Download Acetyl CoA

SCH 511
Secondary Metabolites
Derived
from Acetate
Acetyl CoA
Dr.
Derese
Dr.Solomon
Solomon
Derese
1
LEARNING OBJECTIVES
SCH 511
• Recognize the source, structure and function in
biological systems of fatty acids
• Identify the roles of acetyl coenzyme A and
malonyl coenzyme A in biosynthesis of acetate
derived secondary metabolites.
• To understand how even-numbered, oddnumbered and branched fatty acids are
biosynthesized
• Describe how unsaturated fatty acids are produced
from saturated fatty acids
• Describe how fatty acids can undergo further
modification.
Dr. Solomon Derese
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SCH 511
• To understand the role of essential fatty acids
in animals.
• Recognize the structure of natural products
derived from the polyketide pathway.
• Describe the primary process in which
polyketides are biosynthesized.
• Recognize the various cyclization pathways
encountered in the formation of polyketides.
• Describe how secondary processes give further
structural diversification.
Dr. Solomon Derese
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CO2 + H2O
Photosynthesis
O
SCoA
PO
O
SCoA
CO2
O
OHOH
CO 2
CO2
Acetyl coenzyme A
Glucose
HO
HO
Glycolysis
O
SCH 511
HO
Pyruvate
Phosphoenol pyruvate
Fatty Acids & Polyketides
Prostaglandins
Polyacetylenes
Aromatic compounds.
Malonyl coenzyme A
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SCH 511
O
S
CoA
Acetyl CoA
n
FAS
O
CH2
O
O
S
O
CoA
Malonyl CoA
PKS
CoA
O
H3C
H
O
S
CH2
n-1 S CoA
O
or
O
O
n-2
Saturated thioesters
SCoA
Polyketo thioesters
Saturated fatty acids
Aromatic compounds or other
Polyketide derived metabolites
Unsaturated fatty acids
Prostaglandins
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Polyacetylenes
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SCH 511
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Biosynthesis of Fatty Acids
SCH 511
Acetyl CoA
Malonyl CoA
Fatty Acid Synthase
Saturated thioesters
Saturated fatty acids
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SCH 511
Fatty acids are alkanoic acids and the
majority of naturally occurring fatty acids
have straight-chains possessing an even
number of carbon atoms.
Fatty acids are usually encountered in
nature as their ester derivatives and these
ester derivatives are collectively known as
lipids, a term which recognizes their
insolubility in water.
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SCH 511
Naturally occurring fatty acids (Lipids) are almost
entirely straight chain aliphatic carboxylic acids.
The broadest definition includes all chain
lengths, but most natural fatty acids are C4 to
C22, with C18 being the most common.
The most abundant fatty acids, the saturated
fatty acids have the general formula (example
octadecanoic acid (n=7)):
CH3CH2-(CH2CH2)n-CH2CO2H
a
ω
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Occurrence and function of fatty acids
SCH 511
Fatty acids, esterified to glycerol, are the main
constituents of oils and fats. Storage fats (seed oils
and animal adipose tissue) consist chiefly (98%) of
triglycerides.
Triglyceride
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SCH 511
Animal fats contain a high proportion of glycerides
of saturated fatty acids and tend to be solids,
whilst those from plants and fish contain
predominantly unsaturated fatty acid esters and
tend to be liquids.
Saturated fatty acid
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Cis unsaturated fatty acid
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SCH 511
The biological function fatty acids are:
I. Storage of metabolic fuel,
II. Protective coatings on skin, fur, feathers,
leaves, etc
III. Cell membrane component
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SCH 511
I. Storage of metabolic fuel
Glycerides act as an energy store in biological
systems; they can be broken down into their fatty
acid constituents which can subsequently
undergoes a process termed as b-oxidation.
In b-oxidation, the fatty acid is broken down, two
carbon atoms at a time, into acetyl coenzyme A
units to provide energy.
Triglycerides are a highly concentrated store of
energy (9 kcal/g).
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SCH 511
b-Oxidation of fatty acids
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SCH 511
II. Protective coatings on skin, fur, feathers, leaves
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SCH 511
III. Cell membrane component
Fatty acids are also
the major component
of the cell membrane.
A cell is composed of nucleic acids,
proteins, and other biochemicals
surrounded by a membrane.
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SCH 511
The membranes completely enclose their
contents, and so cells have a defined inside and
outside.
A
typical
membrane-forming
lipid
is
phosphatidyl choline.
Hydrophobic
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Hydrophilic
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SCH 511
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SCH 511
The ubiquity of many of the common
fatty acids and the vital roles they play,
puts them into the class of primary
metabolites.
It is only the more unusual or
uncommon fatty acids that can be
considered
as
true
secondary
metabolites.
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SCH 511
Naturally occurring fatty acids share a
common biosynthesis. The chain is built
from two carbon units, and cis double
bonds are inserted by desaturase
enzymes at specific positions relative to
the carboxyl group.
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SCH 511
This results in even-chain-length fatty acids with a
characteristic pattern of methylene interrupted cis
double bonds. A typical example of a fatty acid is
linoleic acid.
O
H
O
Methylene separated by
cis-double bonds
Linoleic acid
A large number of fatty acids varying in chain
length and unsaturation result from this pathway.
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SCH 511
Fatty acids with trans or non-methyleneinterrupted unsaturation also occur naturally.
Examples
O
O
H
Vaccenic acid (18:1) (11t))
O
O
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Rumenic acid (18:2 (9t, 11c))
H
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SCH 511
Nomenclature of fatty acids
Systematic names for fatty acids are too
cumbersome for general use, and shorter
alternatives are widely used.
Two numbers separated by a colon give,
respectively, the chain length and number of
double bonds: octadecenoic acid with 18
carbons and 1 double bond is therefore 18:1.
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SCH 511
The position of double bonds is indicated in a
number of ways: explicitly, defining the position
and configuration; or locating double bonds
relative to the methyl or carboxyl ends of the chain.
Double-bond position relative to the methyl end is
shown as n-x or x, where x is the number of
carbons from the methyl end. The n-system is now
preferred, but both are widely used. The position
of the first double bond from the methyl end is
designated x.
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SCH 511
Example
Linoleic acid
O
18
1
O
H
9
12
9Z,12Z-Octadecadienoic acid
18:2 (9c, 12c)
18:2 n-6
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18:2 ∆9,12
18:2 ω6
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SCH 511
The terms cis and trans, abbreviated c and t, are
used widely for double-bond geometry; as with
only two substituents, there is no ambiguity that
requires the systematic E/Z convention.
Acetylinic bond (abbreviated as “a”)
Crepenynic acid
12
18
1
9
cis double bond abbreviated as “c”
18 : 2 (9c , 12a)
[18 carbons: 2 points of unsaturation (cis double bond at position 9,
acetylinic bond at the 12-position)
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SCH 511
Biosynthesis of Fatty Acids
O
S
Acetyl CoA
CoA
O
n
H
O
O
S
CoA
Malonyl CoA
O
H3C
CH2
CH2
n-1 S CoA
Saturated thioesters
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Saturated fatty acids
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SCH 511
Sources of Acetyl CoA
A. b-Oxidation of fatty acids
Acetyl CoA is formed in the cell by
degredation of fatty acids (b-oxidation). Fatty
acids esters are energy stores which during
metabolism yield acetyl CoA and energy.
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SCH 511
b-Oxidation
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SCH 511
a
b
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SCH 511
b
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SCH 511
b
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SCH 511
B. Decarboxylation of pyruvic acid which is
obtained via glycolysis of glucose also
yields acetyl CoA.
O
O
C6 H12O6
Glucose
H
O
Pyruvic acid
CoASH
NAD
S
CoA
O
Acetyl coenzyme A
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SCH 511
Synthesis of Malonyl CoA
The formation of Malonyl coenzyme A takes
place in two steps:
Step I:Carboxylation of biotin (involving ATP)
O
O
HO
ATP
O
HO
OP
Coupling to ATP ‘hydrolysis’ provides energy to
drive carboxylation process.
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SCH 511
O
HO
OP
O
HN
NH
H
H
OH
S
Biotin (Cofactor)
O
O
O
NH
N
HO
H
H
OH
S
N'-Carboxybiotin
Dr. Solomon Derese
O
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SCH 511
Step II: Transfer of the carboxyl group to Acetyl CoA
to form Malonyl CoA
OH
O
Keto-enol tautomerization
CoA
CoA
S
S
O
HO
Acetyl CoA
N
O
NH
H
H
OH
S
N'-Carboxybiotin
O
O
O
CoA
S
OH
Malonyl-CoA
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SCH 511
Synthesis of Malonyl CoA
Acetyl-CoA carboxylase
O
HCO3
ATP
CoA
O
O
CoA
S
Acetyl CoA
Dr. Solomon Derese
BIOTIN
S
OH
Malonyl CoA
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