mevalonate pathway
DESCRIPTION
TRANSCRIPT
MEVALONATE PATHWAY
RAMANDEEP KAUR BRAR
Terpenes: The Isoprene Rule. Isoprenoids- C10 (terpenes), C15 (sesquiterpenes) and C20 (diterpenes) plant; essential oils
Ruzicka isoprene rule: terpenoids are derived from “isoprene units” (C5)
O
O
Camphour
(+)-Carvone (caraway seeds)(-)-Carvone (spearmint)
(+)-limonene (oranges)(-)-limonene (lemons)
-pinene -pinene
OH
Grandisol
CH3H3C
H3CCH3
patchouli alcohol(patchouli oil)
H
O
Citral(lempon grass)
isoprene(2-methyl-1,3-butadiene)
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The precursor to C10 terpenoids (monoterpenes) is geraniol 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 diphosphate, which consists of three C5 “isoprene units” that are joined “head-to-tail”
OPP
C20 diterpenoids are derived from geranylgeranyl diphosphate, which consists of four C5 “isoprene units” that are joined “head-to-tail”
OPP
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C25 sesterpenoids are derived from geranylfarnesyl diphosphate, 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 “tail-to-tail”
C40 tetraterpenoids are derived from phytocene, which consists of two C20 geranylgeranyl units” that are joined “tail-to-tail”
OPP
Despite great diversity in form and function, the terpenoids are unified in their common biosynthetic origin. The biosynthesis of all terpenoids from simple, primary metabolites can be divided into four overall steps: (a) Synthesis of the fundamental precursor IPP; (b) Repetitive additions of IPP to form a series of prenyl
diphosphate homologs, which serve as the immediate precursors of the different classes of terpenoids;
(c) Elaboration of these allylic prenyl diphosphates by specific terpenoid synthases to yield terpenoid skeletons; and
(d) Secondary enzymatic modifications to the skeletons (largely redox reactions) to give rise to the functional properties and great chemical diversity of this family of natural products.
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O OH
OO
H
O
O
O
OH
C6H5
NHC6H5
O
O
O
HO
O OH
OO
H
O
O
O
OH
C6H5
NHC6H5
O
O
O
HO
CH3
CH3
CH3
H3C
H
cedrane
Taxol
CH3
CH3
CH3
H3C
H
HO
Lanosterol
-carotene
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Isopentyl Diphosphate: The Biological Isoprene Unit.Mevalonic acid is the biosynthetic precursor to the actual C5 “isoprene units,” which are isopentyl diphosphate (IPP, tail) and dimethylallyl diphosphate (DMAPP, head)
The Pathway from Acetate to Isopentenyl Diphosphate.Mevalonate Pathway
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
C
O
H2C SCoA
HB:
H2C SCoAC
O
acetyl CoA
SCoA
OOClaisen
condensation
acetoacetyl CoA
C
O
H3C S-Cys-Enzyme
acetyl CoA
acetoacetyl-CoAacetyltransferase
C
O
H3C SCoAEnzyme-Cys-SH
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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 HB:
O
CH3
P O
O-
O
P O-
O
O-
O
O
H
- PO43-
Carbon-Carbon Bond Formation in Terpene Biosynthesis.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
- OPPMg2+
OPP
OPPH H
B:
OPP
farnesyl pyrophosphate (C15)
geranyl pyrophosphate (C10)
- OPPMg2+
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OPP PPO
squalene synthase
Conversion of genanyl-PP to monoterpenesLimonene & -Terpineol
OPP
OPP
geranyl diphosphate
neryl diphosphate
OPP
- H+
H:B
HO
H2O
C=C bond actsas a nucleophile
-terpineol
limonene
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Steroids
Cholesterol biosynthesis part a: the cyclization
O
H A
HO HO
Squalene Oxide (C30H50O)Squalene (C30H50)
+
Squalene epoxidase
+
Squalenecyclase
HO
+
HO +
HO +
Heme , O2
Protosterol cation
HO
+
HO+
A B
C D1
2
34
56
7
89
10
1112
13
1415
16
17
HO Cholesterol (C27H46O)
H H
H
H
H
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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
CH3H
Lanosterol (C30H50O)
Cholesterol biosynthesis, part b: the 1,2-shifts
HO HO
Cholesterol (C27H46O)Lanosterol (C30H50O)
H H
H
H
H
H
H
H
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Vitamin D
HO7-Dehydrocholesterol
H H
H
H
HO
H
H
H
Vitamin D3
sunlight
Bile Acids
Corticosteroids
O
OOH
H H
OH
H
O
Cortisone
13
Sex hormones androgens (male)
estrogens (female)
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
HC CH
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
dianabolH
Carotenoids derived from phytocene (C40)
Lycopene
-carotene