Chapter 16: Lipid Metabolism Flashcards
what are the 4 ways fatty acids differ from one another?
- length of hydrocarbon tails
- number of carbon-carbon double bonds
- positions of the double bonds in the chain
- the number of branches
what is the purpose of fatty acid synthesis?
to make fatty acids
what are the starting molecules of fatty acid synthesis?
- acetyl CoA
- malonyl ACP
what are the ending molecules of fatty acid synthesis?
- palmitate (16)
- stearate (18)
how are fatty acids synthesized?
- fatty acids are synthesized by the repetitive adding of 2-carbon units to the growing ends of a hydrocarbon chain
- the growing chain is covalently attached to acyl carrier protein (ACP)
- the linkage is a thioester
- two main stages are initiation and elongation
what is the precursor for all fatty acid synthesis? what is it made from?
malonyl ACP, formed from acetyl CoA, is the precursor for all fatty acid synthesis
what are the steps of Malonyl ACP synthesis?
- Carboxylation of acetyl CoA in the cytosol to form malonyl CoA
- Transfer of malonyl from CoA to ACP
which enzyme catalyzes the carboxylation of acetyl CoA to form malonyl CoA?
- biotin-dependent enzyme acetyl-CoA carboxylase
- uses a molecule of ATP
which enzyme catalyzes the transfer of malonyl from CoA to ACP?
malonyl CoA:ACP transacylase
what do malonyl ACP and acetyl ACP come together to form?
Acetoacetyl ACP
how is Acetoacetyl ACP formed?
- *reaction catalyzed by 3-ketoacyl ACP synthase
- a 2 carbon unit from acetyl ACP is transferred to the enzyme where it is covalently bound via a thioether linkage
- the enzyme then catalyzes the transfer of this 2 carbon unit to the end of malonyl ACP, generating a 4 carbon intermediate (Acetoacetyl ACP) and CO2
what are the steps of initiation?
- An acetyl group gets transferred from CoA to ACP by acetyl CoA-ACP transacylase
- An acetyl (acyl) group next gets transferred to the K arm of the FAS complex
- A malonyl group gets transferred from CoA to ACP by malonyl CoA ACP transacylase - results in both arms of FAS occupied forming acylmalonyl ACP
what are the steps of elongation?
- 3-ketoacyl ACP reductase (KR) catalyzes the first reduction (ketone to alcohol)
- requires NADPH
- 3-hydroxyacyl ACP dehydratase (DH) catalyzes the dehydration (removal of H20)
- Enoyl-ACP reductase (ER) catalyzes the second reduction (adds hydrogens)
- requires NADPH
what is the final product of elongation?
- *the final product is an acyl ACP that is two carbons longer
- this acyl ACP becomes the substrate for elongation by KAS
what is ALWAYS the carbon donor for elongation?
malonyl ACP
why are only 16 and 18 carbon fatty acids made?
longer chain lengths do not fit in the binding site of the condensing enzyme
how are completed fatty acids released from ACP?
thioesterase (TE)
what are the enzymes of the fatty acid synthase?
- MAT: malonyl/acetyl transferase
- KAS: 3-ketoacyl ACP synthase
- KR: 3-ketoacyl ACP reductase
- DH: 3-hydroxyacyl ACP dehydratase
- TE: thioesterase
what happens after thioesterase releases free fatty acids, but subsequent modifications are needed?
- *thioesterase releases free fatty acids, but subsequent modifications of these fatty acids require an activation step where they are converted to thioesters of CoA
- ATP dependent reaction
- catalyzed by acetyl-CoA synthetase
how are fatty acids longer than 16 or 18 carbons made?
- made by extending palmitoyl CoA or stearoyl CoA in separate extension reactions
- the enzymes that catalyze the reaction are called elongases and use malonyl CoA as the source of the 2 carbon extension unit
how are unsaturated fatty acids made in bacteria?
- a double bond is added to a growing chain when it reaches 10 carbons in length
- after desaturation, elongation continues normally
how are unsaturated fatty acids made in eukaryotes?
- double bonds cannot be introduced during fatty acid synthesis since they employ the fatty acid synthase complex
- eukaryotes use desaturase enzymes after synthesis to introduce double bonds
how are polyunsaturated fatty acids (PUFA) synthesized?
by the sequential action of different, highly specific desaturases
which desaturases do mammalian cells not contain?
mammalian cells do not contain desaturases that act beyond the C9 position
which fatty acids do we need from our diet?
- Linolenic acid (omega 3)
- linoleic acid (omega 6)
*interconvert using desaturases and elongases
an intermediate in the synthesis of triacylglycerols and glycerophospholipids
phosphatidate
how is phosphatidate formed?
by transferring the acyl group from fatty acid CoA molecules to the C-1 and C-2 positions of glycerol 3-phosphate
what are the two general classes of Eicosanoids?
- Prostaglandins and thromboxanes
2. Leukotrienes
what is the precursor of many Eicosanoids?
Arachidonate (20:4)
how are prostaglandins synthesized?
- **by the cyclization of arachidonate by an enzyme called prostaglandin H synthase (PGHS)
- this is the cycloogygenase activity of this enzyme (COX-1)
- this forms prostaglandin G2, the precursor for prostaglandin H2, which can be converted to prostacyclin, thromboxane A2, and a variety of prostaglandins
in addition to the cycloogyenase activity of prostaglandin H synthase (PGHS), what other activity does it have?
lipooxygenase activity - leads to the production of leukotrienes
how is ceramide generated?
starting with the condensation of serine and palmitoyl CoA
what are the stages of cholesterol synthesis?
- Acetyl CoA to Isopentyl diphosphate
- Isopentyl diphosphate to squalene
- Squalene to cholesterol
what happens during stage 1 of cholesterol synthesis (Acetyl CoA to Isopentyl diphosphate)?
- the condensation of 3 acetyl CoA molecules leads to HMG CoA, which is reduced to mevalonate
- mevalonate is then converted to isoprenyl diphosphate via two phosphorylations and a decarboxylation
what happens during stage 2 of cholesterol synthesis (Isopentyl diphosphate to squalene)?
- Isopentyl diphosphate is isomerized and then dimerized in a head to tail condensation reaction
- subsequent condensation reactions generate squalene (C 30)
how much ATP is needed to synthesize squalene?
20.5 ATP
what happens during stage 3 of cholesterol synthesis (Squalene to cholesterol)?
- the steps between squalene and the first fully cyclized intermediate (lanasterol) include the addition of a hydroxyl group followed by a concerted series of cyclizations
- no ATP needed
what is cholesterol a precursor of?
- bile salts
- hormones
- the D vitamins
how are fatty acids degraded?
beta oxidation
what is the starting molecule of beta oxidation?
fatty acyl CoA
what are the products of beta oxidation?
- acetyl CoA
- NADH
- QH2
- fatty acyl reduced by 2 carbons
which carbon of the fatty acid is oxidized?/
the beta carbon
where does fatty acid synthesis occur?
cytosol
where does beta oxidation occur?
mitochondria and perioxisomes
what are the four steps of beta oxidation?
- Fatty acyl CoA oxidized to trans-enoyl CoA
- Trans-enoyl CoA hydrated to form L-3-hydroxyacyl CoA
- L-3-hydroxyacyl CoA oxidized to form 3-ketoacyl CoA
- 3-ketoacyl CoA thiolysis to form acetyl CoA and a fatty acyl CoA shortened by two carbons
what happens during the first step of beta oxidation (Fatty acyl CoA oxidized to trans-enoyl CoA)?
-oxidation of fatty acyl CoA to trans-enoyl CoA
-accompanied by reduction of FAD to FADH2
~acyl-CoA dehydrogenase
-pass electrons along to Fe-S
-electrons move onto Q to form QH2
what enzyme is used in the hydration of trans-enoyl CoA to form L-3-hydroxyacyl CoA?
2-enoyl-CoA hydratase
what happens during the third step of beta oxidation (L-3-hydroxyacyl CoA oxidized to form 3-ketoacyl CoA)?
- L-3-hydroxyacyl CoA oxidized to form 3-ketoacyl CoA
- NAD+ reduced to NADH
- L-3-hydroxyacyl CoA dehydrogenase
what happens during the fourth step of beta oxidation (3-ketoacyl CoA thiolysis to form acetyl CoA and a fatty acyl CoA shortened by two carbons)?
- 3-ketoacyl CoA thiolysis to form acetyl CoA and a fatty acyl CoA shortened by two carbons
- 3-ketoacyl CoA thiolase
- HS-CoA goes in, acetyl CoA comes out
what does the carnitine shuttle system?
- long chain fatty acyl CoA formed in the cytosol cannot diffuse across the inner mitochondrial membrane to the matrix where beta oxidation occurs
- carnitine shuttle system actively transports the long-chain fatty acids
how is bacteria beta oxidation unusual?
bacteria synthesize odd-chain fatty acids that are degraded by beta oxidation except that the final product is a 3-carbon acyl CoA - propionyl CoA
what happens to propionyl CoA?
can be converted to succinyl CoA and eventually oxaloacetate
do saturated and unsaturated fatty acids require the same enzymes for oxidation?
unsaturated fatty acids require 2 enzymes in addition to those usually needed for fatty acid oxidation
where does most lipid biosynthesis in eukaryotic cells occur?
- **endoplasmic reticulum
- the biosynthetic enzymes are membrane bound with their active sites oriented toward the cytosol, so they can have access to water-soluble cytosolic compounds
what are the principle hormone regulators of fatty acid metabolism?
- glucagon
- epinephrine
- insulin
what is the key regulatory enzyme for fatty acid synthesis?
acetyl-CoA carboxylase (step 1 of making malonyl CoA)
how does high insulin affect fatty acid metabolism?
- inhibit the hydrolysis of stored triaglycerols
- stimulate the formation of malonyl CoA by acety CoA carboxylase
how do high glucagon and epinephrine affect lipid metabolism?
- glucagon and epinephrine are high in the fasted state and will signal the mobilization of fatty acids to serve as fuel
- high glucagon inhibits fatty acetyl-CoA carboxylase, slowing storage
where does digestion of dietary lipids occur?
mainly in the small intestine where suspended fat particles are coated with bile salts, which help them become soluble
how/where are triaglycerols broken down?
triacylglycerols are broken down in the small intestine by lipases
why can’t triacylglycerols, cholesterol, and cholesteryl esters be transported int he blood or lymph as free molecules?
How is this problem fixed?
- they are insoluble in water
- instead, these lipids assemble with phospholipids and amphipathic lipid-binidng proteins to form spherical macromolecules called lipoproteins
what happens to acetyl CoA produced in the liver from fatty acid oxidation?
most is routed to the krebs cycle, but some can follow an alternate pathway
what happens during fasting when glycolysis is decreased and the gluconeogenic pathway is active?
- the pool of oxaloacetate becomes temporarily depleted and the amount of acetyl CoA exceeds the capacity of the krebs cycle
- the excess acetyl CoA is used to form ketone bodies
what are common ketone bodies?
- beta-hydroxybutyrate
- acetoacetate
- acetone
where are ketone bodies made?
ketone bodies are synthesized in the liver during starvation, becoming substitutes for glucose
where are ketone bodies oxidized?
ketone bodies are oxidized in the mitochondria in skeletal muscle and the intestine during starvation
