Inbiochemistry andmetabolism,beta oxidation (also β-oxidation) is thecatabolic process by whichfatty acid molecules are broken down in thecytosol in prokaryotes and in themitochondria in eukaryotes to generateacetyl-CoA. Acetyl-CoA enters thecitric acid cycle, generatingNADH andFADH2, which are electron carriers used in theelectron transport chain. It is named as such because thebeta carbon of the fatty acid chain undergoes oxidation and is converted to acarbonyl group to start the cycle all over again. Beta-oxidation is primarily facilitated by themitochondrial trifunctional protein, an enzyme complex associated with theinner mitochondrial membrane, althoughvery long chain fatty acids are oxidized inperoxisomes.
The overall reaction for one cycle of beta oxidation is:
Free fatty acids cannot penetrate any biological membrane due to their negative charge. Free fatty acids must cross the cell membrane through specifictransport proteins, such as theSLC27 family fatty acid transport protein.[1] Once in thecytosol, the following processes bring fatty acids into the mitochondrial matrix so that beta-oxidation can take place.
| Step 1 | Step 2 | Step 3 | Step 4 |
|---|---|---|---|
 |  |  |  |
Once the fatty acid is inside themitochondrial matrix, beta-oxidation occurs by cleaving two carbons every cycle to form acetyl-CoA. The process consists of 4 steps.[2]
This acetyl-CoA then enters the mitochondrial tricarboxylic acid cycle (TCA cycle). Both the fatty acid beta-oxidation and the TCA cycle produce NADH and FADH2, which are used by the electron transport chain to generate ATP.
Fatty acids are oxidized by most of the tissues in the body. However, some tissues such as thered blood cells of mammals (which do not contain mitochondria) and cells of thecentral nervous system do not use fatty acids for their energy requirements, but instead use carbohydrates (red blood cells and neurons) orketone 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.
Once inside the mitochondria, each cycle of β-oxidation, liberating a two carbon unit (acetyl-CoA), occurs in a sequence of four reactions:[3]
| Description | Diagram | Enzyme | End product |
|---|---|---|---|
| Dehydrogenation byFAD: The first step is the oxidation of the fatty acid by Acyl-CoA-Dehydrogenase. The enzyme catalyzes the formation of a trans-double bond between the C-2 and C-3 by selectively remove hydrogen atoms from the β-carbon. The regioselectivity of this step is essential for the subsequent hydration and oxidation reactions. |  | acyl CoA dehydrogenase | trans-Δ2-enoyl-CoA |
| Hydration: The next step is thehydration of the bond between C-2 and C-3. The reaction isstereospecific, forming only the Lisomer. Hydroxyl group is positioned suitable for the subsequent oxidation reaction by 3-hydroxyacyl-CoA dehydrogenase to create a β-keto group. |  | enoyl CoA hydratase | L-β-hydroxyacyl CoA |
| Oxidation byNAD+: The third step is theoxidation of L-β-hydroxyacyl CoA by NAD+. This converts thehydroxyl group into aketo group. |  | 3-hydroxyacyl-CoA dehydrogenase | β-ketoacyl CoA |
| Thiolysis: The final step is the cleavage of β-ketoacyl CoA by thethiol group of another molecule ofCoenzyme A. The thiol is inserted between C-2 and C-3. |  | β-ketothiolase | Anacetyl-CoA molecule, and anacyl-CoA molecule that is two carbons shorter |
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 FADH2, NADH and acetyl CoA are formed.
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.[4] Long-chain fatty acids with an odd number of carbon atoms are found particularly in ruminant fat and milk.[5]
Chains with an odd-number ofcarbons are oxidized in the same manner as even-numbered chains, but the final products arepropionyl-CoA and acetyl-CoA.
Propionyl-CoA is first carboxylated using abicarbonateion into a D-stereoisomer ofmethylmalonyl-CoA. This reaction involves abiotinco-factor, ATP and the enzymepropionyl-CoA carboxylase.[6] 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 bymethylmalonyl-CoA epimerase. It then undergoes intramolecular rearrangement, which is catalyzed bymethylmalonyl-CoA mutase (requiring B12 as a coenzyme) to form succinyl-CoA. Thesuccinyl-CoA formed then enters thecitric acid cycle.
However, whereas acetyl-CoA enters the citric acid cycle by condensing with an existing molecule ofoxaloacetate, 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 exceedscataplerotic demand (such as foraspartate orglutamate synthesis), some of them can be extracted to thegluconeogenesis pathway, in the liver and kidneys, throughphosphoenolpyruvate carboxykinase, and converted to free glucose.[7]
β-Oxidation of unsaturated fatty acids poses a problem since the location of a cis-bond can prevent the formation of a trans-Δ2 bond which is essential for continuation of β-Oxidation as this conformation is ideal for enzyme catalysis. This is handled by additional two enzymes,Enoyl CoA isomerase and2,4 Dienoyl CoA reductase.[8]
β-oxidation occurs normally until the acyl CoA (because of the presence of a double bond) is not an appropriate substrate foracyl CoA dehydrogenase, orenoyl CoA hydratase:
Fatty acid oxidation also occurs inperoxisomes when the fatty acid chains are too long to be processed by the mitochondria. The same enzymes are used in peroxisomes as in the mitochondrial matrix and acetyl-CoA is generated. Very long chain (greater than C-22) fatty acids, branched fatty acids,[9] someprostaglandins andleukotrienes[10] undergo initial oxidation in peroxisomes untiloctanoyl-CoA is formed, at which point it undergoes mitochondrial oxidation.[11]
One significant difference is that oxidation in peroxisomes is not coupled toATP synthesis. Instead, the high-potential electrons are transferred to O2, which yieldshydrogen peroxide. The enzymecatalase, found primarily in peroxisomes and thecytosol oferythrocytes (and sometimes inmitochondria[12]), converts thehydrogen peroxide intowater andoxygen.
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:
Peroxisomal oxidation is induced by a high-fat diet and administration of hypolipidemic drugs likeclofibrate.
Theoretically, the ATP yield for each oxidation cycle where two carbons are broken down at a time is 17, as each NADH produces 3 ATP, FADH2 produces 2 ATP and a full rotation of Acetyl-CoA in citric acid cycle produces 12 ATP.[13] In practice, it is closer to 14 ATP for a full oxidation cycle as 2.5 ATP per NADH molecule is produced, 1.5 ATP per each FADH2 molecule is produced and Acetyl-CoA produces 10 ATP per rotation of the citric acid cycle[13](according to theP/O ratio). This breakdown is as follows:
| Source | ATP | Total |
|---|---|---|
| 1FADH2 | x 1.5 ATP | = 1.5 ATP (Theoretically 2 ATP)[13] |
| 1NADH | x 2.5 ATP | = 2.5 ATP (Theoretically 3 ATP)[13] |
| 1Acetyl CoA | x 10 ATP | = 10 ATP (Theoretically 12 ATP) |
| 1Succinyl CoA | x 4 ATP | = 4 ATP |
| Total | = 14 ATP |
For an even-numbered saturated fat (Cn), 0.5 * n - 1 oxidations are necessary, and the final process yields an additional acetyl CoA. In addition, two equivalents ofATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as:
or
For instance, the ATP yield ofpalmitate (C16,n = 16) is:
Represented in table form:
| Source | ATP | Total |
|---|---|---|
| 7FADH2 | x 1.5 ATP | = 10.5 ATP |
| 7NADH | x 2.5 ATP | = 17.5 ATP |
| 8Acetyl CoA | x 10 ATP | = 80 ATP |
| Activation | = -2 ATP | |
| Total | = 106 ATP |
For an odd-numbered saturated fat (Cn), 0.5 * n - 1.5 oxidations are necessary, and the final process yields 8 acetyl CoA and 1 propionyl CoA. It is then converted to a succinyl CoA by a carboxylation reaction and generates additional 5 ATP (1 ATP is consumed in carboxylation process generating a net of 4 ATP). In addition, two equivalents ofATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as:
or
For instance, the ATP yield ofNonadecylic acid (C19,n = 19) is:
Represented in table form:
| Source | ATP | Total |
|---|---|---|
| 8FADH2 | x 1.5 ATP | = 12 ATP |
| 8NADH | x 2.5 ATP | = 20 ATP |
| 8Acetyl CoA | x 10 ATP | = 80 ATP |
| 1Succinyl CoA | x 4 ATP | = 4 ATP |
| Activation | = -2 ATP | |
| Total | = 114 ATP |
There are at least 25 enzymes and specific transport proteins in the β-oxidation pathway.[16] Of these, 18 have been associated with human disease asinborn errors of metabolism.
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 mitochondrialfatty acid oxidation (FAO) that are involved in diverse aspects of tumorigenesis and cell growth.[17] Several specific β-oxidation disorders have been identified.
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency[18] is the most common fatty acid β-oxidation disorder and a prevalent metabolic congenital error It is often identified through newborn screening. Although children are normal at birth, symptoms usually emerge between three months and two years of age, with some cases appearing in adulthood.
Medium-chain acyl-CoA dehydrogenase (MCAD) plays a crucial role in mitochondrial fatty acid β-oxidation, a process vital for generating energy during extended fasting or high-energy demand periods. This process, especially important when liver glycogen is depleted, supports hepatic ketogenesis. The specific step catalyzed by MCAD involves the dehydrogenation of acyl-CoA. This step converts medium-chain acyl-CoA to trans-2-enoyl-CoA, which is then further metabolized to produce energy in the form of ATP.
Symptoms
Treatments
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency[19] is a mitochondrial effect of impaired enzyme function.
LCHAD performs the dehydrogenation of hydroxyacyl-CoA derivatives, facilitating the removal of hydrogen and the formation of aketo group. This reaction is essential for the subsequent steps in beta oxidation that lead to the production of acetyl-CoA, NADH, and FADH2, which are important for generating ATP, the energy currency of the cell.
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a condition that affects mitochondrial function due to enzyme impairments. LCHAD deficiency is specifically caused by a shortfall in the enzymelong-chain 3-hydroxyacyl-CoA dehydrogenase. This leads to the body's inability to transform specific fats into energy, especially during fasting periods.
Symptoms
Treatments
Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency) is a genetic disorder that affects the body's ability to break down certain fats. In the β-oxidation cycle, VLCAD's role involves the removal of two hydrogen atoms from the acyl-CoA molecule, forming a double bond and converting it into trans-2-enoyl-CoA. This crucial first step in the cycle is essential for the fatty acid to undergo further processing and energy production. When there is a deficiency in VLCAD, the body struggles to effectively break down long-chain fatty acids. This can lead to a buildup of these fats and a shortage of energy, particularly during periods of fasting or increased physical activity.[20]
Symptoms
Treatments
{{cite journal}}:Cite journal requires|journal= (help)Metabolism map | ||
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 Majormetabolic pathways inmetro-style map. Click any text (name of pathway or metabolites) to link to the corresponding article. Single lines: pathways common to most lifeforms. Double lines: pathways not in humans (occurs in e.g. plants, fungi, prokaryotes).  Orange nodes:carbohydrate metabolism. Violet nodes:photosynthesis. Red nodes:cellular respiration. Pink nodes:cell signaling. Blue nodes:amino acid metabolism. Grey nodes:vitamin andcofactor metabolism. Brown nodes:nucleotide andprotein metabolism. Green nodes:lipid metabolism. | ||
