co2h - vanderbilt universityas.vanderbilt.edu/chemistry/rizzo/chem220b/chapter_27.pdf · mevalonic...
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Chapter 27. Biomolecules: Lipids
Naturally occurring compounds that are typically of low molecular weight and are hydrophobic (soluble in organic solvent).
• fatty acids and waxes• essential oils• many vitamins• hormones (non-peptide)• components of cell membranes (non-peptide)
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27.1: Waxes, fats and oilsFatty acids: refers to long, straight-chain saturated and
unsaturated acids, typically from C12 - C20. saturated fatty acids:
CH3(CH2)nCO2H n=10, lauric acidn=12, myristic acidn=14, palmitic acidn=16, steric acid
unsaturated fatty acidC18, oleic acid
polyunsaturated fatty acids (PUFA)
C18, linolenic acid (18:3)C18, linoleic acid (18:4)C20, arachidonic acid (20:4)
CO2H
CO2H
CO2H
CO2H3
6
6
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Fatty acid amides (FAA):
Waxes: esters of long chain fatty acids (C16 - C36) with long chain alcohols (C24 - C36)
CH3(CH2)nCO2–(CH2)nCH3
Fats and Oils: Triacylglcerols (triglycerides), fatty acid (C12 - C20) esters of glycerol, HOH2C-CH(OH)-CH2OH.
HO OH
OH
glycerol
fatty acids
H2C
HC
O
O
H2C O
C
C
C R1
O
R2
O
R3
O
O
H
HOH
tetrahydrocannabinolArachidonic Acid (C20)
O
NH
OH
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27.2 Soapsodium & potassium salts of fatty acid produced from thesaponification (base hydrolysis) of animal fats (glycerides)
H2C
HC
O
O
H2C O
C
C
C Rn
O
Rn
O
Rn
O
NaOH
H2C
HC
OH
OH
H2C OH
Rn C O
O
Na+3
Soaps have a hydrophilic, polar “head group” (carboxylate salt)and a hydrophobic, non-polar “tail.”
In aqueous solution they form a micelle structure in which the soap molecules orient so that the the hydrophobic tail cluster in the middle of the micelle where their interaction with water is minimized; the polar carboxylate groups are on the solvent exposed outside of the micelle.
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Micelle:
dodecylphosphocholine (DPC)
polar headgroup
hydrophobic tail
O
O
Steric acid
OP
O
O O
N
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27.3 Phospholipids: diesters of phosphoric acid (H3PO4)
Glycerophospholipids: structurally related to a triglycerideglycerol backbone and two C12 - C20 fatty acid ester
H2C O
H2C O P
C Rsaturated
O
O
O
COCunsaturatedR
O
H
O
CH2CH2N(CH3)3
Phosphatidylcholine (lechtins)(L-configuration)
Phosphatidylethanolamine (cephalins)(L-configuration)
H2C O
H2C O P
C Rsaturated
O
O
O
COCunsaturatedR
O
H
O
CH2CH2NH3
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Nonpolar tails aggregate in the center of a bilayerIonic head is exposed to solventCell membranes are on the order of 50 Å (5 nm) thick
Sphingomyelins:
Glycerophospholipids are important components of cell membranes
CHOH
H2C O P O
O
HC
O
CH2CH2N(CH3)3
CH(CH2)12CH3HC
HN C
O
(CH2)nCH3
CHOH
H2C OH
HC
CH(CH2)12CH3HC
NH2
sphingosine sphingomyelin
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27.4 Prostaglandins (eicosanoids): C20 compounds derived from arachidonic acid and related fatty acids
hormone: (Greek, horman, to set in motion) chemical messenger from one cell to another, that acts as a signalfor a biochemical event.
HO
HOOH
CO2H
Prostaglandin F2!
O
HOOH
CO2H
Prostaglandin E2
HOOH
O
CO2H
Prostaglandin I2
(Prostacyclin)
Arachidonic acid
CO2H
O
O
OH
CO2H
prostaglandin H(PGH) synthase, 2 O2
HO
OOH
CO2H
Prostaglandin D2
prostacyclin (PGI)synthase
prostaglandinendoperoxide
reductase
prostaglandinendoperoxide E
isomerase
phospholipid
prostaglandinendoperoxide D
isomerase
Prostaglandin H2 (PGH2)
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Prostaglandin biosynthesisO
O
OOH
Arachidonic acid
PGG2
CO2HCO2H
O
O
OH
CO2H
prostaglandin H synthase
cyclooxygenase(COX-1 or COX-2)
PGH2
Tyr385
O
CO2H
HH
CO2H CO2H
O
O
CO2H
OO
CO2H
O
O
O
O
CO2HO2 thene•, H+
PGG2
401
cell membrane
Tyr-385
Ser-530
Structure of COX-2
CO2H
O
O
acetylsalicylic acid
HN
O
NH
OH
Ser-530COX
+
HN
O
NH
O
O
covalently modifiedenzyme
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Aracidonic acid
CO2H
C5H11
OCO2HLipoxygenase
Leukotriene A4
Heme, O2
C5H11
HO
CO2H
S
NH2HN
O
CO2H
Leukotriene D4
Thromboxanes: named for their role in thrombosis, the formation of a clot inside a blood vessel
O
CO2H
OH
O
Thromboxane A2
PGH2
thromboxanesynthase
O
CO2H
OH
HO
OH
Thromboxane B2
Leukotrienes”
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COX-1 is a constitutive enzyme that is expressed in virtuallyall mammalian cells
COX-2 is an inducible enzyme that is expressed as a results of a biochemical response; expressed in phagocytes (macrophages) as part of an inflammation response.
NSAIDs: non-steroidal anti-inflammatory drugsAspirin, ibuprofren, and naproxen are non-selective
inhibitors of COX
Celebrex, vioxx, and brextra are selective inhibitorsof COX-2 (Coxibs)
OAc
CO2H
CO2H CO2H
H3CO
NN
SNH2
OO
CH3
F3C O
SNH2
OO
O
O
N
SNH2
OO
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27.5 Terpenoids (isoprenoids): C10, C15 and C20 plant essential oilsRuzicka isoprene rule: terpenoids are derived from“isoprene units” (C5)
O
O
Camphour (+)-Carvone (caraway seeds)(-)-Carvone (spearmint)
(+)-limonene (oranges)(-)-limonene (lemons)
!-pinene "-pinene
CO2H
Chryanthemic acids
OH
Grandisol
CH3H3C
H3CCH3
patchouli alcohol(patchouli oil)
isoprene(2-methyl-1,3-butadiene)
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The precursor to C10 terpenoids (monoterpenes) is geraniolpyrophosphate (diphosphate), which consists of two C5 “isoprene units” that are joined “head-to-tail”
OPP
head - tail head - tail
head tail P
O
O
O P O
O
O
PP =
C15 sesquiterpenoids are derived from farnesyl pyrophosphate, which consists of three C5 “isoprene units” that are joined “head-to-tail”
OPP
C20 diterpenoids are derived from geranylgeranyl pyrophosphate, which consists of four C5 “isoprene units” that are joined “head-to-tail”
OPP
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C25 sesterpenoids are derived from geranylfarnesyl pyrophosphate, which consists of five C5 “isoprene units” that are joined “head-to-tail”
C30 triterpenoids and steroids are derived from squalene, which consists of two C15 farnesyl units” that are joined “head-to-head”
C40 tetraterpenoids are derived from phytocene, which consists of two C20 geranylgeranyl units” that are joined “head-to-head”
OPP
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Lycopene
!-carotene
HO
Lanosterol
CH3
CH3
CH3
H3C
H
cedrane
OO
HOH
CO2H
H OH
Gibberellic acid
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27.6 Biosynthesis of TerpenoidsMevalonic acid is the biosynthetic precursor to the actual C5
“isoprene units,” which are isopentyl pyrophosphate (IPP, tail) and dimethylallyl pyrophosphate (DMAPP, head)
Mevalonate Pathway
N
N
N
NH2
N
O
OP
O
OH
O P O
OH
OH
O
HN
HN
O
HS
OHO
OH
PHO
O
O
CoAS =
Coenzyme A
C
O
H2C SCoA
HB:
H2C SCoAC
O
acetyl CoA
SCoA
OOClaisen
condensation
acetoacetyl CoA
C
O
H3C S-Cys-Enzyme
acetyl CoA
SCoA
OO
E-Cys-S
!-ketoacylthiolase
C
O
H3C SCoAEnzyme-Cys-SH
409
H2C SCoAC
O
SCoA
OO
SCoAHO2C
OHH3C O
3-Hydroxy-3-methylglutaric acid(HMG-CoA)
HMG-CoAreductase
2 NADPH OHHO2C
OHH3C
Mevalonic acid
C
O
H2C SCoA
HB:
acetyl CoAB H
aldolcondensation
HMG-CoAsynthase
acetoacetyl CoA
N
CONH2
R
HH
NADPH
R SCoA
O
N
CONH2
R
NADP+
H
N
CONH2
R
HH
NADPH
R H
O
N
CONH2
R
NADP+
H
H-B
RH
OH
H
OH
O N
HO
P
O
OH
OP
O
OH
O OH
O O O
PO32-
NH2
O
HH
N
N
N
N
H2N
NADPH
H
R
O
OO
O
R=H, compactinR=CH3, mevinolin (Lovastatin)
HMG-CoA reductase inhibitorsCholesterol lowering agents
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Conversion of mevalonic acid to IPP and DMAPP
OHHO2C
OHH3C
Mevalonic acid
ATP AMP
O
OHH3C
P O
O-
O
P O-
O
O-
O
O
H
rearrangmentO P O
O-
O
P O-
O
O-H
dimethylallyl-PP(DMAPP)
isopentenyl-PP (IPP)
B:
H+
ATP ADP
O
OPO32-H3C
P O
O-
O
P O-
O
O-
O
O
H
O P O
O-
O
P O-
O
O-H H
B:
O
CH3
P O
O-
O
P O-
O
O-
O
O
H
- PO43-
Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PPelectrophilichead group
nucleophilictail group
electrophilichead group
nucleophilictail group
OPP
OPPH H
OPP
OPP B:DMAPP IPP
- OPP
Mg2+
OPP
OPP
H H
B:
OPP
farnesyl pyrophosphate (C15)
geranyl pyrophosphate (C10)
- OPP
Mg2+
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OPP PPO
squalene synthase
Conversion of genanyl-PP to monoterpenesLimonene:
limoneneC=C bond actsas a nucleophile
OPP
OPPOPP
Linallyl-PP
OPP
- H+
Can notcyclize
H
:B
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α-terpineol OPP
Linallyl-PP
OPP
OH
H2O
Problem 27.8a (hint)
Carbocation rearrangements:
H
H
1,2-hydrideshift
H2O
H
OH
terpinen-4-ol
!-pinene"-pinene
O
thujone
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27.7 Steroids
Adenocortical: metabolic hormones (please read) Sex hormones: (please read)
androgens (male)
estrogens (female)
Synthetic steroids (please read)
Ring designationand numbering
H3C
HO
H
O
H
H
Estrone
H3C
HO
H
OH
H
H
Estradiol
H3C
HO
HH
H
O
Progesterone
H3C
HO
H
OH
H
HCCH
Ethynylestradiol
H3C
H3C
O
H
OH
H
H
Testosterone
H3C
H3C
HO
H
O
H
H
Androsterone
H3C
H3C
O
H
O
H
H
Androstenedione
H3C
H3C
O
H
OH
H
H
CH3
dianabol
H
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27.8 Stereochemistry of steroidsstereochemistry of the ring fusion (two rings that share a
common C-C bond)decalin: two fused cyclohexanes (C10)
H
H
H
H
trans-decalin:
cis-decalin
H
H
H
H
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The A-B ring fusion of steroids can be either cis or trans (most commonly trans)
The B–C and C–D ring fusions are usually transH3C
H3C
O
H
OH
H
H
H
Dihydrotestosterone
HO
CO2H
H
H H
H
H
H
OH
Cholic acid
HO
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27.9 Cholesterol biosynthesis (figure 27.6, pages 1050-1052)part a: the cyclization
O
H A
HO HO
Squalene Oxide (C30H50O)Squalene (C30H50)
+
Squalene epoxidase
+
Squalenecyclase
HO
+
HO+
HO +
Heme , O2
Protosterol cation
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Protosterol cation (C30H50O)
CH3
H3C
HO
CH3CH3
CH3H
H
H
+CH3
H3C
HO
CH3CH3
CH3H
H
H
H
+ H
1,2-hydrideshift
1,2-hydrideshift
CH3
H3C
HO
CH3CH3
CH3H
H
H+
H1,2-methyl
shiftCH3
H3C
HO
CH3
CH3H
H H3CH
H
+
CH3
H3C
HO
CH3
H
H H3CH
H
H3C+
- H+
B:
1,2-methylshift
CH3
H3C
HO
CH3
H
CH3
CH3
H
Lanosterol (C30H50O)
Cholesterol biosynthesis, part b: the 1,2-shifts
HO HO
Cholesterol (C27H46O)Lanosterol (C30H50O)
H
H H
H
H
H
H
H
H