Ch 23 - Biosynthesis of Fatty acids & eicosanoids Flashcards
Fatty acids are synthesized by an ______________, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the CYTOSOL.
extramitochondrial system
In most mammals, __________ is the primary substrate for lipogenesis, but in ruminants it is __________, the main fuel molecule they obtain from the diet.
Glucose
Acetate
However, inhibition of lipogenesis occurs in _______________, and variations in the activity of the process affect the nature and extent of _________.
type 1 (insulin-dependent) diabetes mellitus
Obesity
______________ in phospholipids of the cell membrane are important in maintaining membrane fluidity.
Unsaturated fatty acid
A high ratio of ______________ in the diet is considered to be beneficial in preventing coronary heart disease.
polyunsaturated fatty acids to saturated fatty acids (P:S ratio)
______________ mediate inflammation, pain, and induce sleep and also reg-ulate blood coagulation and reproduction.
Prostaglandins
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as __________ and _________ act by inhibiting prostaglandin synthesis.
aspirin and ibuprofen
_______________ have muscle contractant and chemotactic properties and are important in allergic reactions and inflammation.
Leukotrienes
THE MAIN PATHWAY FOR DE NOVO SYNTHESIS OF FATTY ACIDS (LIPOGENESIS) OCCURS IN THE ______________.
CYTOSOL
This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue. Its cofactor requirements include:
- NADPH
- ATP
- Mn2+
- biotin
- HCO3 (as a source of CO2)
_____________ is the immediate substrate, and ____________ is the end product.
Acetyl-CoA
free palmitate
production of ____________ is the Initial & Controlling Step in Fatty acid Synthesis
Malonyl-Coa
_____________ as a source of CO2 is required in the initial reaction for the carboxylation of acetyl-CoA to malonyl-CoA in the presence of ATP and ________________.
Bicarbonate
acetyl-CoA carboxylase
This enzyme has a major role in the regulation of fatty acid synthesis.
Acetyl-CoA carboxylase
_______________ has a requirement for the B vitamin biotin and is a multienzyme protein containing biotin, biotin carboxylase, biotin carboxyl carrier protein, and a carboxyl transferase, as well as a regulatory allosteric site.
Acetyl-CoA carboxylase
The _______________ Is a homodimer of Two polypeptide Chains Containing Six Enzyme activities.
Fatty acid Synthase Complex
After the formation of malonyl-CoA, fatty acids are formed by the _______________.
fatty acid synthase enzyme complex
The individual enzymes required for fatty acid synthesis are linked in this multienzyme polypeptide complex that incorporates the _______________, which has a similar function to CoA in the β-oxidation pathway. It contains the vitamin ____________ in the form of 4′-phosphopantetheine.
acyl carrier protein (ACP)
pantothenic acid
X-ray crystallography of the three-dimensional structure, however, has shown that the complex is a __________, with two identical subunits, each containing 6 enzymes and an ACP, arranged in an ___________.
homodimer
X shape
The position of the ACP and thioesterase domains cannot be resolved as yet by x-ray crystallography, possibly because they are too __________, but they are thought to lie close to the _______________ enzyme.
Flexible
3-ketoacylreductase
The use of one _________________ has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene.
multienzyme functional unit
Initially, a priming molecule of acetyl-CoA combines with a ______________ while malonyl-CoA combines with the adjacent ´SH on the _________________ of ACP of the other monomer.
cysteine ‘SH group
4′-phosphopantetheine
These reactions are catalyzed by _____________, to form acetyl (acyl)-malonyl enzyme.
malonyl acetyl transacylase
The acetyl group attacks the methylene group of the malonyl residue, catalyzed by ________________, and liberates CO2, forming 3-ketoacyl enzyme (acetoacetyl enzyme) (reaction 2), freeing the cysteine —SH group.
3-ketoacyl synthase
_______________ allows the reaction to go to completion, pulling the whole sequence of reactions in the forward direction.
Decarboxylation
The 3-ketoacyl group is reduced, dehydrated, and reduced again (reactions 3-5) to form the corresponding _____________.
saturated acyl-S-enzyme.
The sequence of reactions is repeated six more times until a saturated _________________ has been assembled.
16-carbon acyl radical (palmitoyl)
It is liberated from the enzyme complex by the activity of the sixth enzyme in the complex, _______________.
thioesterase (deacylase)
The free palmitate must be activated to ___________ before it can proceed via any other metabolic pathway
acyl-CoA
In mammary gland, there is a separate thioesterase specific for acyl residues of ______________, which are subsequently found in milk lipids.
C8, C10, or C12
The acetyl-CoA used as a primer forms carbon atoms ____ and ____ of palmitate.
15 and 16
The addition of all the subsequent C2 units is via __________.
malonyl-CoA
_____________ acts as primer for the synthesis of long-chain fatty acids having an odd number of carbon atoms, found particularly in ruminant fat and milk.
Propionyl CoA
The Main Source of NADPH for Lipogenesis Is the _____________.
pentose phosphate pathway
________ is involved as a donor of reducing equivalents in both the reduction of the 3-ketoacyl and of the 2,3-unsaturated acyl derivatives.
NADPH
The oxidative reactions of the pentose phosphate pathway are the chief source of the ___________ required for the reductive synthesis of fatty acids.
hydrogen
Significantly, tissues specializing in active _____________ —ie, liver, adipose tissue, and the lactating mammary gland— also possess an active pentose phosphate pathway.
lipogenesis
True or False:
Moreover, both metabolic pathways are found in the cytosol of the cell; so, there are no membranes or permeability barriers against the transfer of NADPH.
True
Other sources of NADPH include the reaction that converts malate to pyruvate catalyzed by the ___________ (NADP malate dehydrogenase) and the extramitochondrial _______________ reaction (probably not a substantial source, except in ruminants).
“malic enzyme”
isocitrate dehydrogenase
_________ Is the principal Building Block of Fatty acids
acetyl-Coa
____________ is formed from glucose via the oxidation of pyruvate in the matrix of the mitochondria.
Acetyl-CoA
However, as it does not diffuse readily across the mitochondrial membranes, its transport into the cytosol, the principal site of fatty acid synthesis, requires a special mechanism involving __________.
citrate
After condensation of acetyl-CoA with oxaloacetate in the citric acid cycle within mitochondria, the citrate produced can be translocated into the extramitochondrial compartment via the _______________, where in the presence of CoA and ATP, it undergoes cleavage to acetyl-CoA and oxaloacetate catalyzed by ______________, which increases in activity in the well-fed state.
tricarboxylate transporter
ATP-citrate lyase
Note that the _____________ in the mitochondrial membrane requires malate to exchange with citrate.
citrate (tricarboxylate) transporter
There is little ATP-citrate lyase or malic enzyme in ruminants, probably because in these species _________ (derived from carbohydrate digestion in the rumen and activated to acetyl-CoA extramitochondrially) is the main source of acetyl-CoA.
acetate
Elongation of Fatty acid Chains Occurs in the _____________.
Endoplasmic reticulum
This pathway (the “______________”) elongates saturated and unsaturated fatty acyl-CoAs (from C10 upward) by two carbons, using malonyl-CoA as the acetyl donor and NADPH as the reductant, and is catalyzed by the __________________ system of enzymes
microsomal system
microsomal fatty acid elongase
Elongation of _____________ in brain increases rapidly during myelination in order to provide C22 and C24 fatty acids for sphingolipids.
stearyl-CoA
THE NUTRITIONAL STATE REGULATES ______________.
LIPOGENESIS
____________ converts surplus glucose and intermediates such as pyruvate, lactate, and acetyl-CoA to fat, assisting the anabolic phase of this feeding cycle.
Lipogenesis
The nutritional state of the organism is the main factor regulating the rate of ___________.
lipogenesis
These latter conditions are associated with increased concentrations of plasma-free fatty acids, and an ____________ has been demonstrated between hepatic lipogenesis and the concentration of serum-free fatty acids.
inverse relationship
Lipogenesis is increased when __________ is fed instead of glucose because fructose bypasses the phosphofructokinase control point in glycolysis and floods the lipogenic pathway.
sucrose
SHORT- & LONG-TERM MECHANISMS REGULATE _____________
LIPOGENESIS
Long-chain fatty acid synthesis is controlled in the ________ by allosteric and covalent modification of enzymes and in the __________ by changes in gene expression governing rates of synthesis of enzymes.
Short term
Long term
_______________ Is the Most Important Enzyme in the regulation of Lipogenesis
acetyl-Coa Carboxylase
Acetyl-CoA carboxylase is an allosteric enzyme and is activated by _________, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetylCoA.
citrate
_________ promotes the conversion of the enzyme from an inactive dimer (two subunits of the enzyme complex) to an active polymeric form, with a molecular mass of several million.
Citrate
Inactivation is promoted by phosphorylation of the enzyme and by long-chain acyl-CoA molecules, an example of ______________ by a product of a reaction
negative feedback inhibition
Acyl-CoA also inhibits the mitochondrial ______________, thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol.
tricarboxylate transporter
Acetyl-CoA carboxylase is also regulated by hormones such as _________, ________ and __________ via changes in its phosphorylation state.
glucagon, epinephrine, and insulin
Acyl-CoA causes an inhibition of pyruvate dehydrogenase by inhibiting the _______________ of the inner mitochondrial membrane, which leads to increased intramitochondrial (ATP)/(ADP) ratios and therefore to conversion of active to inactive pyruvate dehydrogenase thus regulating the availability of acetyl-CoA for lipogenesis.
ATP-ADP exchange transporter
_______ stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity.
Insulin
It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol-3-phosphate for triacylglycerol synthesis via esterification of the newly formed fatty acids and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue, but not in liver.
Insulin
________ also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and reducing the concentration of plasma-free fatty acids and, therefore, long-chain acyl-CoA, which are inhibitors of lipogenesis.
Insulin
The Fatty acid Synthase Complex & acetylCoa Carboxylase are ____________.
adaptive Enzymes.
__________ plays an important role, causing gene expression and induction of enzyme biosynthesis, and __________ (via cAMP) antagonizes this effect.
Insulin
Glucagon
Other C20, C22, and C24 polyenoic fatty acids may be derived from ________, ________ and __________ by chain elongation.
oleic, linoleic, and α-linolenic acids
_________ and _________ are not essential in the diet because the tissues can introduce a double bond at the Δ9 position of a saturated fatty acid.
Palmitoleic and oleic acids
_________ and _________ are the only fatty acids known to be essential for the complete nutrition of many species of animals, including humans, and are termed the nutritionally essential fatty acids.
Linoleic and α-linolenic acids
In most mammals, ____________ can be formed from linoleic acid.
arachidonic acid
True or False:
Double bonds can be introduced at the Δ4, Δ5, Δ6, and Δ9 positions in most animals, but never beyond the Δ9 position.
True
In contrast, plants are able to synthesize the nutritionally essential fatty acids by introducing double bonds at the Δ____ and Δ____ positions.
12 and 15
MONOUNSATURATED FATTY ACIDS ARE SYNTHESIZED BY A _______________.
Δ9 DESATURASE SYSTEM
Several tissues including the ______ are considered to be responsible for the formation of nonessential monounsaturated fatty acids from saturated fatty acids.
liver
The first double bond introduced into a saturated fatty acid is nearly always in the _____________.
Δ9 position
An enzyme system— _____________ in the endoplasmic reticulum catalyzes the conversion of palmitoyl-CoA or stearoyl-CoA to palmitoleoyl-CoA or oleoyl-CoA, respectively.
Δ9 desaturase
The enzymes appear to be similar to a monooxygenase system involving ______________.
cytochrome b5
Additional double bonds introduced into existing monounsaturated fatty acids are always separated from each other by a ____________ except in bacteria.
methylene group (methylene interrupted)
Since animals have a _____________, they are able to synthesize the ω9 (oleic acid) family of unsaturated fatty acids completely by a combination of chain elongation and desaturation after the formation of saturated fatty acids.
Δ9 desaturase
Linoleic acid is converted to arachidonic acid (20:4 ω6) via _______________.
γ-linolenic acid (18:3 v6).
Rats fed a purified nonlipid diet containing vitamins A and D exhibit a reduced growth rate and reproductive deficiency which may be cured by the addition of __________, ___________ and _____________ to the diet.
linoleic, α-linolenic, and arachidonic acids
These fatty acids are found in high concentrations in vegetable oils and in small amounts in animal carcasses
linoleic, α-linolenic, and arachidonic acids
__________________ are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation and they also have various other functions that are less well defined.
Essential fatty acids
They are found in the structural lipids of the cell, often in the __________ of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane.
position 2
Arachidonic acid is present in membranes and accounts for ____________ of the fatty acids in phospholipids.
5% to 15%
________________, which is synthesized to a limited extent from α-linolenic acid or obtained directly from fish oils, is present in high concentrations in retina, cerebral cortex, testis, and sperm.
Docosahexaenoic acid (DHA; ω3, 22:6)
_____________ is particularly needed for development of the brain and retina and is supplied via the placenta and milk.
DHA
Patients with _____________ are reported to have low blood levels of DHA.
retinitis pigmentosa
In ______________, nonessential polyenoic acids of the ω9 family, particularly Δ5,8,11-eicosatrienoic acid (ω9 20:3) replace the essential fatty acids in phospholipids, other complex lipids, and membranes.
essential fatty acid deficiency
The ____________ in plasma lipids can be used to diagnose the extent of essential fatty acid deficiency.
triene:tetraene ratio
