO
Cholecalciferol
(Vitamin D3)
21
20
18
22
23
12
1
2
19
11
9
10
17
13
8
14
Steroid Biosynthetic Pathways
24
16
27
25
15
26
3
*
4
7
5
Cholesterol
6
P450scc
O
P45017
Pregnenolone
HO
Dehydroepiandrosterone
(DHEA)
O
OH
17-HydroxyPregnenolone
HO
O
P45017
HO
O
Sulfotransferase
O
HO
O S O
O
DHEA-Sulfate
O
3-Hydroxysteroid Dehydrogenase/5-4-isomerase
O
O
O
Progesterone
O
17-HydroxyProgesterone
O
Androstenedione
O
P45021
P450arom
OH
HO
Estrone
17-Hydroxysteroid Dehydrogenase
OH
OH
O
O
OH
OH
OH
Deoxycorticosterone
O
*
P45018
Deoxycortisol
O
*
P45011
OH
5-Reductase
OH
O
O
HO
HO
Corticosterone
O
*
P45018
O
OH
OH
Cortisol
O
P45017 (17-hydroxylase/lyase)
O
HO
P45021 (21-hydroxylase)
P45011 (11-hydroxylase)
P45018 (18-hydroxylase)
O
Dihydrotestosterone
(DHT)
P450scc (cholesterol side-chain cleavage enzyme)
OH
O
Testosterone
O
Aldosterone
P450arom (aromatase)
HO
Estradiol
Glucocorticoid effects
Liver
Gluconeogenesis and glucose release
Glycogen synthesis
Amino acid uptake
Mineralocorticoid Effects
Sodium excretion
Potassium excretion
Blood pressure
Phosphoenolpyruvate carboxykinase
Fructose-bisphosphatase
Glucose-6-phosphatase
Glycogen synthase
Estrogen effects
Maturation of internal sex organs in
female
Breast development
Uterine lining growth
Skeletal muscle
Glucose uptake
Amino acid uptake
Protein synthesis
Protein breakdown
Adipose Tissue
Glucose uptake
Hormone sensitive lipase expression
Lipid mobilization and redistribution
Skin structure
Blood vessel structure
Coagulation
Lipid profiles
Bone resorption
Progesterone receptor
Effects in brain
Immune System
Number and activity of lymphocytes
Capillary permeability
Inflammation
Progestin effects
Breast development
Uterine lining differentiation
Susceptibility to infection
Insulin levels
General Permissive effects
Maintenance of blood pressure
Kidney function
Survival of stress
Effects in brain
Other effects
Insulin release
Insulin action
Androgen effects
Internal male sex organs
External male sex organs
Sperm production
Short-term memory formation
Skeletal muscle
Phenylethanolamine-Nmethyltransferase (Adrenal medulla)
Bone formation
Libido
Lung surfactant formation
Wound healing
Psychological effects
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Causes of Congenital Adrenal Hyperplasia
21Hydroxylase
deficiency
11Hydroxylase
deficiency
Aldosterone
synthase
deficiency
17Hydroxylase
deficiency
3-Hydroxysteroid
dehydrogenase/54 isomerase
deficiency
Lipoid
hyperplasia
CYP21
CYP11B1
CYP11B2
CYP17
HSD3B2
STAR
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
Disorder
Defective gene
Ambiguous
genitalia
OH
O
OH
HO
O
HO
O
O
Aldosterone
O
Aldosterone
O
OH
OH
O
HO
O
OH
CH3
O
OH
F
Dexamethasone
O
Prednisone
O
OH
O
HO
OH
F
O
9-Fluorocortisol
O
OH
Equilin
HO
OH
HO
Ethinylestradiol
HO
O
HO
OH
O
OH
Coumestrol
O
O
Genistein
O
HO
N
O
S
OH
O
Raloxifene
O
N
Tamoxifen
O
Exemestane
O
N
OH
Mifepristone
O
OH
O
OH
OH
O
OH
OH
O
NH
O
S OH
HO
OH
Cholic acid
HO
Deoxycholic acid
HO
OH Taurocholic acid
O