Ch 22 - Oxidation Of Fatty Acids: Ketogenesis Flashcards
Each step in fatty acid oxidation involves _______________, is catalyzed by separate enzymes, utilizes ____ and _____ as coenzymes, and generates ATP.
Acyl-CoA derivatives
NAD+ and FAD
It is an aerobic process, requiring the presence of oxygen.
Fatty acid oxidation
_____________ is a characteristic of starvation and of diabetes mellitus and leads to increased ketone body production by the liver (ketosis).
Increased fatty oxidation
Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to _________.
Hypoglycemia
This occurs in various states of CARNITINE DEFICIENCY, or deficiency of essential enzymes in fatty acid oxidation, for example _______________ or inhibtion of fatty acid oxidation by poisons, for example ___________.
Carnitine palmitoyltransferase
Hypoglycin
Oxidation of fatty acids occurs in ___________.
Mitochondria
Fatty acids are transported in the blood as ______________.
Free fatty acids
Free fatty acids (FFAs) also called __________ or _________ are fatty acids that are in the UNESTERIFIED STATE.
Unesterified (UFA) or nonesterified (NEFA) fatty acids
In plasma, longer chain FFA are combined with _______ and in the cell they are attached to a FATTY ACID BINDING PROTEIN so that in fact they are never really “free”.
Albumin
____________ are more WATER-SOLUBLE and exist as the UNIONIZED ACID or as a FATTY ACID ANION.
Shorter chain fatty acids
Fatty acids are activated before being _________.
Catabolized
True or False:
Fatty acids must be first converted to an active intermediate before they can be catabolized.
True
This is the only step in the complete degradation of a fatty acid that requires energy from ATP.
Fatty acids are activated before being catabolized
In the presence of ATP and coenzyme A, the enzyme ____________ catalyzes the conversion of a fatty acid to an “active fatty acid” or ____________ using one high-energy phosphate and forming AMP and PPi.
Acyl-coA synthetase (thiokinase)
Acyl-CoA
The PPi is hydrolyzed by ___________ with the loss of a further high-energy phosphate ensuring that the overall reaction goes to completion
Inorganic pyrophosphatase
Found in the endoplasmic reticulum, peroxisomes and inside and on the outer membrane of mitochondria
Acyl-CoA synthetases
Long-chain fatty acids penetrate the inner mitochondrial membrane as _____________.
Carnitine derivatives
Is widely distributed and is particularly abundant in muscle.
Carnitine (B-hydroxy-y-trimethylammonium butyrate)
True or False: Long-chain acyl-CoA cannot penetrate the inner membrane of mitochondria.
True
Located in the outer mitochondrial membrane, transfers long-chain acyl group from CoA to carnitine forming __________ and releasing CoA.
Carnitine palmitoyltransferase-I
Acylcarnitine
Acylcarnitine is able to penetrate the inner membrane and gain access to the B-oxidation system of enzymes via the inner membrane exchange transporter _________________.
Carnitine-acylcarnitine translocase
The acyl group is then transferred to CoA so that acyl-CoA is reformed and carnitine is liberated. This reaction is catalyzed by ____________ which is located on the inside of the inner membrane
Carnitine palmitoyltransferase II
In the ____________, two carbons at a time are cleaved from acyl-CoA molecules starting at the CARBOXYL END.
B-oxidation pathway
The two-carbon units formed are acetyl-CoA thus __________ forms eight acetyl-CoA molecules.
Palmitoyl-CoA
The B-oxidation cycle generates ________ and _______.
FADH2 and NADH
Several enzymes known collectively as __________ are found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain.
Fatty acid oxidase
In the process, large quantities of the reducing equivalents FADH2 and NADH are generated and are used to form ATP by _____________.
Oxidative phosphorylation
The first step is the removal of TWO hydrogen atoms from the 2(a) and 3(b) carbon atoms, catalyzed by __________ and requiring ______. This results in the formation of 🔼2-trans-enoyl-CoA and FAD.
Acyl-CoA dehydrogenase
FAD
The reoxidation of FADH2 by the respiratory chain requires the meditation of another flavoprotein termed _____________.
Electron-transferring flavoprotein
Water is added to saturate the double bond and form 3-hydroxy-acyl-CoA, catalyzed by _______________.
🔼2-enoyl-CoA hydratase
The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon cataylzed by _______________ to form the corresponding 3-ketoacyl-CoA compound. In this case, _____ is the coenzyme involved.
L (+) - 3-hydroxyacyl-CoA dehydrogenase
NAD+
Finally, 3-ketoacyl-CoA is split at the 2,3-position by _________ forming acetyl-CoA and a new acyl-CoA two carbons shorter than the original acyl-CoA molecule.
Thiolase (3-ketoacyl-CoA-thiolase)
The shorter acyl-CoA formed in the cleavage reenters the oxidative pathway at __________.
Reaction 2
For example, after SEVEN cycles the C16 fatty acid, _________ would be converted to eight acetyl CoA molecules.
Palmitate
Since acetyl-CoA can be oxidized to CO2 and water via the ______________, the complete oxidation of fatty acids is achieved.
Citric acid cycle
Oxidation of a fatty acid with an ODD NUMBER of carbon atoms yields ACETYL-CoA plus a molecule of ___________.
Propionyl-CoA
Fatty acids with an odd number of carbon atoms are oxidized by the pathway of B-oxidation described above producing acetyl CoA until a three-carbon __________ residue remains.
Propionyl-CoA
This compound is converted to __________, a consistuent of the citric acid cycle.
Succinyl-CoA
Hence, the propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is _________.
Glucogenic
Oxidation of fatty acids produces a large quantity of ______.
ATP
Transport of electrons from FADH2 and NADH via the respiratory chain leads to the synthesis of ____ high-energy phosphates for each of the seven cycles needed for the breakdown of the C16 fatty acid, palmitate to acetyl-CoA. (7 x 4 = 28)
4
A total of ___ mol of acetyl-CoA is formed and each gives rise to ___ mol of ATP on oxidation in the CTA making ___ mol.
8
10
80
Two must be substracted for the initial activation of the fatty acid, yielding a net gain of ____ mol of ATP per mole of palmitate or 106 x 30.5 = 3233 kJ. This represents ___% of the free energy of combustion of palmitic acid.
106 mol
33%
_______ oxidize very long chain fatty acids.
Peroxisomes
A modified form of B-oxidation is found in _______ and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by ______.
Peroxisomes
Catalase
True or False:
Thus, the dehydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP.
True
The system facilitates the oxidation of VERY LONG CHAIN FATTY ACIDS. The enzymes responsible are induced by high-fat diets and in some species by hypolipidemic drugs such as _________.
Clofibrate
The enzymes in peroxisomes do not attack shorter chain fatty acids; the B-oxidation sequence ends at __________.
Octanoyl-CoA
Octanoyl and acetyl groups are both further oxidized in ____________.
Mitochondria
Another role of peroxisomal B-oxidation is to _______ the side chain of cholesterol in bile acid formation.
Shorten
__________ also take part in the synthesis of ETHER GYLCEROLIPIDS, CHOLESTEROL and DOLICHOL.
Peroxisomes
Oxidatiom of unsaturated fatty acids occurs by a _______________.
Modified B-oxidation pathway
The CoA esters of unsaturated fatty acids are degraded by the enzymes normally responsible for B-oxidation until either a ______________ compound or a _____________ compound is formed, depending upon the position of the double bonds.
🔼3-cis-acyl-CoA or 🔼4-cis-acyl-CoA compound
The former compound is isomerized _________________ to the corresponding 🔼2-trans-CoA stage of B-oxidation for subsequent hydration and oxidation.
🔼3cis -> 🔼2-trans-enoyl-CoA isomerase
____________ occurs when there is a high rate of fatty-acid oxidation in the liver.
Ketogenesis
Under merabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of _______ and _________.
Acetoacetate and D(–)-3-hydroxybutyrate (B-hydroxybutyrate)
Acetoacetate continually undergoes spontaneous decarboxylation to yield ____________.
Acetone
Acetoacetate and 3-hydroxybutyrate are interconverted by the mitochondrial enzyme ________________; the equilibrium is controlled by the mitochondrial [NAD+]/[NADH] ratio, that is the ____________.
D(-)-3-hydroxybutyrate dehydrogenase
The concentration of total ketone bodies in the blood of well-fed mammals does not normally exceed ____ mmol/L except in ruminants, where 3-hydroxybutyrate is formed continously from _________ (a product of ruminal fermentation) in the rumen wall.
0.2 mmol/L
Butyric acid
In vivo, _____ appears to be the only organ in nonruminants to add significant quantities of ketone bodies to th blood.
Liver
Extrahepatic tissues utilize acetoacetate and B-hydroxybutyrate as ______________.
Respiratory substrates
________ is a waste product which, as it is VOLATILE, can be excreted via the lungs.
Acetone
True or False:
Because there is active synthesis but LITTLE UTILIZATION of ketone bodies in the liver, while they are used but not produced in extrahepatic tissues, there is a net flow of the compounds to the extrahepatic tissues.
True
________________ is an intermediate in the pathway of ketogenesis.
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
Enzymes responsible for ketone body formation are associated mainly with the _________.
Mitochondria
The term ketones should not be used as there are ketones in blood that are not ketone bodies, for example, __________ and _________.
Pyruvate and fructose
Two acetyl-CoA molecules formed in B-oxidation condense to form acetoacetyl-CoA by a reversal of the __________ reaction.
Thiolase
___________, which is a starting material for ketogenesis, also arises directly from the terminal FOUR carbons of a fatty acid during B-oxidation.
Acetoacetyl-CoA
Condensatiom of acetoacetyl-CoA with another molecule of acetyl-CoA by _________________ forms 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
3-hydroxy-3-methylglutaryl-CoA synthase
______________ then causes acetyl-CoA to split off from the HMG-CoA, leaving free aceto-acetate.
3-hydroxy-3-methylglutaryl-CoA lyase
True or False:
BOTH ENZYMES must be present in mitochondria for ketogenesis to take place.
True
____________ is quantitatively the predominant ketone body present in the blood and urine in ketosis
D(-)-3-hydroxybutyrate
Serve as a fuel for extrahepatic tissues.
Ketone bodies
Acetoacetat once formed cannot be reactivated directly except in the _________, where it is used in a much less active pathwat as a precursor in cholesterol synthesis.
Cytosol
In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by ___________________.
Succinyl-CoA-acetoacetate CoA transferase
With the addition of CoA, the acetoacetyl-CoA is split into two acetyl-CoAs by _________ and oxidized in the citric acid cycle.
Thiolase
If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of ~____ mmol/L, the oxidative machinery is saturated.
12 mmol/L
Is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues.
Ketonemia
Is difficult to oxidixe IN VIVO and to a large extent is volatilized in the lungs.
Acetone
In ____________, the loss of ketone bodies via the urine is only a few percent of the total ketone body production and utilization.
Moderate ketonemia
Measurement of the ________, not the ketonuria, is the preferred method of assesing the severity of ketosis.
Ketonemia
Ketosis does not occur in vivo unless there is an increase in the level of circulating ______ that arise from lipolysis of triacylglycerol in adipose tissue.
FFAs
Are the precursors of ketone bosies in the liver.
FFAs
The liver, both in fed and in fasting conditions, extracts ~__% of the FFAs passing through it, so that a high concentrations the flux passing into the liver is substantial.
30%
Therefore, the factors regulating ______________ from adipose tissue are important in controlling ketogenesis.
Mobilization of FFA
After uptake by the liver, FFAs are either _________ to CO2 or ketone bodies or ___________ to triacylglycerol and phospholipid.
B-oxidized
Esterified
There is regulation of entry of fatty acids into th oxidative pathway by _______________ and the remainder of the fatty acid taken up is eterified.
Carnitine palmitoyltransferase-I (CPT-I)
CPT-I activity is ____ in the fed state, leading to depression of fatty acid oxidation and ____ in starvation, allowing fatty acid oxidation to increase.
Low
High
____________ the initial intermediate in fatty acid biosynthesis formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CPT-I.
Malonyl-CoA
FFA enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out of the liver in _______.
VLDL
These events are reinforced in starvation by a decrease in ____________.
Insulin/glucagon ratio
Impaired oxidation of fatty acids gives rise to disease often associated with _____________.
Hypoglycemia
A fall in the concentration of _____________, particularly within the mitochondria, can impair the ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward ketogenesis.
oxaloacetate
_______________ can occur particularly in the newborn— and especially in preterm infants—owing to inadequate biosynthesis or renal leakage.
Carnitine deficiency
Symptoms of deficiency include __________, which is a consequence of impaired fatty acid oxidation and lipid accumulation with muscular weakness.
hypoglycemia
______________ affects only the liver, resulting in reduced fatty acid oxidation and ketogenesis, with hypoglycemia.
Inherited CPT-I deficiency
_________________ affects primarily skeletal muscle and, when severe, the liver
CPT-II deficiency
The sulfonylurea drugs (_____________________), used in the treatment of type 2 diabetes mellitus, reduce fatty acid oxidation and, therefore, hyperglycemia by inhibiting CPT-I.
glyburide [glibenclamide] and tolbutamide
Inherited defects in the enzymes of β-oxidation and ketogenesis also lead to _____________, _______________ and _____________.
nonketotic hypoglycemia, coma, and fatty liver.
Defects are known in long-and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of __________________).
acute fatty liver of pregnancy
3-KetoacylCoA thiolase and HMG-CoA lyase deficiency also affect the degradation of ___________, a ketogenic amino acid.
leucine
Jamaican vomiting sickness is caused by eating the unripe fruit of the akee tree, which contains the toxin _____________.
hypoglycin
This inactivates medium- and short-chain acyl-CoA dehydrogenase, inhibiting β-oxidation and causing hypoglycemia.
Jamaican vomitting disease
________________ is characterized by the excretion of C6´C10 ω-dicarboxylic acids and by nonketotic hypoglycemia, and is caused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase.
Dicarboxylic aciduria
______________ is a rare neurologic disorder due to a metabolic defect that results in the accumulation of phytanic acid, which is found in dairy products and ruminant fat and meat.
Refsum disease
___________ is thought to have pathological effects on membrane function, protein prenylation, and gene expression.
Phytanic acid
__________________ occurs in individuals with a rare inherited absence of peroxisomes in all tissues. They accumulate C26´C38 polyenoic acids in brain tissue and also exhibit a generalized loss of peroxisomal functions. The disease causes severe neurological symptoms, and most patients die in the first year of life.
Zellweger (cerebrohepatorenal) syndrome
The basic form of ketosis occurs in ___________ and involves depletion of available carbohydrate coupled with mobilization of FFA.
starvation
_________________ of ketosis are found under conditions of high-fat feeding and after severe exercise in the postabsorptive state.
Nonpathologic forms
Acetoacetic and 3-hydroxybutyric acids are both _____________ and are buffered when present in blood or other tissues.
moderately strong acids
