Flashcards in Fatty Acid Synthesis Deck (105):
When does synthesis of lipids occur?
FED STATE - high I/G after a meal
- have an abundance of nutrients
- also requires energy
- conditions of excess caloric intake
(Most) biosynthetic reactions do not occur during the ________ state
How are FA components of phospholipids?
- Found in membranes
- Consist of 2 fatty acids + phosphate with polar head group on a glycerol backbone
How are FA components and properties of triglycerides?
- 3 FA attached to glycerol backbone
- Energy storage
- Very hydrophobic
Functions of fatty acids (4)
1. Components of phospholipids
2. Components of triglycerides
3. Second messengers
4. Covalent modifications of proteins
How do FA covalently modify proteins?
- Attaching a fatty acid to specific amino acid residue —> palmitate and myristate
- Bring protein to a membrane and affect the protein’s activity
Major source of carbon for synthesis of lipids is _____________
Can also use?
Primarily excess dietary carbohydrates (glucose)
Can also use excess dietary protein
Primary tissue involved in synthesis of lipids
Also occurs in ?
Primary = liver
Also occurs in adipose tissue
Synthesis of fatty acids from glucose
Dietary carbohydrates —>
Dietary carbohydrates —> glucose —> acetyl CoA —> fatty acids —> triacylglycerols
Dietary proteins —>
Dietary proteins —> amino acids —> acetyl CoA —> fatty acids —> triacylglycerols
Insulin promotes conversion of acetyl CoA —>
If take away insulin, what happens to acetyl CoA ?
Acetyl CoA builds up and goes to form ketone bodies
Untreated Type I diabetes
Overproduction of ketone bodies
- Can be used for energy by anything but RBC
- Occurs during periods of starvation
- They are oxidized like fatty acids in the mitochondria
Early phase of low carb diet
Dec insulin -> any carbons go through acetyl CoA then make ketone bodies which are relied on for energy
5 Requirements for Fatty Acid Synthesis
1. Acetyl CoA as starting substrate
2. Reducing equivalents
3. High I/G ratio (fed state)
5. Integration of 3 pathways
Acetyl CoA as starting substrate problem
It is not permeable to mitochondrial membrane and fatty acid synthesis occurs in the cytoplasm of liver cell
3 molecules that cannot cross mitochondrial membrane directly
1. Acetyl CoA
3. NADH / NAD+
- Produce e- and H+
- Uses NADPH
NADPH is from:
1. Pentose phosphate pathway
2. Malic enzyme
Why can NADH not be used as reducing equivalent in fatty acid synthesis?
NAD+ is needed to keep glycolysis going so that predominates there in the cytoplasm
Integration of what 3 pathways is required for fatty acid synthesis?
2. TCA Cycle (citrate)
3. Pentose Phosphate Pathway
Glucose can be oxidized in 2 ways:
1. Glycolysis- produce pyruvate and NAD+ picks up electrons to give NADH
2. Pentose phosphate pathway- produce a 5-C sugar and NADP+ picks up electrons to give NADPH
Both ways to oxidize glucose occurs during?
During the fed state.
Which pathway predominates depends on the respective Kms on the enzymes in each pathway:
Lower Km = higher affinity so gets glucose first
8 acetyl CoA + 7 ATP (activation step) + 8 ATP (citrate lyase step) + 14 NADPH —> Palmitate + 14 NADP+ + 8 CoA + 6 H2O + 15 ADP + 7 Pi
Fatty acids are built from
2-C units (acetyl CoA)
Starting point for all fatty acids =
16-C saturated fatty acid
____ acetyl CoA total are required
- Consumes 7 ATP total
- Needs to occur for every acetyl CoA molecule except the first one
- Acetate units are activated for transfer by conversion to malonyl-CoA (3-C)
Malonyl- CoA serves as __________
“ Active 2-C donor “
What drives chain growth?
1. Decarboxylation of malonyl Co-A
2. Reducing power of NADPH
How many glucose are required for 1 palmitate (16-C)?
Problem once pyruvate gets into mitochondria?
1. Need to keep TCA cycle going but OAA is very limiting..
Reaction that produces OAA is not favorable and only reason TCA cycle goes forward is because whatever OAA is made is immediately bound to citrate synthase to make a binding site for acetyl CoA and form citrate
2. Also need to produce enough citrate for it to exit mitochondria
How is the glucose conversion to Acetyl Co-A problem solved?
Converts pyruvate —> 4-C OAA
Acetyl CoA _________ modifies pyruvate carboxylase
Converts pyruvate —> Acetyl CoA
Acetyl CoA _________ modifies pyruvate dehydrogenase
What else regulates PDC?
Insulin activates via dephosphorylation
Support pyruvate dehydrogenase is the lower Km enzyme....
Acetyl CoA will be in slight excess —> if it builds up, PDC slows down —> any pyruvate entering mitochondria is diverted to pyruvate carboxylase and also acetyl CoA positively modifies the pyruvate carboxylase —> make enough OAA to condense with acetyl CoA to form citrate that can exit the mitochondira
ATP-Citrate Lyase reaction
Citrate + ATP + CoA-SH + H2O —> Acetyl CoA + ADP + Pi + OAA
Acetyl CoA is made in the __________ but __________
Made in the mitochondria but is not permeable to the mitochondrial membrane
Acetyl CoA is transferred out of the _______ into the ________ as ________
Out of the mitochondria into the cytoplasm as citrate
Enzyme that catalyzes the split of citrate back into acetyl CoA and OAA
ATP- citrate lyase
Even though you hydrolyze an ATP for every citrate that exits the mitochondria and used in cytoplasm for FA synthesis there are 2 benefits:
1. Make NAD+ for glycolysis
2. Make NADPH for FA synthesis (in addition to pentose phosphate pathway)
What happens to the acetyl CoA from ATP-citrate lyase reaction?
Goes towards fatty acid synthesis
What happens to the OAA from ATP-citrate lyase reaction?
Must return to the mitochondria for TCA cycle to continue
BUT it is impermeable to the membrane
2 enzymes involved in getting OAA back into the mitochondria (as pyruvate)
1. Cytoplasmic malate dehydrogenase
2. Malic enzyme
Cytoplasmic malate dehydrogenase reaction
OAA + ADP + NADH —> Malate + NAD+
- NAD+ can go to glycolysis
Malic enzyme reaction
Malate + NADP+ —> pyruvate + NADPH
- Pyruvate enters mitochondria
- NADPH goes toward FA synthesis
Rate-Limiting Step of Fatty Acid Synthesis
- The activation step
Acetyl CoA + ATP + HCO3- —> Malonyl CoA + ADP + Pi + H+
Enzyme: Acetyl CoA Carboxylase (ACC)
Substrate for fatty acid synthesis
Acetyl CoA (cytoplasm)
Acetyl CoA Carboxylase (ACC)
Type of reaction?
Catalyzes the carboxylation of acetyl CoA (2-C) to form malonyl CoA (3-C)
ACC requires ?
Biotin is a coenzyme
2-steps of ACC reaction
1. Biotin accepts HCO3-
3. Add C from HCO3- to form malonyl CoA “active 2-C donor”
How is Acetyl CoA Carboxylase is regulated?
Hormonally AND allosterically
Hormonal regulation of ACC
Dephosphorylated and active in FED state
Phosphorylated and inactive in FASTED state
Mechanism of ACC being dephosphorylated and active in fed state
Insulin signaling activates protein phosphatase 2A which activates ACC
Mechanism of ACC being phosphorylated and inactive in fed state
Glucagon signaling activates AMP-dependent protein kinase (AMPK) which inactivates ACC by directly phosphorylating it
AMPK activated by? Inhibited by?
Activated by AMP
Inhibited by ATP
So during times of low energy charge (glucagon predominates during fasted state), AMPK is activated and goes to inactivate ACC by phosphorylating it
ACC is normally a _____ —> ends up _________ to become active
Normally a dimer —> polymerizes to become active
Active as a polymer.
Positive allosteric modifier of Acetyl CoA Carboxylase
Activates ACC by facilitating the polymerization of the inactive dimer.
Negative allosteric modifier of Acetyl CoA Carboxylase
Palmitoyl CoA is generated at end of synthesis of FA —> when it builds up it causes depolymerization
Citrate’s effect on phosphorylated ACC
Can take phosphorylated ACC —> add citrate to it —> restore part of ACC’s activity
- Advantage for efficiency/conservation in terms of using carbon skeletons because hormonal control is still slower than changes in metabolite flux
- Metabolite flux changes rapidly - concentrations matter
What enzyme extends the fatty acid chain?
Fatty acid synthase
The intermediates are ______ as a ______ to either ____ or _____ during the entire biosynthesis
Covalently bonded as a thioester bond to either ACP or condensing enzyme
3 reaction types in fatty acid extending chain
Put 2 molecules together
Get rid of all double bonds to make saturated fatty acid
4 important structural domains of fatty acid synthase
1. Condensing domain
2. Modification domain
3. Thioesterase (TE)
4. Acyl carrier protein
Where reduction and dehydration reactions occur
Split fatty acid chain and release it from complex
Acyl carrier protein (ACP)
Has an SH group to form thioester bond to link intermediates to ACP with growing chain throughout entire biosynthesis
2 important steps to occur before elongation
1. Priming reaction
Acetyl CoA + ACP —> Acetyl-ACP + CoA
Malonyl CoA + ACP —> Malonyl-ACP + CoA
Explain what happens during priming reaction.
First load acetyl CoA and then load malonyl CoA onto the acyl carrier protein.
Enzyme: Malonylacetyl transferase (MAT)
Important prosthetic group on ACP
- from vitamin phosphopantetheine
- identical to portion of CoA
- SH group is point of attachment
ACP does what?
Shuttles intermediates (similar to what lipoamide arm does)
Acetyl-ACP + Malonyl-ACP —> acetoacetyl-ACP + ACP+ CO2
Process of condensation reaction
Acetyl CoA binds to carrier protein —> moves over to condensing enzyme freeing up its site on the carrier protein —> ACP binds malonyl CoA —> condensing enzyme catalyzes a decarboxylation —> CO2 that was added by acetyl CoA carboxylase comes off —> 2 carbons that originated from acetyl CoA will end up where the CO2 was lost from (at the bottom-defining the omega end of the fatty acid)
Decarboxylation reaction purpose
It is favorable — makes the condensation favorable by providing the energy for it
Synthesize fatty acid from _____ end to ______ end
Omega end to Carboxy terminus end
Growing end of the fatty acid is on the
Acyl carrier protein
Elongation involves a step wise reduction of ________ to __________
Keto group at C-3 to a methylene group (CH2)
Acetyl CoA goes in as acetyl CoA when?
ONLY THE FIRST ONE that makes up the omega end
The liver being the primary site of FAS also explains why
Glycolysis increases in the fed state in the liver
ATP in the fed state
Make a lot of it but it is rapidly consumed.
As always, cell tries to maintain ATP levels so energy charge is around 0.85
Biosynthetic reactions occur when
You have plenty of carbon sources coming in from diet so that you can use some of them for energy and put the others into storage (which also requires energy to do).
Order of reaction type in FAS
Condensation —> reduction —> dehydration —> reduction
Products formed (in order) during fatty acid synthesis
Acetyl-ACP —> malonyl ACP —> acetoacetyl ACP —> 3-hydroxbutyryl ACP —> crotonyl ACP —> butyryl ACP —> butyryl ACP then condenses with malonyl ACP to begin another round
Introduction of double bonds occurs in
The endoplasmic reticulum
Mammals cannot add double bond beyond?
2 essential fatty acids
Linoleate (omega-6) structure and use?
18:2 ; double bond at carbon 9 and 12
Used to synthesize arachidonic acid (20:4)
Arachidonic acid use
Precursor for prostaglandins, leukotrienes, thromboxanes
Aspirin does what?
Inhibits synthesis of prostaglandins by occupying site on prostaglandin synthase which prevents arachidonic acid from getting access to active site
Lineolenate (omega-3) structure
Double bonds at carbon 9,12,15
Pentose Phosphate Pathway has?
2 branches- oxidative and nonoxidative
Oxidative branch of pentose phosphate pathway chemistry
Going from 6 carbons to 5 carbons
- Oxidation / reduction
- Occurs in 3 steps
Glucose-6-Phosphate + 2 NADP+ —> ribulose-5-phosphate + 2 NADPH + CO2
Step 1 of oxidative branch of pentose phosphate pathway
Glucose-6-phosphate + NADP+ —> 6-phosphoglucono-delta-lactone + NADPH
- OH group becomes C=O
-NADP+ picks up electrons to form NADPH
- Rate limiting step!
Enzyme: glucose-6-phosphate dehydrogenase
Step 2 of oxidative branch of pentose phosphate pathway
6-phosphoglucono-delta-lactone + H2O —> 6-phosphogluconate + H+
- Goes from closed structure to open structure
- C=O —> CO2 with resonance
Step 3 of oxidative branch of pentose phosphate pathway
6-phosphogluconate + NADP+ —> Ribulose-5-phosphate +NADPH + CO2
Enzyme: 6-phosphogluconate dehydrogenase
Non oxidative branch of pentose phosphate pathway primary function
Produce 5-C sugars (ribulose-5-phosphate) for nucleotide biosynthesis
- where ribose and deoxyribose come from