Flashcards in Fatty acid synthesis Deck (50):
sources of FA
-dietary FA (most here)
-excess dietary protein and carbs converted to FA for storage
-De Novo synthesis
De Novo synthesis
in adults: most FA synthesis is in liver and lactating mammary glands, some in adipose
-synthesized in the cytosol
-cytosolic acetyl CoA is the carbon source for growing FA chain
-energy source: ATP and NADPH
acetyl group of acetyl CoA
-generated in the mitochondria
-required for FA production in the cytosol
CoA portion of the acetyl CoA..
cannot cross the mitochondrial membrane
production of cytosolic acetyl CoA
requires a process for generation and delivery of the acetyl-group of mitochondria acetyl-CoA to the cytosol
-charged, converted to citrate, this CAN cross the inner mitochondrial membrane to cytosol
citrate to OAA and acetyl CoA to get in the cytosol
step 1 of de novo synthesis
mitochondrial acetyl CoA is generated from
-oxidation of pyruvate
-B-oxidation of long carbon chain CoA
-catabolism of keno bodies and some amino acids
step 2 of de novo synthesis
-acetate exits mitochondria and enters the cytosol as citrate
1. citrate is produced from condensation of OAA and the acetyl group of mitochondria acetyl CoA
2. citrate accumulates to a high level in mitochondria when isocitrate dehydrogenase is inhibited by high ATP levels
3.citrate exits mitochondria to the cytosol
4. citrate is cleaved by ATP-citrate lyase to produce cytosolic acetyl CoA and OAA
What has to happen for citrate to accumulate in the mitochondria?
the accumulation of citrate in the mitochondria requires that high levels of ATP inhibit isocitrate dehydrogenase. This fatty acids are likely to be generated only in the well fed state
what is the regulatory step of de novo synthesis?
carboxylation of cytosolic acetyl COA to form malonyl CoA
acetyl CoA carboxylase
uses CO2 and energy from ATP hydrolysis to carboxylate the acetyl group of Acetyl CoA in the carboxylation of cytosolic acetyl CoA to form malignly CoA
-stored energy- C-C bonding in synthesis
what is important about carboxylation of cytosolic acetyl CoA to form Malonyl CoA?
-this carboxylation and subsequent decarboxylation reaction provides the energy for carbon to carbon condensations to elongate the growing FA chain
-carboxylation of acetyl CoA is the rate limiting and regulated step for FA synthesis
Where is energy stored for FA?
short term regulation of acetyl CoA carboxylase (ACC)
-inactive ACC dimers are allosterically activated to its polymerized form by citrate
-activated ACC is depolymerized by the end product long-chain fatty acyl CoA
what is ACC promoted by?
short term regulation of acetyl CoA carboxylase (ACC) (fasting)
-AMP-activated protein kinase (AMPK) reversibly phosphorylates and inhibits ACC (fasting)
-AMPK is allosterically activated by AMP and by phosphorylation by kinases, one of which is cAMP dependent PKA
What is ACC indirectly inhibited by?
epinephrine and glucagon
long term regulation of acetyl CoA carboxylase (ACC)
-prolonged high calorie, high carb diets increase ACC synthesis which increase fatty acid synthesis
-a low calorie or high-fat diet reduces FA synthesis by decreasing ACC synthesis
Fatty acid synthase (FAS)
-a multifunctional dimeric enzyme in eukaryotes
-7 different enzymatic activities
-a domain for covalently binding 4'-phosphopantetheine
FAS domain for binding 4'-phosphopantetheine
-this domain function as an acyl carrier protein (ACP)
-ACP carries acyl units on its terminal thiol-group (-SH) during FA synthesis
At ACP site...
-acetyl CoA deliver CoA to this
-move 2-C molecule to holding site (cysteine)
-opens up APC site for malonyl CoA, transfers 3-C
-attack malignly group and decarboxylate that 3-C
-4-C structure @ ACP site
-Keeps happening over and over again (about 7X)
-needs a lot of NADPH
What is required for chain elongation?
repeating the 7 steps of FA synthase
initiation of elongation requires what?
transfer of butyryl to the cysteine reside holding sire of FAS
What is the end product of FA synthesis
what is the rate limiting step and regulation step of FA synthesis
Acetyl CoA carboxylation to generate malonyl CoA
how many times do the steps go through for FA synthesis?
-each round adds 2 carbons to the growing chain
cleaves the thirster bond releasing saturated palmitate
NADPH FA synthesis
functions as a biochemical reductant, a source of reducing agents for FA synthesis
What is the predominant source of NADPH in FA synthesis?
-G6PDH: rate limiting, irreversible activitiy
-G6PDH utilizes NADP+ as a coenzyme acceptor to oxidize glucose 6-P
-from each HMP committed glucose 6-P, two NADPH are produced
what is an additional source of NADPH in FA synthesis?
-malate oxidation and decarboxylation by malic enzyme
-ME oxidizes and decarboxylates malate to pyruvate
-NADP+ functions as a coenzyme acceptor to oxidize malate generating NADPH
Where does FA elongation take place at?
How is palmitate elongated?
malonyl CoA gives 2-carbon units and the reduction of NADPH at the smooth ER
brain tissue and FA elongation
special elongation capabilities to generate VLCFA (>22) that are require for brain lipids
Where does desaturation of VLCFA occur?
What is a common mono unsaturated FA?
16:1(9) is less common
storage of FA as components of triacylglycerols
-formation of mono, di, and triacylglycerol as FA are esterified via their carboxyl group to the carbons glycerol
-esterified FA loose their charge, forming 'neutral' TAG molecules
structure of TAG
carbon 1-saturated FA of varied length
carbon 2: unsaturated FA of varied length
carbon 3: saturated or unsaturated FA of varied length
*wanna make sure the terminal two are saturated
-only slightly soluble in water
-unable to form micelles independently
-able to coalesce and form nearly anhydrous, cytosolic oil droplets
what is the primary storage place of TAG?
What is the site of FA synthesis?
synthesis of TAG requires the production of TAG building blocks
-glycerol phosphate-the initial acceptor of activated FA during TAG synthesis
-acyl CoA-free FA must be converted to the activated form
synthesis of glycerol phosphate in the liver
glycerol kinase converts free glycerol to glycerol phosphate
Where are the two pathways to produce glycerol phosphate?
liver and adipose tissue
-produced from glucose via the glycolytic pathway
-uses lots of energy, must be in the well fed state
-glucose to DHAP
-DHAP is reduced to glycerol phosphate by glycerol phosphate dehydrogenase
GLUT 4 activity in adipocytes
-when plasma glucose and insulin levels are low, adipose tissue cannot synthesize glycerol phosphate: no TAG production
What is the conversion of free FA to acetyl CoA catalyzed by?
CoA synthase (thiokinase)
synthesis of a TAG molecule
-sequential addition of 2 FA from fatty acyl COA to glycerol phosphate by acyltransferase
-removal of the phosphate group by a phosphatase
-addition of the third FA by an acyltransferase
Fates of TAG in the adipose tissue
-TAG is stored as cytosolic lipid droplets
-TAG in this format is easily mobilized when fuel is required
Fates of TAG in the liver tissue
-small amounts of TAG are stored in the liver
-TAG generated in the liver is packaged with other lipids and apoproteins to form lipoprotein particles called VLDL
-Nascent VLDL are secreted to the blood and function to deliver endogenously synthesized lipids to the peripheral tissue
exogenous dietary acquired lipids