From Wikipedia, the free encyclopedia Fatty acid synthesis
Fatty acid synthesis
Step Enzyme Reaction Description
(a) Acetyl CoA:ACP transacy- Activates acetyl CoA for reaction with malonyl-ACP
lase
(b) Malonyl CoA:ACP transacy- Activates malonyl CoA for reaction with acetyl-ACP
lase
(c) 3-ketoacyl-ACP synthetase Reacts priming acetyl-ACP with chain-extending malonyl-
ACP.
(d) 3-ketoacyl-ACP reductase Reduces the carbon 3 ketone to a hydroxyl group
(e) 3-hydroxyacyl-ACP dehy- Removes water
drase
(f) Enoyl-ACP reductase Reduces the C3-C4 double bond.
Fatty acid synthesis is the creation of fatty acids from Much like β-oxidation, straight-chain fatty acid synthesis
acetyl-CoA and malonyl-CoA precursors through action occurs via the six recurring reactions shown below, until
of enzymes called fatty acid synthases. It is an important the 16-carbon palmitic acid is produced.[1]
part of the lipogenesis process, which - together with gly- The diagrams presented show how fatty acids are
colysis - stands behind creating fats from blood sugar in synthesized in microorganisms and list the enzymes
living organisms. found in Escherichia coli.[1] These reactions are per-
formed by fatty acid synthase II (FASII), which in general
Straight-Chain Fatty Acids contain multiple enzymes that act as one complex. FASII
is present in prokaryotes, plants, fungi, and parasites, as
Straight-chain fatty acids occur in two types; saturated well as in mitochondria.[2]
and unsaturated. In animals, as well as yeast and some fungi, these
same reactions occur on fatty acid synthase I (FASI), a
Saturated Straight-Chain Fatty Acids large dimeric protein that has all of the enzymatic activ-
ities required to create a fatty acid. FASI is less efficient
than FASII; however, it allows for the formation of more
molecules, including “medium-chain” fatty acids via ear-
ly chain termination.[2]
Once a 16:0 carbon fatty acid has been formed, it can
undergo a number of modifications, in particular by fatty
acid synthase III (FASIII), which uses 2 carbon molecules
to elongate preformed fatty acids.[2]
Regulation
Acetyl-CoA is formed into malonyl-CoA by acetyl-CoA
carboxylase, at which point malonyl-CoA is destined to
feed into the fatty acid synthesis pathway. Acetyl-CoA
carboxylase is the point of regulation in saturated
straight-chain fatty acid synthesis, by both phosphory-
lation and allosteric regulation. Regulation by phospho-
Synthesis of saturated fatty acids via Fatty Acid Synthase II in rylation occurs mostly in mammals, while allosteric reg-
E. coli ulation occurs in most organisms. Allosteric control oc-
curs as feedback inhibition by palmitol-CoA and activa-
tion by citrate. When there are high levels of palmitol-
CoA, the final product of saturated fatty acid synthesis, it
1
From Wikipedia, the free encyclopedia Fatty acid synthesis
allosterically inactivates acetyl-CoA carboxylase to pre- • FabA is a β-hydroxydecanoyl-ACP dehydrase - it is
vent a build-up of fatty acids in cells. Citrate acts to ac- specific for the 10-carbon saturated fatty acid
tivate acetyl-CoA carboxylase under high levels, because synthesis intermediate (β-hydroxydecanoyl-ACP).
high levels indicate that there is enough acetyl-CoA to • FabA catalyzes the dehydration of β-
feed into the Krebs cycle and produce energy.[3] hydroxydecanoyl-ACP, causing the release of water
De Novo Synthesis in Humans and insertion of the double bond between C7 and C8
In humans, fatty acids are formed predominantly in counting from the methyl end. This creates the
the liver and lactating mammary glands, and, to a lesser trans-2-decenoyl intermediate.
extent, the adipose tissue. Most acetyl-CoA is formed • Either the trans-2-decenoyl intermediate can be
from pyruvate by pyruvate dehydrogenase in the mito- shunted to the normal saturated fatty acid synthesis
chondria. Acetyl-CoA produced in the mitochondria is pathway by FabB, where the double bond will be
condensed with oxaloacetate by citrate synthase to form hydrolyzed and the final product will be a saturated
citrate, which is then transported into the cytosol and fatty acid, or FabA will catalyze the isomerization
broken down to yield acetyl-CoA and oxaloacetate by into the cis-3-decenoyl intermediate.
ATP citrate lyase. Oxaloacetate in the cytosol is reduced • FabB is a β-ketoacyl-ACP synthase that elongates and
to malate by cytoplasmic malate dehydrogenase, and channels intermediates into the mainstream fatty
malate is transported back into the mitochondria to par- acid synthesis pathway. When FabB reacts with the
ticipate in the Citric acid cycle.[4] cis-decenoyl intermediate, the final product after
elongation will be an unsaturated fatty acid.[6]
Desaturation • The two main unsaturated fatty acids made are
Unsaturated fatty acids are essential components to Palmitoleoyl-ACP (16:1ω7) and cis-vaccenoyl-ACP
prokaryotic and eukaryotic cell membranes. These fatty (18:1ω7).[7]
acids function primarily in maintaining membrane fluid- Most bacteria that undergo anaerobic desaturation con-
ity.[5] They have also been associated with serving as sig- tain homologues of FabA and FabB.[8] Clostridia are the
naling molecules in other processes such as cell differen- main exception; they have a novel enzyme, yet to be
tiation and DNA replication.[5] There are two pathways identified, that catalyzes the formation of the cis double
organisms use for desaturation: Aerobic and Anaerobic. bond.[7]
Regulation
Anaerobic Desaturation This pathway undergoes transcriptional regulation
Many bacteria use the anaerobic pathway for synthesiz- by FadR and FabR. FadR is the more extensively studied
ing unsaturated fatty acids. This pathway does not uti- protein and has been attributed bifunctional characteris-
lize oxygen and is dependent on enzymes to insert the tics. It acts as an activator of fabA and fabB transcription
double bond before elongation utilizing the normal fatty and as a repressor for the β-oxidation regulon. In con-
acid synthesis machinery. In Escherichia coli, this pathway trast, FabR acts as a repressor for the transcription of
is well understood. fabA and fabB.[6]
Aerobic Desaturation
Aerobic desaturation is the most widespread pathway
for the synthesis of unsaturated fatty acids. It is utilized
in all eukaryotes and some prokaryotes. This pathway
utilizes desaturases to synthesize unsaturated fatty acids
from full-length saturated fatty acid substrates.[9] All de-
saturases require oxygen and reducing equivalents ac-
quired from the electron transport chain. Desaturases
are specific for the double bond they induce in the sub-
strate. In Bacillus subtilis, the desaturase, Δ5-Des, is spe-
cific for inducing a cis-double bond at the Δ5 posi-
tion.[5][9] Saccharomyces cerevisiae contains one desat-
urase, Ole1p, which induces the cis-double bond at Δ9.[5]
Regulation
In B. subtilis, this pathway is regulated by a two-com-
ponent system: DesK and DesR. DesK is a membrane-as-
sociated kinase and DesR is a transcriptional regulator of
Synthesis of unsaturated fatty acids via anaerobic desatura- the des gene.[5][9] The regulation responds to tempera-
tion ture; when there is a drop in temperature, this gene is
upregulated. Unsaturated fatty acids decrease the fluidi-
2
From Wikipedia, the free encyclopedia Fatty acid synthesis
Branch-Chain Fatty Acid Synthesizing
System
The branched-chain fatty acid synthesizing system uses
α-keto acids as primers. This system is distinct from the
branched-chain fatty acid synthetase that utilizes short-
chain acyl-CoA esters as primers.[14] α-Keto acid primers
are derived from the transamination and decarboxyla-
tion of valine, leucine, and isoleucine to form
2-methylpropanyl-CoA, 3-methylbutyryl-CoA, and
2-Methylbutyryl-CoA, respectively.[15]
2-Methylpropanyl-CoA primers derived from valine are
elongated to produce even-numbered iso-series fatty
acids such as 14-methyl-pentadecanoic (isopalmitic)
acid, and 3-methylbutyryl-CoA primers from leucine may
be used to form odd-numbered iso-series fatty acids such
as 13-methyl-tetradecanoic acid. 2-Methylbutyryl-CoA
primers from isoleucine are elongated to form anteiso-
series fatty acids containing an odd number of carbon
atoms such as 12-Methyl tetradecanoic acid.[16] Decar-
boxylation of the primer precursors occurs through the
branched-chain α-keto acid decarboxylase (BCKA) en-
Synthesis of unsaturated fatty acids via aerobic desaturation
zyme. Elongation of the fatty acid follows the same
biosynthetic pathway in Escherichia coli used to produce
ty of the membrane and stabilize it under lower temper- straight-chain fatty acids where malonyl-CoA is used as
atures. DesK is the sensor protein that, when there is a a chain extender.[17] The major end products are 12-17
decrease in temperature, will autophosphorylate. DesK- carbon branched-chain fatty acids and their composition
P will transfer its phosphoryl group to DesR. Two DesR-P tends to be uniform and characteristic for many bacterial
proteins will dimerize and bind to the DNA promoters of species.[16]
the des gene and recruit RNA polymerase to begin tran- BCKA decarboxylase and relative activities of α-keto
scription.[5][9] acid substrates
Pseudomonas aeruginosa The BCKA decarboxylase enzyme is composed of two
In general, both anaerobic and aerobic unsaturated subunits in a tetrameric structure (A2B2) and is essential
fatty acid synthesis will not occur within the same sys-
for the synthesis of branched-chain fatty acids. It is re-
tem, however Pseudomonas aeruginosa and Vibrio ABE-1
sponsible for the decarboxylation of α-keto acids formed
are exceptions.[10][11][12] While, P. aeruginosa undergoes
by the transamination of valine, leucine, and isoleucine
primarily anaerobic desaturation, it also undergoes two
and produces the primers used for branched-chain fatty
aerobic pathways. One pathway utilizes a Δ9 desaturase
acid synthesis. The activity of this enzyme is much high-
(DesA) that catalyzes a double bond formation in mem-
er with branched-chain α-keto acid substrates than with
brane lipids. Another pathway uses two proteins, DesC
straight-chain substrates, and in Bacillus species its
and DesB, together to act as a Δ9 desaturase, which in-
specificity is highest for the isoleucine-derived α-keto-
serts a double bond into a saturated fatty acid-CoA mole-
β-methylvaleric acid, followed by α-ketoisocaproate and
cule. This second pathway is regulated by repressor pro-
α-ketoisovalerate.[16][17] The enzyme’s high affinity to-
tein DesT. DesT is also a repressor of fabAB expression
ward branched-chain α-keto acids allows it to function
for anaerobic desaturation when in presence of exoge-
as the primer donating system for branched-chain fatty
nous unsaturated fatty acids. This functions to coordi-
acid synthetase.[17]
nate the expression of the two pathways within the or-
Factors affecting chain length and pattern distribution
ganism.[11][13]
α-Keto acid primers are used to produce branched-
chain fatty acids that, in general, are between 12 and 17
Branched-chain fatty acids carbons in length. The proportions of these branched-
chain fatty acids tend to be uniform and consistent
Branched-chain fatty acids are usually saturated and are
among a particular bacterial species but may be altered
found in two distinct families: the iso-series and anteiso-
due to changes in malonyl-CoA concentration, tempera-
series. It has been found that Actinomycetales contain
ture, or heat-stable factors (HSF) present.[16] All of these
unique branch-chain fatty acid synthesis mechanisms,
factors may affect chain length, and HSFs have been
including that which forms tuberculosteric acid.
demonstrated to alter the specificity of BCKA decarboxy-
3
From Wikipedia, the free encyclopedia Fatty acid synthesis
Substrate BCKA activity CO2 Produced (nmol/min mg) Km (μM) Vmax (nmol/min mg)
L-α-keto-β-methyl-valerate 100% 19.7 .
[3] Diwan, Joyce J. "Fatty Acid Synthesis." Rensselaer
Polytechnic Institute (RPI) :: Architecture, Leucine primer
Business, Engineering, IT, Humanities, Science.
Web. 30 Apr. 2011. . from bacteria to humans." Molecular microbiology
[4] Ferre, P.; F. Foufelle (2007). "SREBP-1c 62.6 (2006):1507-14.
Transcription Factor and Lipid Homeostasis: [6] ^ Feng, Youjun, and John ECronan. "Complex
Clinical Perspective". Hormone Research 68 (2): binding of the FabR repressor of bacterial
72–82. doi:10.1159/000100426. PMID 17344645. unsaturated fatty acid biosynthesis to its cognate
http://content.karger.com/ProdukteDB/ promoters." Molecular microbiology 80.1
produkte.asp?Aktion=ShowFulltext&ArtikelNr=100426&Ausgabe=232805&ProduktNr=224036.
(2011):195-218.
Retrieved 2010-08-30. "this process is outlined [7] ^ Zhu, Lei, et al. "Functions of the Clostridium
graphically in page 73" acetobutylicium FabF and FabZ proteins in
5
From Wikipedia, the free encyclopedia Fatty acid synthesis
unsaturated fatty acid biosynthesis." BMC [16] ^ Naik, Devaray N., and Toshi Kaneda.
microbiology 9(2009):119. "Biosynthesis of Branched Long-chain Fatty Acids
[8] Wang, Haihong, and John ECronan. "Functional by Species of Bacillus: Relative Activity of Three α-
replacement of the FabA and FabB proteins of keto Acid Substrates and Factors Affecting Chain
Escherichia coli fatty acid synthesis by Length." Can. J. Microbiol. 20 (1974): 1701-708.
Enterococcus faecalis FabZ and FabF homologues." [17] ^ Oku, Hirosuke, and Toshi Kaneda. "Biosynthesis
Journal of biological chemistry 279.33 of Branched-chain Fatty Acids in Bacillis Subtilis."
(2004):34489-95. The Journal of Biological Chemistry 263.34 (1988):
[9] ^ Mansilla, Mara C, and Diegode Mendoza. "The 18386-8396.
Bacillus subtilis desaturase: a model to understand [18] ^ Christie, William W. "Fatty Acids: Natural
phospholipid modification and temperature Alicyclic Structures, Occurrence, and
sensing." Archives of microbiology 183.4 Biochemistry." The AOCS Lipid Library. 5 Apr. 2011.
(2005):229-35. Web. 24 Apr. 2011. .
of biosynthesis of unsaturated fatty acids in [19] Ratledge, Colin, and John Stanford. The Biology of
Pseudomonas sp. strain E-3, a psychrotrophic the Mycobacteria. London: Academic, 1982. Print.
bacterium." Journal of bacteriology 171.8 [20] Kubica, George P., and Lawrence G. Wayne. The
(1989):4267-71. Mycobacteria: a Sourcebook. New York: Dekker,
[11] ^ Subramanian, Chitra, Charles ORock, and Yong- 1984. Print.
MeiZhang. "DesT coordinates the expression of
anaerobic and aerobic pathways for unsaturated
fatty acid biosynthesis in Pseudomonas
External links
aeruginosa." Journal of bacteriology 192.1 • Overview at Rensselaer Polytechnic Institute
(2010):280-5. • Overview at Indiana State University
[12] Morita, N, et al. "Both the anaerobic pathway and
aerobic desaturation are involved in the synthesis
of unsaturated fatty acids in Vibrio sp. strain
ABE-1." FEBS letters 297.1-2 (1992):9-12.
[13] Zhu, Kun, et al. "Two aerobic pathways for the
formation of unsaturated fatty acids in
Pseudomonas aeruginosa." Molecular microbiology
60.2 (2006):260-73.
[14] ^ Kaneda, Toshi. "Iso- and Anteiso-Fatty Acids in
Bacteria: Biosynthesis, Function, and Taxonomic
Significance." Microbiological Reviews 55.2 (1991):
288-302
[15] ^ "Branched-chain Fatty Acids, Phytanic Acid,
Tuberculostearic Acid Iso/anteiso- Fatty Acids."
Lipid Library - Lipid Chemistry, Biology,
Technology and Analysis. Web. 01 May 2011.
http://lipidlibrary.aocs.org/lipids/fa_branc/
index.htm.
Retrieved from "http://en.wikipedia.org/w/index.php?title=Fatty_acid_synthesis&oldid=473404568"
Categories:
• Metabolism
• Fatty acids
• Biosynthesis
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From Wikipedia, the free encyclopedia Fatty acid synthesis
Isoleucine primer
Synthetic pathways of the branched-chain fatty acid synthe-
sizing system given differing primers
7