19
Fatty Acid Biosynthesis Acetyl-CoA Acetyl-CoA carboxylase CO 2 + ATP P i + ADP Malonyl-CoA N NH HN S H H H O O H Lys-Enzyme Carboxylase prosthetic group H 3 C C O S CoA H 2 C C O S CoA C O O O CH 2 C CH 3 H 3 C CH HO C O NH H 2 C CH 2 C O H N O P O CH 2 O Phosphopantetheine group of Acyl-Carrier Protein CH 2 CH 2 SH O CH 2 C CH 3 H 3 C CH HO C O NH H 2 C CH 2 C O H N O P O O OH OH CH 2 O N N N N NH 2 P O O O Coenzyme A (CoA-SH) CH 2 CH 2 SH ACP KR MAT DH ER KR ACP TE KR MAT DH ER KR ACP TE Acetyl-CoA CoA-SH ACP-SH H 3 C C O S CoA H 3 C C O S ACP Malonyl/acetyl-CoA-ACP transacetylase (MAT)

Fatty Acid Biosynthesis - Rose-Hulman Institute of …brandt/Chem331/Lipid_synthesis... · of Acyl-Carrier Protein CH2 CH2 SH O CH H C C CH HO CH O C NH H C CH C O H N O P O O OH

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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

8-?)#;"("A.>

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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

ON

Tamoxifen

SOH

O

ON

HO

Raloxifene

O

O Exemestane

OH

O Mifepristone

N

HO OH

OH

OH

O

Cholic acid HO OH

OH

NH

O

Taurocholic acid

S

O

O

OH

HO

OH

OH

O

Deoxycholic acid