Phytochemistry 1
Lecture 2
Date : 8/2/2015
Acetate-malonate pathway
Done By :Sanaa Otoom
Previously we mentioned that our compounds either we call them primary metabolites or
secondary metabolites , we mentioned that the most important compound presented in nature is
glucose.
Glucose is the first product in the photosynthesis , and we have to remember that whether higher
plant or lower plant simply having chlorophyll they must produce sugar .
Our sugar glucose is subjected to hydrolysis or what we call Glycolysis : it means the splitting of
our sugar glucose:
H
HO
H
H
CHO
OH
H
OH
OH
CH2OH
OH O
H3C C C O
H
O O
H3C C C O
3C atoms ,it’s
Glucose here
In it’s open chain
keto acid
Note : the simplest hydrocarbon is three
carbon atoms , if we have two carbon
atoms we call it acetic acid,so the
simplest is pyruvate ,or 3 carbon atoms
(glycerine,glycerol,glycereldehyde) all of
them are 3 carbon atoms
reduction
reaction by reductase
,hexose aldose
What are the reactions and the enzymes that are essential for acetate-malonate pathway?
1- Acetyl Coenzyme A. AcSCoA is a thioester:
NH2
N
R
S
H
N
OH
H
N
O
O
O O
O O
P
P
O
O
O
O
O
N
N
N
OH
O P O
O
As we see CoA is complex enzyme , as we see we have phosphate groups , if the R that is
attached to S is:
1- H , we call it Coenzyme A (CoASH).
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Phytochemistry 1
2- Acetyl group we call it Acetyl Coenzyme A (AcSCoA): this very important enzyme
responsible for and facilitate all the reactions of acetate-malonate pathway.
**if we see the enzyme contain sulfur group (thiol) ,it’s thioester .. if we remember from organic
chemistry the most important is Oxygen for ester but here we have thiol (because of that in each
abbreviation we have sulfur group).
2- Pyruvate dehydrogenase (from the name Dehydro “removing H “) : very important
enzyme ,multienzyme complex that convert Pyruvate to Acetyl CoA ,
H2N
O
Glucose
CO2
Glycolysis
+ CoASH +
O
N
O
N
N
O
O
N
P
O
O
pyruvate
HO
P
O
O
N
NH2
O
O
HO
OH
OH
NAD
thiamin diphosphate (vitamin B1)
Lipoic Acid
Flavin adenine diphosphate (VitaminB2)
H
H2N
O
+
S-CoA
AcSCoA
N
O
N
N
O
O
N
P
O
O
HO
O
P
O
O
N
H
O
NH2
O
OH
HO
+ CO2
+ H+
OH
NADH



We note from the figure above pyruvate originated from glycolysis of glucose ,
pyruvate with CoASH is converted into AcSCoA by enzyme Pyruvate
dehydrogenase (Note: note also the catalysts in the reaction because the Dr
mention them in the lecture ,, Thiamin Diphosphate(vitamin B1) ,, Lipoic acid &
flavin adenine diphosphate(Vitamin B2)).
Now Acetyl CoA have two carbon atoms meanwhile in pyruvic acid we have
three ,so here from the name of the enzyme pyruvate dehydrogenase 
reduction of carbon atoms  acetyl . The plant have the enzyme CoASH and it
also have acetyl CoA so the origin of acetyl group in acetyl CoA is pyruvic acid.
Acetyl CoA is a thioester. Thioesters are more reactive toward nucleophilic acyl
substititution than esters. Also we have to know it’s very good leaving group ,but
considered less reactive than acid chlorides and anhydride (like choline):
O
O
+ Nu-H
S-CoA
+
CoASH
Nu
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Phytochemistry 1
choline
acetyltransferase
O
+
S-CoA
HO
O
N(CH3)3
N(CH3)3
O
+
CoASH
acetylcholine
choline
Also Thioesters enolize more readily than esters :
Electrophile
O
OH
S-CoA
O
E
E
S-CoA
S-CoA
Note here , the Dr added this backward arrow and he said in enolization we
have keto and hydroxyl (enol) , and this is keto enolization .
From Internet : “In organic chemistry, keto–enol tautomerism refers to a
chemical equilibrium between a keto form (a ketone or an aldehyde) and an
enol (an alcohol). The enol and keto forms are said to be tautomers of each
other”

in the reaction above,, if we have Oxygen instead of Sulfur :
We remember that oxygen have two pairs of unshared electrons and these electrons are very
strong attracting group so they prevent enolization in most of the times ,BUT sulfur group is not
strong attracting group like O ,so here we have advantage of being thioester : 1- it’s very good
leaving group as we mentioned & 2- formation of enol or enolize more readily than esters.
**The enol can react with electrophile to afford α-substitution products .Again this is cannot
happen without the presence of thioester.
acetyl-CoA
carboxylase
O
S-CoA
+ HCO3
biotin, ATP
O
O
O
S-CoA
Malonyl CoA

Here the Acetyl CoA reacts with Carbonate to form Malonyl CoA ,in Malonyl CoA we have
three carbon atoms : two from Acetyl CoA and the origin of the third carbon atom is
carbonate.
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Phytochemistry 1
 Conclusion:
1- if we Return to the title of the lecture (Acetate-malonate pathway) now we know the origin
of acetate from Pyruvate , pyruvate have three carbon atoms , by removing one carbon by
pyruvate dehydrogenase enzyme we form acetyl CoA .
2- Acetyl CoA reacts with Carbonate to form Malonyl CoA.
 Fats, Oils, and Fatty Acids:
Fatty acids: refers to long, straight-chain saturated and unsaturated acids, typically from
C12 –
saturated fatty acids
CH3(CH2)nCO2H
n=10, lauric acid (C12)
n=12, myristic acid (C14)
n=14, palmitic acid (C16)
n=16, steric acid (C18)
unsaturated fatty acid
C18, oleic acid
polyunsaturated fatty acids (PUFA)
C18, linolenic acid (18:3)
C18, linoleic acid (18:4)
C20, arachidonic acid (20:4)
*Fatty acids whether they are saturated ,Monosaturated or polyunsaturated all of them
have even number of carbons.
O
OH
HO
OH
glycerol
+
fatty
acids
- H2O
H2C
O
C
O
R1
HC
O
C
O
R2
H2C
O
C
R3
The R groups can
be saturated or
unsaturated, the
same or different
The reaction above shows Triglycerides that originated from acetate.we have our
compounds (triglycerides) from glycerol and fatty acids (that can be simple or different) ,
regardless the type of fatty acid we call these compounds triglycerides.
The importance of fatty acids can be found in the plant is they are the origin of fixed oil
(Such as olive oil that’s rich in polyunsaturated fatty acid) , for this reason fatty acids are
more valuable as food source , energetic source for human consumption.
Meanwhile the saturated fatty acids like coconut oil they do not have any nutritional value
,mostly we use them in manufacture of soaps.
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Phytochemistry 1

Fatty acid amides (FAA):
O
N
H
OH
H
OH
H
Anandamide
an ethanolamine amide of
arachidonic Acid (C20)
O
tetrahydrocannabinol
Arachidonic acid is eicosanoic acid (20C) , we have compound known as Anandamide
which is ethanolamine amide(When we have nitrogen atom next to carbonyl we call it
amide) of arachidonic acid.
Tetrahydrocannabinol (THC) : we will study it in details , but for now we have to know
(THC) is found in Cannabis sativa plant(natural) . Anandamide is found in our body
(endogenous) , but both of them have similar effect despite they have different structure
.Also for now we have to keep both compounds in our mind.

Ketoreductase: NADPH (nicotinamide adenine diphosphate phosphate) is a
nucleophilic hydride (H–) donor (reducing agent)
We have to know from the previous slide :
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Phytochemistry 1
1- Ketoreductase is reducing agent , gives H .
2- Dehydratase : remove OH group .
3- Enoyl Reductase : remove the double bonds.
Note
Don’t go in depth with those enzymes , but know the name of it and its
function ,
Also you have to know that they are very important in biosynthetic
pathways.

Prostaglandins :
Prostaglandins are compounds originated from arachidonic acid (20C),if we want go to their
synthetic pathway , it’s from acetate-malonate pathway .
hormone: (Greek, horman, to set in motion) chemical messengers from one cell to another, that
acts as a signal for a biochemical event.
We have arachidonic acid in our bodies , and from it we can get prostaglandins, also as we
remember prostaglandins are not a single chemical identity , not single compounds , we have
differences :
CO2H
phospholipid
Arachidonic acid
CO2H
prostaglandin H
(PGH) synthase, 2 O2
HO
CO2H
prostaglandin
endoperoxide
reductase
O
CO2H
prostacyclin (PGI)
synthase
O
O
HO
OH
OH
Prostaglandin F2
(PGF2 )
prostaglandin
endoperoxide D
isomerase
Prostaglandin H 2
(PGH 2)
prostaglandin
endoperoxide E
isomerase
HO
OH
Prostaglandin I2
(Prostacyclin)
HO
O
CO2H
O
OH
Prostaglandin D 2
(PGE2 )
CO2H
HO
OH
Prostaglandin E2
(PGE2)
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Phytochemistry 1
Prostaglandins have major role in responses of our body toward pain , and we have to remember
the COX-1 and COX-2 :
1- COX-1 is a constitutive enzyme that is expressed in virtually all mammalian cells
2- 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.
** We have Drugs that inhibit COX-1 and COX-2 (NSAIDs)”non-selective” like :
CO2H
CO2H
CO2H
OAc
H3CO
Aspirin
Ibuprofen
naproxen
In addition we have COX-2 inhibitors , they are selective inhibitors like :
O O
S
NH2
N
F3C
O O
S
NH2
O O
S
NH2
N
O
O
N
O
CH3
celebrex
vioxx
brextra
other compounds which originate from arachidonic acid are Thromboxanes : they have role in
formation of clot inside blood vessels.
OH
PGH2
thromboxane
synthase
CO2H
O
CO2H
HO
O
OH
Thromboxane A 2
O
OH
Thromboxane B2
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Phytochemistry 1
Also we have Leukotrienes that originate from arachidonic acid :
O
CO2H
CO2H
Lipoxygenase
C5H11
Heme, O2
Leukotriene A4
Aracidonic acid
HO
CO2H
NH2
C5H11
Leukotriene D4

H
N
S
CO2H
O
Another material originated from our fatty acid known as Isoprene unit :
this is isoprene (5C ) and responsible for terpenoids synthesis :
-
If we have 10 carbon atoms we call it monoterpenes (2 Isoprene units)
If we have another extra isoprene unit (total 15 carbon atoms) we call it sesquiterpenes (3
isoprene unit).
Generally all plants have monoterpenes or sesquiterpenes we call them volatile oil, since
the two materials are volatile in their nature “volatile oil or essential oil or ethereal oil.
Also we have to know that not all plants containing terpenoids are volatile in nature , and
not every 10 carbon atoms must be terpenoid.
O
H2C C SCoA
H
B:
HMG-CoA
synthase
H2C
acetyl CoA
B H
O
O
C
aldol
condensation
H3C OH O
HO2C
SCoA
HMG-CoA
reductase
2 NADPH
SCoA
3-Hydroxy-3-methylglutaric acid
(HMG-CoA)
O
H3C OH
HO2C
OH
Mevalonic acid
SCoA
acetoacetyl CoA
ATP
H3C OH
HO2C
OH
AMP
O H3C OH
H
O
Mevalonic acid
ATP
ADP
O
O
O P O P OOO-
O H3C OPO 23
H
O
O
O
- PO43O P O P OOO-
H+
O
H
B:
O
CH3
O
O
O P O P OOO-
H H
B:
O
O
O P O P OOO-
isopentenyl-PP
(IPP)
rearrangment
H
O
O
O P O P OOO-
dimethylallyl-PP
(DMAPP)
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Phytochemistry 1
- OPP
Mg2+
H H
OPP
B:
OPP
DMAPP
- OPP
Mg2+
OPP
OPP
IPP
geranyl pyrophosphate (C10)
OPP
OPP
H H
OPP
B:
farnesyl pyrophosphate (C15)
Mevalonic acid is 5 Carbon , we have to know that our Isoprene starts from acetate , and
then conversion of mvalonic acid to Isppentyl Pyrophosphate and then dimethylallyl
pyrophosphate ,after that we convert it into terpene. (when we study the volatile oil we are
going to study them in details).
For our purpose we have to know that isoprene originated from acetate-malonate pathway.
**isoprenes have head and tail ,that’s mean two isoprene units must connect to each other
via head to tail , any compound to call it terpenoid it must have two isoprene units head to
tail (other than that we don’t call them terpenoids) :
OPP
head - tail head - tail
**another Examples :
1-
head to tail
If we look at this we can see the two isoprene units are connected via head to tail.
2- The structure of carvone (from caraway seeds):
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Phytochemistry 1
as we see we have keto group here , there’s no proplem we still call it
terpene since
It’s extra oxygen not carbon atom and it joined via head-to-tail.
3- Limonene : the most abundant volatile oil present :
4-
5- If we have more than two isoprene units they must have head-to-tail , head-to-tail ,
head-to-tail ,etc :
An example the camomile that found in chamomile flower and Zingiberene found in
ginger plant.
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Phytochemistry 1
6- C20 diterpenoids are derived from geranylgeranyl diphosphate, which consists of four C5
“isoprene units” that are joined “head-to-tail” :
OPP
It’s NOT volatile oil . volatile oils must be either monoterpene or sesquiterpenoid , while
biosynthetically head-to-tail ,head-to-tail ….etc.
 Examples on diterpenes :
1- Taxol , contains four isoprene units :
7- C25 sesterpenoids are derived from geranylfarnesyl diphosphate, which consists of five
C5 “isoprene units” that are joined “head-to-tail” : “not common”
OPP
8- C30 triterpenoids and steroids are derived from squalene, which consists of two C15
farnesyl units” that are joined “tail-to-tail” : these not arise from sesterpenoids (25C) ,
they are not biosynthesized by adding another isoprene unit ,simply it biosynthesized
from sesquiterpenoid “farnesyl” :
Tail-to-tail
9- C40 tetraterpenoids are derived from phytocene, which consists of two C20
geranylgeranyl units (two Diterpenes) that are joined “tail-to-tail” :
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Phytochemistry 1
-carotene
10- Lanosterol , the most abundant triterpene :
(1)
(2)
 important Note :
We can know if the compound is triterpene or not by looking to the structure, if we see
at position number 4 (arrow 1) have two methyl groups , and position 21 (arrow 2) have
the third methyl group ,immediately say it’s triterpene , and this is due to the
biosynthetic pathway.
H
H
H
H
H
H
HO
H
Lanosterol (C30H 50O)
H
HO
Cholesterol (C27H 46O)
Now look at cholesterol ,and look for lanosterol ,which one is triterpene ?
Lanosterol .
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Phytochemistry 1
Note : these three methyl groups are easily removed ,if we lose three methyl groups
“they are removed together not one by one or two of them” ,then the compound is
steroid “cholesterol” it’s not triterpene but synthesized from triterpene.
*steroids whether male or female steroids are originated from acetate-malonate
pathway , for this reason we never see steroid with 28 or 29 C , highest is 27 , or less.
Good Luck 
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