In
biochemistry
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
and
metabolism, beta-oxidation is the
catabolic process by which
fatty acid molecules are broken down in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
in prokaryotes and in the
mitochondria in eukaryotes to generate
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
, which enters the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protei ...
, and
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
and
FADH2, which are co-enzymes used in the
electron transport chain. It is named as such because the
beta carbon
In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule.
Numeric locants
The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of n ...
of the fatty acid undergoes oxidation to a
carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
group. Beta-oxidation is primarily facilitated by the
mitochondrial trifunctional protein
Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits:
* HADHA
* HA ...
, an enzyme complex associated with the
inner mitochondrial membrane
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
, although
very long chain fatty acid A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell.
Unlike most fatty acids, VL ...
s are oxidized in
peroxisome
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
s.
The overall reaction for one cycle of beta oxidation is:
:C
''n''-acyl-CoA + FAD + + + CoA → C
''n''-2-acyl-CoA + + NADH + + acetyl-CoA
Activation and membrane transport
Free fatty acids cannot penetrate any biological membrane due to their negative charge. Free fatty acids must cross the cell membrane through specific
transport proteins, such as the
SLC27 family fatty acid transport protein. Once in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
, the following processes bring fatty acids into the mitochondrial matrix so that beta-oxidation can take place.
#
Long-chain-fatty-acid—CoA ligase
The long chain fatty acyl-CoA ligase (or synthetase) is an enzyme () of the ligase family that activates the oxidation of complex fatty acids. Long chain fatty acyl-CoA synthetase catalyzes the formation of fatty acyl-CoA by a two-step process p ...
catalyzes the reaction between a fatty acid with
ATP to give a fatty acyl adenylate, plus inorganic pyrophosphate, which then reacts with free
coenzyme A
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a substr ...
to give a fatty acyl-CoA ester and
AMP.
#If the fatty acyl-CoA has a long chain, then the
carnitine shuttle must be utilized:
##Acyl-CoA is transferred to the hydroxyl group of carnitine by
carnitine palmitoyltransferase I
Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by cat ...
, located on the cytosolic faces of the
outer and
inner mitochondrial membrane
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
s.
##Acyl-carnitine is shuttled inside by a
carnitine-acylcarnitine translocase
Carnitine-acylcarnitine translocase (CACT) is responsible for passive transport of carnitine and carnitine-fatty acid complexes and across the inner mitochondrial membrane as part of the carnitine shuttle system.
Function
Fatty acyl–carnitin ...
, as a carnitine is shuttled outside.
##Acyl-carnitine is converted back to acyl-CoA by
carnitine palmitoyltransferase II
Carnitine O-palmitoyltransferase 2, mitochondrial is an enzyme that in humans is encoded by the ''CPT2'' gene.
Function
Carnitine palmitoyltransferase II precursor (CPT2) is a mitochondrial membrane protein which is transported to the mitocho ...
, located on the interior face of the
inner mitochondrial membrane
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
. The liberated carnitine is shuttled back to the cytosol, as an acyl-carnitine is shuttled into the matrix.
#If the fatty acyl-CoA contains a short chain, these
short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...
s can simply diffuse through the inner mitochondrial membrane.
General mechanism
Once the fatty acid is inside the
mitochondrial matrix
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...
, beta-oxidation occurs by cleaving two carbons every cycle to form acetyl-CoA. The process consists of 4 steps.
#A long-chain fatty acid is
dehydrogenated
In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. At ...
to create a trans
double bond between C2 and C3. This is catalyzed by
acyl CoA dehydrogenase Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) ...
to produce trans-delta 2-enoyl CoA. It uses FAD as an electron acceptor and it is reduced to FADH
2.
#Trans-delta2-enoyl CoA is hydrated at the double bond to produce L-3-hydroxyacyl CoA by
enoyl-CoA hydratase.
#L-3-hydroxyacyl CoA is dehydrogenated again to create 3-ketoacyl CoA by 3-hydroxyacyl CoA dehydrogenase. This enzyme uses NAD as an electron acceptor.
#
Thiolysis Thiolysis is a reaction with a thiol (R-SH) that cleaves one compound into two. Thiolysis involves the addition of coenzyme A to one of the products. This reaction is similar to hydrolysis, which involves water instead of a thiol. This reaction is s ...
occurs between C2 and C3 (alpha and beta carbons) of 3-ketoacyl CoA. Thiolase enzyme catalyzes the reaction when a new molecule of coenzyme A breaks the bond by nucleophilic attack on C3. This releases the first two carbon units, as acetyl CoA, and a fatty acyl CoA minus two carbons. The process continues until all of the carbons in the fatty acid are turned into acetyl CoA.
Fatty acids are oxidized by most of the tissues in the body. However, some tissues such as the
red blood cells
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
of mammals (which do not contain mitochondria), and cells of the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
do not use fatty acids for their energy requirements,
but instead use carbohydrates (red blood cells and neurons) or
ketone bodies (neurons only).
Because many fatty acids are not fully saturated or do not have an even number of carbons, several different mechanisms have evolved, described below.
Even-numbered saturated fatty acids
Once inside the mitochondria, each cycle of β-oxidation, liberating a two carbon unit (
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
), occurs in a sequence of four reactions:
This process continues until the entire chain is cleaved into acetyl CoA units. The final cycle produces two separate acetyl CoAs, instead of one acyl CoA and one acetyl CoA. For every cycle, the Acyl CoA unit is shortened by two carbon atoms. Concomitantly, one molecule of FADH
2, NADH and acetyl CoA are formed.
Odd-numbered saturated fatty acids
In general, fatty acids with an odd number of carbons are found in the lipids of plants and some marine organisms. Many ruminant animals form a large amount of 3-carbon propionate during the fermentation of carbohydrates in the rumen. Long-chain fatty acids with an odd number of carbon atoms are found particularly in ruminant fat and milk.
Chains with an odd-number of
carbons are oxidized in the same manner as even-numbered chains, but the final products are
propionyl-CoA
Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain (without the coenzyme, it is a 3 carbon structure) and its production and metabolic fate depend on which organism it is present in. Several diffe ...
and Acetyl CoA
Propionyl-CoA is first carboxylated using a
bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochemic ...
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conv ...
into D-stereoisomer of methylmalonyl-CoA, in a reaction that involves a
biotin
Biotin (or vitamin B7) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name ''biotin'', bor ...
co-factor, ATP, and the enzyme
propionyl-CoA carboxylase
Propionyl-CoA carboxylase (, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylma ...
. The bicarbonate ion's carbon is added to the middle carbon of propionyl-CoA, forming a D-methylmalonyl-CoA. However, the D conformation is enzymatically converted into the L conformation by
methylmalonyl-CoA epimerase
Methylmalonyl CoA epimerase (, ''methylmalonyl-CoA racemase'', ''methylmalonyl coenzyme A racemase'', ''DL-methylmalonyl-CoA racemase'', ''2-methyl-3-oxopropanoyl-CoA 2-epimerase ncorrect') is an enzyme involved in fatty acid catabolism that is ...
, then it undergoes intramolecular rearrangement, which is catalyzed by
methylmalonyl-CoA mutase
Methylmalonyl-CoA mutase (, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the ''MUT'' gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succiny ...
(requiring B
12 as a coenzyme) to form succinyl-CoA. The
succinyl-CoA
Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A.
Sources
It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...
formed can then enter the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protei ...
.
However, whereas acetyl-CoA enters the citric acid cycle by condensing with an existing molecule of oxaloacetate, succinyl-CoA enters the cycle as a principal in its own right. Thus the succinate just adds to the population of circulating molecules in the cycle and undergoes no net metabolization while in it. When this infusion of citric acid cycle intermediates exceeds
cataplerotic demand (such as for
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
or
glutamate synthesis), some of them can be extracted to the
gluconeogenesis pathway, in the liver and kidneys, through
phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase (, PEPCK) is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.
It is found in two forms, cytosolic and mitoch ...
, and converted to free glucose.
Unsaturated fatty acids
β-Oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a trans-Δ
2 bond. These situations are handled by an additional two enzymes,
Enoyl CoA isomerase or
2,4 Dienoyl CoA reductase.
Whatever the conformation of the hydrocarbon chain, β-oxidation occurs normally until the acyl CoA (because of the presence of a double bond) is not an appropriate substrate for
acyl CoA dehydrogenase Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) ...
, or
enoyl CoA hydratase:
*If the acyl CoA contains a ''cis-Δ
3 bond'', then ''cis-Δ
3''-
Enoyl CoA isomerase will convert the bond to a ''trans-Δ
2'' bond, which is a regular substrate.
*If the acyl CoA contains a ''cis-Δ
4 double bond'', then its dehydrogenation yields a 2,4-dienoyl intermediate, which is not a substrate for enoyl CoA hydratase. However, the enzyme
2,4 Dienoyl CoA reductase reduces the intermediate, using NADPH, into ''trans-Δ
3''-enoyl CoA. As in the above case, this compound is converted into a suitable intermediate by 3,2-Enoyl CoA isomerase.
To summarize:
*''Odd-numbered'' double bonds are handled by the isomerase.
*''Even-numbered'' double bonds by the reductase (which creates an odd-numbered double bond)
Peroxisomal beta-oxidation
Fatty acid oxidation also occurs in
peroxisome
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
s when the fatty acid chains are too long to be handled by the mitochondria. The same enzymes are used in peroxisomes as in the mitochondrial matrix, and acetyl-CoA is generated. It is believed that very long chain (greater than C-22) fatty acids, branched fatty acids,
some
prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deri ...
s and
leukotrienes
undergo initial oxidation in peroxisomes until
octanoyl-CoA
Octanoyl-coenzyme A is the endpoint of beta oxidation in peroxisomes. It is produced alongside acetyl-CoA and transferred to the mitochondria to be further oxidized into acetyl-CoA.
See also
*Caprylic acid
Caprylic acid (), also known under ...
is formed, at which point it undergoes mitochondrial oxidation.
One significant difference is that oxidation in peroxisomes is not coupled to
ATP synthesis. Instead, the high-potential electrons are transferred to O
2, which yields H
2O
2. It does generate heat however. The enzyme
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
, found primarily in peroxisomes and the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
of
erythrocyte
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s (and sometimes in
mitochondria), converts the
hydrogen peroxide into
water and
oxygen.
Peroxisomal β-oxidation also requires enzymes specific to the peroxisome and to very long fatty acids. There are four key differences between the enzymes used for mitochondrial and peroxisomal β-oxidation:
#The NADH formed in the third oxidative step cannot be reoxidized in the peroxisome, so reducing equivalents are exported to the cytosol.
#β-oxidation in the peroxisome requires the use of a peroxisomal
carnitine acyltransferase
Carnitine O-palmitoyltransferase (also called carnitine palmitoyltransferase) is a mitochondrial transferase enzyme () involved in the metabolism of palmitoylcarnitine into palmitoyl-CoA. A related transferase is carnitine acyltransferase.
Mole ...
(instead of carnitine acyltransferase I and II used by the mitochondria) for transport of the activated acyl group into the mitochondria for further breakdown.
#The first oxidation step in the peroxisome is catalyzed by the enzyme
acyl-CoA oxidase.
#The
β-ketothiolase used in peroxisomal β-oxidation has an altered substrate specificity, different from the mitochondrial
β-ketothiolase.
Peroxisomal oxidation is induced by a high-fat diet and administration of hypolipidemic drugs like
clofibrate
Clofibrate (trade name Atromid-S) is a lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It belongs to the class of fibrates. It increases lipoprotein lipase activity to promote the conversio ...
.
Energy yield
The ATP yield for every oxidation cycle is theoretically a maximum yield of 17, as NADH produces 3 ATP, FADH
2 produces 2 ATP and a full rotation of Acetyl-CoA in citric acid cycle produces 12 ATP. In practice it is closer to 14 ATP for a full oxidation cycle as the theoretical yield is not attained - it is generally closer to 2.5 ATP per NADH molecule produced, 1.5 ATP for each FADH
2 molecule produced and this equates to 10 ATP per cycle of the TCA
(according to the
P/O ratio), broken down as follows:
For an even-numbered saturated fat (C
n), 0.5 * n - 1 oxidations are necessary, and the final process yields an additional acetyl CoA. In addition, two equivalents of
ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as:
:(0.5 * n - 1) * 14 + 10 - 2 = total ATP
or
:7n-6 (alternatively)
For instance, the ATP yield of
palmitate
Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The L ...
(C
16, ''n = 16'') is:
:7 * 16 - 6 = 106 ATP
Represented in table form:
For an odd-numbered saturated fat (C
n), 0.5 * n - 1.5 oxidations are necessary, and the final process yields an additional propionyl CoA, which is then converted to a succinyl CoA by carboxylation reaction and thus generates additional 5 ATP (1 ATP is however consumed in carboxylation process thus generating net 4 ATPs). In addition, two equivalents of
ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as:
:(0.5 * n - 1.5) * 14 + 4 - 2 = total ATP
or
:7n-19 (alternatively)
For instance, the ATP yield of
margaric acid (C
17, ''n = 17'') is:
:7 * 17 - 19 = 100
For sources that use the larger ATP production numbers described above, the total would be 129 ATP = equivalents per palmitate.
Beta-oxidation of unsaturated fatty acids changes the ATP yield due to the requirement of two possible additional enzymes.
Similarities between beta-oxidation and citric acid cycle
The reactions of beta oxidation and part of citric acid cycle present structural similarities in three of four reactions of the beta oxidation: the oxidation by FAD, the hydration, and the oxidation by NAD
+. Each enzyme of these metabolic pathways presents structural similarity.
Clinical significance
There are at least 25 enzymes and specific transport proteins in the β-oxidation pathway.
Of these, 18 have been associated with human disease as
inborn errors of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...
.
Furthermore, studies indicate that lipid disorders are involved in diverse aspects of tumorigenesis, and fatty acid metabolism makes malignant cells more resistant to a hypoxic environment. Accordingly, cancer cells can display irregular lipid metabolism with regard to both fatty acid synthesis and mitochondrial
fatty acid oxidation
Fatty is a derogatory term for someone who is obese. It may refer also to:
People
* Mai Fatty, Gambian politician
* Roscoe Arbuckle (1887–1933), American actor and comedian
* Fatty Briody (1858–1903), American Major League Baseball player ...
(FAO) that are involved in diverse aspects of tumorigenesis and cell growth.
See also
*
Fatty acid metabolism
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes ...
*
Fatty-acid metabolism disorder
*
Lipolysis
*
Krebs cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protei ...
*
Omega oxidation Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most dista ...
*
Alpha oxidation Enzymatic steps of alpha oxidation, 250px
Alpha oxidation (α-oxidation) is a process by which certain branched-chain fatty acids are broken down by removal of a single carbon from the carboxyl end. In humans, alpha-oxidation is used in peroxisome ...
References
Further reading
*
External links
*
*
*
{{Fatty-acid metabolism disorders
Cell biology
Metabolic pathways
Fatty acids
Citric acid cycle
Cellular respiration