Download Fatty acid synthesis

Fatty acid synthesis
Source of acetyl-CoA:
food carbohydrates,
some amino acids
But mitochondrial reactions
are required too!
NADPH producing enzymes:
glu-6P dehydrogenase
6P-gluconate dehydr.
malic enzyme
cytoplasmic isocitrate deh.
Acetyl-CoA is the precursor
of all kind of lipids.
First, commited, regulated, rate-limiting step of fatty acid synthesis is catalyzed by:
acetyl CoA carboxylase
summary
mixed acidic anhydride is formed
then carboxyl group is transfered
to biotin
from carboxy-biotin to
acetyl coA the carboxyl
group is transfered
to form malonyl CoA
Acetyl CoA carboxylase domains
It is a monomer here, but it is active only as polymer.
Fatty acid synthase is a multifunctional dimer in humans: two proteins, each has
7 enzyme activity and one carrier arm called ACP
domains:
transferase
reductase
thioesterase
Just the dimer is
functional, because
the synthesis of one
fatty acid requires
both proteins. Two
fatty acids are
produced at the same
time.
not a separate protein,
but part of transferase
domain
R-C-S-CH2-CH2-N-pantothenate-R
║
│
O
H
THIOESTER BOND between fatty acid and
CoA or ACP
1st cycle:
then C4 (6-14) is translocated from ACP to ketoacyl synthase SH instead of acetyl-CoA
acyl group translocation from ACP
to ketoacyl synthase (KS)
2nd, 3rd...7th cycle
of the FA synthesis
till 16 C long
palmityl-ACP,
or in lactating mammary
gland till C 6-12 long
fatty acid
After 7 cycles of elongation the very last step:
palmitoyl-S-ACP + H2O → palmitate + H+ + HS-ACP
thioesterase last domain
palmitate = C 16, saturated fatty acid
The overall fatty acid synthase equation for seven cycles
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+ → palmitate + 7 CO2 +
8 HSCoA + 14 NADP + 6 H2O
Energy cost of fatty acid synthesis:
acetyl CoA carboxylase
7 acetyl-CoA + 7 ATP + 7 CO2 + 7 H2O → 7 malonyl-CoA + 7 H+ + 7 ADP + 7 Pi
citrate lyase
8 citrate + 8 ATP + 8 HSCoA → 8 acetyl-CoA + 8 oxaloacetate + 8 ADP + 8 Pi
REGULATION OF FATTY ACID SYNTHESIS
AMP functions as an energy sensor and regulator of metabolism.
When ATP production does not keep up with needs, a higher portion
of a cell's adenine nucleotide pool is in the form of AMP. AMP
promotes catabolic pathways that lead to synthesis of ATP, while
inhibiting energy-utilizing synthetic pathways. For example, AMP
regulates fatty acid synthesis and catabolism by controlling
availability of malonyl-CoA.
AMP-Activated Kinase catalyzes phosphorylation of Acetyl-CoA
Carboxylase causing inhibition of the ATP-utilizing production of
malonyl-CoA . Fatty acid synthesis is diminished by lack of the
substrate malonyl-CoA. Fatty acid oxidation is stimulated due to
decreased inhibition by malonyl-CoA of transfer of fatty acids into
mitochondria (see section fatty acid oxidation ).
A cyclic-AMP cascade, activated by the hormones glucagon and epinephrine when
blood glucose is low, may also result in phosphorylation of Acetyl-CoA Carboxylase
via cAMP-Dependent Protein Kinase. With Acetyl-CoA Carboxylase inhibited,
acetyl-CoA remains available for synthesis of ketone bodies, the alternative
metabolic fuel used when blood glucose is low. The antagonistic effect of insulin,
produced when blood glucose is high, is attributed to activation of Protein
Phosphatase.
Regulation of Acetyl-CoA Carboxylase by local metabolites:
Palmitoyl-CoA, the product of Fatty Acid Synthase, promotes the inactive
conformation of Acetyl-CoA Carboxylase (diagram above), diminishing production
of malonyl-CoA, the precursor of fatty acid synthesis. This is an example of
feedback inhibition.
Citrate allosterically activates Acetyl-CoA Carboxylase. Citrate concentration is
high when there is adequate acetyl-CoA entering Krebs Cycle. Excess acetyl-CoA
is then converted via malonyl-CoA to fatty acids for storage.
Fatty Acid Synthase is transcriptionally regulated.
•In liver:
•Fatty Acid Synthase expression is stimulated by insulin, a hormone produced
when blood glucose is high. Thus excess glucose is stored as fat. Transcription
factors that that mediate the stimulatory effect of insulin include USFs (upstream
stimulatory factors) and SREBP-1. SREBPs (sterol response element binding
proteins) were first identified for their role in regulating cholesterol synthesis.
•Polyunsaturated fatty acids diminish transcription of the Fatty Acid Synthase
gene in liver cells, by suppressing production of SREBPs.
•In fat cells: Expression of SREBP-1 and of Fatty Acid Synthase is inhibited by
leptin, a hormone that has a role in regulating food intake and fat metabolism. Leptin
is produced by fat cells in response to excess fat storage. Leptin regulates body
weight by decreasing food intake, increasing energy expenditure, and inhibiting fatty
acid synthesis.