Vol. 5 (1), pp. 158-172, December, 2018
©Global Science Research Journals International Journal of Clinical Biochemistry
Author(s) retain the copyright of this article.
http://www.globalscienceresearchjournals.org/
Review Article
Beta (β)-Oxidation of Fatty Acid and its associated
Disorders
Satyam Prakash
Assistant Professor, Dept. of Biochemistry, Janaki Medical College Teaching Hospital, Janakpur, Nepal
Mobile: +977-9841603704, E-mail:
Accepted 18 December, 2018
The lipids of metabolic significance in the mammalian organisms include triacylglycerols,
phospholipids and steroids, together with products of their metabolism such as long-chain fatty acids,
glycerol and ketone bodies. The fatty acids which are present in the triacylglycerols in the reduced form
are the most abundant source of energy and provide energy twice as much as carbohydrates and
proteins. Fatty acids represent an important source of energy in periods of catabolic stress related to
increased muscular activity, fasting or febrile illness, where as much as 80% of the energy for the heart,
skeletal muscles and liver could be derived from them. The prime pathway for the degradation of fatty
acids is mitochondrial fatty acid β-oxidation (FAO). The relationship of fat oxidation with the utilization
of carbohydrate as a source of energy is complex and depends upon tissue, nutritional state, exercise,
development and a variety of other influences such as infection and other pathological states. Inherited
defects for most of the FAO enzymes have been identified and characterized in early infancy as acute
life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting or febrile illness.
Therefore, this review briefly highlights mitochondrial β-oxidation of fatty acids and associated
disorders with clinical manifestations.
Keywords: Carnitine, Fatty acid β-oxidation, Jamaican vomiting sickness, Stoichiometry, Sudden infant death
syndrome.
INTRODUCTION fatty acids travel through the blood to other tissues such
as muscle where they are oxidized to provide energy
Mitochondrial β-oxidation of fatty acids plays an important through the mitochondrial β-oxidation pathway.
role in energy production, especially during starvation, Mitochondria, as well as peroxisomes harbor all
prolonged fasting or low intensity exercise. The principal enzymes necessary for FAO. Mitochondria are the main
sources of fatty acids for oxidation are dietary and site for the oxidation of plasma free fatty acids or
mobilization of triacylglycerols mainly stored in lipoprotein associated triglycerides. The use of fatty acids
adipocytes of adipose tissue (Lopaschuk et al., 1994; by the liver provides energy for gluconeogenesis and
McGarry & Foster, 1980). The release of metabolic ureagenesis (Liang et al; 2001). Equally important, the
energy, in the form of fatty acids, is controlled by a liver uses fatty acids to synthesize ketones, which serve
complex series of interrelated cascades that result in the as a fat derived fuel for the brain, and thus further reduce
activation of hormone-sensitive lipase, which hydrolyzes the need for glucose utilization. More than a dozen
fatty acids from triacylglycerols and diacylglycerols genetic defects in the fatty acid oxidation pathway are
(Gibbons et al., 2000). The final fatty acid is released currently known. Nearly all of these defects present in
from monoacylglycerols through the action of early infancy as acute life-threatening episodes of
monoacylglycerol lipase, an enzyme active in the hypoketotic, hypoglycemic coma induced by fasting or
absence of hormonal stimulation. Once released, these febrile illness (Robert MO et al., 2009). Recognition of the
, Int'l J. Clin. Biochem. 159
fatty acid oxidation disorders is often difficult because the need for energy as ATP to spark the oxidation of fatty
patients can appear well until exposed to prolonged acids and to be essential for the activation of fatty acids.
fasting, and screening tests of metabolites may not Wakil and Mahler, as well as by Kornberg and Pricer
always be diagnostic. Therefore, this review briefly revealed activated fatty acids to be thioesters formed
highlights the overall pathway of mitochondrial β- from fatty acids and coenzyme A. This progress was only
oxidation of fatty acids and its associated deficiencies made promising by prior studies of Lipmann and his
with its clinical correlation. collaborators who isolated and distinguished coenzyme
A. The structure of active acetate is acetyl-CoA was
Historical Preview of β- oxidation proved by Lynen and co-workers. They also determined
that the acetyl-CoA was identical with the two-carbon
Fatty acids are a key source of energy in animals. fragment removed from fatty acids during their
George Franz Knoop, a German biochemist in 1904 degradation (Lynen, 1952-1953). Finally, the sub-cellular
studied the biological degradation of fatty acid with his location of the β-oxidation system was established by
classical experiments which led him to formulate the Kennedy and Lehninger, who confirmed that
theory of β-oxidation (Knoop, 1904). His experiments mitochondria were the cellular components which are
used fatty acids with phenyl residues in place of the most active during fatty acid oxidation. The mitochondrial
terminal methyl groups. The phenyl residue was not site of this pathway agreed with the observed coupling of
metabolized which served as a reporter group and was fatty acid oxidation to the citric acid cycle and to oxidative
excreted in the urine. During his experiment, Knoop fed phosphorylation.
phenyl substituted fatty acids with an odd number of Moreover, in 1950s , the laboratories of Green in
carbon atoms, like phenylpropionic acid (C6 H5-CH2 -CH2 - Wisconsin, Lynen in Munich, and Ochoa in New York
COOH) or phenylvaleric acid (C 6H5 -CH2-CH2-CH2 -CH2 - demonstrated the direct evidence for the proposed β-
COOH) to dogs, and isolated hippuric acid (C6H5-CO-NH- oxidation cycle by enzyme studies which were greatly
CH2-COOH), the conjugate of benzoic acid and glycine facilitated by recently developed techniques of protein
from their urine. In contrast, the excretory products in purification and by the use of spectrophotometric enzyme
urine were phenyl-substituted fatty acids with an even assays with chemically synthesized intermediates of β-
number of carbon atoms, such as phenylbutyric acid oxidation as substrates (Vance & Vance, 2002).
(C6H5-CH2-CH2 -CH2 -COOH), were degraded to Although, several studies were carried out to confirm the
phenylacetic acid (C6H5 -CH2-COOH) and excreted as steps mitochondrial β –oxidation, but the initial and
phenylaceturic acid (C 6H5 -CH2 -CO-NH-CH2-COOH). conclusive remarks by Franz Knoop on β–oxidation is still
These annotations led Knoop to propose that the considered as remarkable discovery in biochemistry.
oxidation of fatty acids begins at carbon atom 3, the β- Hence, β–oxidation is also known as Knoop‘s pathway or
carbon, and that the resulting β -keto acids are cleaved β –oxidation Knoop‘s pathway.
between the α-carbon and β -carbon to yield fatty acids
shortened by two carbon atoms. Knoop's experiment on β-oxidation of fatty acid
biological degradation incited the idea that fatty acids are
degraded in a stepwise method by successive β- β-oxidation of fatty acid is defined as a metabolic
oxidation. pathway that oxidizes fatty acids, and generates fatty
Henry Drysdale Dakin followed Knoop's preliminary acyl-CoA ( a thioester of fatty acid and CoA) and acetyl
study and executed analogous experiments with CoA which consists of a series of four repeated reactions,
phenylpropionic acid (Dakin, 1909). He isolated the in which a molecule of acetyl CoA is generated, and an
glycine conjugates of the following β-oxidation end product of the fatty acid by beta-oxidation is also
intermediates: phenylacrylic acid (C6H5 -CH=CH-COOH), acetyl CoA. Since, oxidation at the β-position of the fatty
β-phenyl-β-hydroxypropionic acid (C6 H5-CHOH-CH2 - acyl-CoA was performed step wise, it was named β-
COOH), and benzoylacetic acid (C6H5 -CO-CH2 -COOH) oxidation. Fatty acids are oxidized by most of the tissues
next to hippuric acid. At the same time, the unsubstituted in the body. However, brain, erythrocytes and adrenal
fatty acids are degraded by β-oxidation and converted to medulla cannot utilize fatty acids for energy requirement
ketone bodies in perfused livers which were verified by (Gurr & Harwood , 1991; Schulz,1985; Schulz &
Embden and coworkers. As a result, by 1910 the crucial Kunau,1987). The four steps are involved in β-oxidation
information needed for formulating the pathway of β - spiral of fatty acid metabolism which is oxidation,
oxidation was available. hydration, a second oxidation, and finally thiolysis. These
Due to consistent effort of researchers, after a 30-year happens in repeating cycles through the sequential
period of little progress the oxidation of fatty acids in cell- removal of 2 carbons and production of acetyl-CoA,
free preparations from liver was demonstrated by Munoz which then enters the Krebs cycle for oxidation and ATP
and Leloir in 1943, and Lehninger in 1944. Their production. Another target of acetyl-CoA is the production
endeavor came true with the stage for the complete of ketone bodies in the liver that are elated to tissues like
elucidation of β-oxidation. The studies and detailed the heart and brain for release of energy during
investigations Lehninger with cell-free systems confirmed starvation. Fatty acids with an odd number of carbons in
©Global Science Research Journals International Journal of Clinical Biochemistry
Author(s) retain the copyright of this article.
http://www.globalscienceresearchjournals.org/
Review Article
Beta (β)-Oxidation of Fatty Acid and its associated
Disorders
Satyam Prakash
Assistant Professor, Dept. of Biochemistry, Janaki Medical College Teaching Hospital, Janakpur, Nepal
Mobile: +977-9841603704, E-mail:
Accepted 18 December, 2018
The lipids of metabolic significance in the mammalian organisms include triacylglycerols,
phospholipids and steroids, together with products of their metabolism such as long-chain fatty acids,
glycerol and ketone bodies. The fatty acids which are present in the triacylglycerols in the reduced form
are the most abundant source of energy and provide energy twice as much as carbohydrates and
proteins. Fatty acids represent an important source of energy in periods of catabolic stress related to
increased muscular activity, fasting or febrile illness, where as much as 80% of the energy for the heart,
skeletal muscles and liver could be derived from them. The prime pathway for the degradation of fatty
acids is mitochondrial fatty acid β-oxidation (FAO). The relationship of fat oxidation with the utilization
of carbohydrate as a source of energy is complex and depends upon tissue, nutritional state, exercise,
development and a variety of other influences such as infection and other pathological states. Inherited
defects for most of the FAO enzymes have been identified and characterized in early infancy as acute
life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting or febrile illness.
Therefore, this review briefly highlights mitochondrial β-oxidation of fatty acids and associated
disorders with clinical manifestations.
Keywords: Carnitine, Fatty acid β-oxidation, Jamaican vomiting sickness, Stoichiometry, Sudden infant death
syndrome.
INTRODUCTION fatty acids travel through the blood to other tissues such
as muscle where they are oxidized to provide energy
Mitochondrial β-oxidation of fatty acids plays an important through the mitochondrial β-oxidation pathway.
role in energy production, especially during starvation, Mitochondria, as well as peroxisomes harbor all
prolonged fasting or low intensity exercise. The principal enzymes necessary for FAO. Mitochondria are the main
sources of fatty acids for oxidation are dietary and site for the oxidation of plasma free fatty acids or
mobilization of triacylglycerols mainly stored in lipoprotein associated triglycerides. The use of fatty acids
adipocytes of adipose tissue (Lopaschuk et al., 1994; by the liver provides energy for gluconeogenesis and
McGarry & Foster, 1980). The release of metabolic ureagenesis (Liang et al; 2001). Equally important, the
energy, in the form of fatty acids, is controlled by a liver uses fatty acids to synthesize ketones, which serve
complex series of interrelated cascades that result in the as a fat derived fuel for the brain, and thus further reduce
activation of hormone-sensitive lipase, which hydrolyzes the need for glucose utilization. More than a dozen
fatty acids from triacylglycerols and diacylglycerols genetic defects in the fatty acid oxidation pathway are
(Gibbons et al., 2000). The final fatty acid is released currently known. Nearly all of these defects present in
from monoacylglycerols through the action of early infancy as acute life-threatening episodes of
monoacylglycerol lipase, an enzyme active in the hypoketotic, hypoglycemic coma induced by fasting or
absence of hormonal stimulation. Once released, these febrile illness (Robert MO et al., 2009). Recognition of the
, Int'l J. Clin. Biochem. 159
fatty acid oxidation disorders is often difficult because the need for energy as ATP to spark the oxidation of fatty
patients can appear well until exposed to prolonged acids and to be essential for the activation of fatty acids.
fasting, and screening tests of metabolites may not Wakil and Mahler, as well as by Kornberg and Pricer
always be diagnostic. Therefore, this review briefly revealed activated fatty acids to be thioesters formed
highlights the overall pathway of mitochondrial β- from fatty acids and coenzyme A. This progress was only
oxidation of fatty acids and its associated deficiencies made promising by prior studies of Lipmann and his
with its clinical correlation. collaborators who isolated and distinguished coenzyme
A. The structure of active acetate is acetyl-CoA was
Historical Preview of β- oxidation proved by Lynen and co-workers. They also determined
that the acetyl-CoA was identical with the two-carbon
Fatty acids are a key source of energy in animals. fragment removed from fatty acids during their
George Franz Knoop, a German biochemist in 1904 degradation (Lynen, 1952-1953). Finally, the sub-cellular
studied the biological degradation of fatty acid with his location of the β-oxidation system was established by
classical experiments which led him to formulate the Kennedy and Lehninger, who confirmed that
theory of β-oxidation (Knoop, 1904). His experiments mitochondria were the cellular components which are
used fatty acids with phenyl residues in place of the most active during fatty acid oxidation. The mitochondrial
terminal methyl groups. The phenyl residue was not site of this pathway agreed with the observed coupling of
metabolized which served as a reporter group and was fatty acid oxidation to the citric acid cycle and to oxidative
excreted in the urine. During his experiment, Knoop fed phosphorylation.
phenyl substituted fatty acids with an odd number of Moreover, in 1950s , the laboratories of Green in
carbon atoms, like phenylpropionic acid (C6 H5-CH2 -CH2 - Wisconsin, Lynen in Munich, and Ochoa in New York
COOH) or phenylvaleric acid (C 6H5 -CH2-CH2-CH2 -CH2 - demonstrated the direct evidence for the proposed β-
COOH) to dogs, and isolated hippuric acid (C6H5-CO-NH- oxidation cycle by enzyme studies which were greatly
CH2-COOH), the conjugate of benzoic acid and glycine facilitated by recently developed techniques of protein
from their urine. In contrast, the excretory products in purification and by the use of spectrophotometric enzyme
urine were phenyl-substituted fatty acids with an even assays with chemically synthesized intermediates of β-
number of carbon atoms, such as phenylbutyric acid oxidation as substrates (Vance & Vance, 2002).
(C6H5-CH2-CH2 -CH2 -COOH), were degraded to Although, several studies were carried out to confirm the
phenylacetic acid (C6H5 -CH2-COOH) and excreted as steps mitochondrial β –oxidation, but the initial and
phenylaceturic acid (C 6H5 -CH2 -CO-NH-CH2-COOH). conclusive remarks by Franz Knoop on β–oxidation is still
These annotations led Knoop to propose that the considered as remarkable discovery in biochemistry.
oxidation of fatty acids begins at carbon atom 3, the β- Hence, β–oxidation is also known as Knoop‘s pathway or
carbon, and that the resulting β -keto acids are cleaved β –oxidation Knoop‘s pathway.
between the α-carbon and β -carbon to yield fatty acids
shortened by two carbon atoms. Knoop's experiment on β-oxidation of fatty acid
biological degradation incited the idea that fatty acids are
degraded in a stepwise method by successive β- β-oxidation of fatty acid is defined as a metabolic
oxidation. pathway that oxidizes fatty acids, and generates fatty
Henry Drysdale Dakin followed Knoop's preliminary acyl-CoA ( a thioester of fatty acid and CoA) and acetyl
study and executed analogous experiments with CoA which consists of a series of four repeated reactions,
phenylpropionic acid (Dakin, 1909). He isolated the in which a molecule of acetyl CoA is generated, and an
glycine conjugates of the following β-oxidation end product of the fatty acid by beta-oxidation is also
intermediates: phenylacrylic acid (C6H5 -CH=CH-COOH), acetyl CoA. Since, oxidation at the β-position of the fatty
β-phenyl-β-hydroxypropionic acid (C6 H5-CHOH-CH2 - acyl-CoA was performed step wise, it was named β-
COOH), and benzoylacetic acid (C6H5 -CO-CH2 -COOH) oxidation. Fatty acids are oxidized by most of the tissues
next to hippuric acid. At the same time, the unsubstituted in the body. However, brain, erythrocytes and adrenal
fatty acids are degraded by β-oxidation and converted to medulla cannot utilize fatty acids for energy requirement
ketone bodies in perfused livers which were verified by (Gurr & Harwood , 1991; Schulz,1985; Schulz &
Embden and coworkers. As a result, by 1910 the crucial Kunau,1987). The four steps are involved in β-oxidation
information needed for formulating the pathway of β - spiral of fatty acid metabolism which is oxidation,
oxidation was available. hydration, a second oxidation, and finally thiolysis. These
Due to consistent effort of researchers, after a 30-year happens in repeating cycles through the sequential
period of little progress the oxidation of fatty acids in cell- removal of 2 carbons and production of acetyl-CoA,
free preparations from liver was demonstrated by Munoz which then enters the Krebs cycle for oxidation and ATP
and Leloir in 1943, and Lehninger in 1944. Their production. Another target of acetyl-CoA is the production
endeavor came true with the stage for the complete of ketone bodies in the liver that are elated to tissues like
elucidation of β-oxidation. The studies and detailed the heart and brain for release of energy during
investigations Lehninger with cell-free systems confirmed starvation. Fatty acids with an odd number of carbons in
