- # About the Author
- # About the web site
- # Our second web site
- # Question of the day
- A New Book of Biochemistry
- Acid Base Balance
- Animations Links
- Biochemical Techniques
- Biochemistry Quiz
- Biological Oxidation
- Chemistry of Carbohydrates
- Chemistry of Lipids and Eicosanoids
- Chemistry of Nucleotides
- Chemistry of Proteins
- Diabetes Mellitus
- Diet and Nutrition
- Facebook Group Posts
- Haem Synthesis and Degradation
- Hemoglobin and Hemoglobinopathies
- Liver Function Tests
- Metabolism – Carbohydrates
- Metabolism – Lipids
- Metabolism – Nucleotides
- Metabolism – Proteins
- Metabolism of Alcohol
- Molecular Biology
- Past Papers
- Power Point Presentations
- Practical Biochemistry
- Abnormal Urine
- Blood Glucose Estimation
- Blood Urea and Urea Clearance Estimation
- Normal Laboratory Reference Values
- Normal Urine Analysis
- Power point presentations
- Protein Precipitation Reactions
- Reactions of Carbohydrates
- Serum Creatinine and Creatinine clearance estimation
- Serum Total Protein estimation
- Practice Questions
- Quick revisions
- Renal Function Tests
- Semester Paper
- Students’ corner
- Water and Electrolyte balance and Imbalance
Fatty acid oxidation – A quick revision – part-1
Fatty acids can be obtained from-
- De novo synthesis
Functions of fatty acids – Fatty acids have four major physiological roles.
1) Fatty acids are building blocks of phospholipids and glycolipids.
2) Many proteins are modified by the covalent attachment of fatty acids, which target them to membrane locations
3) Fatty acids are fuel molecules. They are stored as triacylglycerols. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs of a cell or organism.
4) Fatty acid derivatives serve as hormones and intracellular messengers e.g. steroids, sex hormones and prostaglandins.
- Triglycerides are the highly concentrated stores of energy because they are reduced and anhydrous.
- The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1)
- Triacylglycerols are nonpolar, and are stored in a nearly anhydrous form, whereas much more polar proteins and carbohydrates are more highly hydrated.
Triglycerides V/S Glycogen
- A gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen, which is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir.
- The glycogen and glucose stores provide enough energy to sustain biological function for about 24 hours, whereas the Triacylglycerol stores allow survival for several weeks.
Provision of dietary fatty acids
Most lipids are ingested in the form of triacylglycerols, that must be degraded to fatty acids for absorption across the intestinal epithelium.
Figure-1- Free fatty acids and monoacylglycerols obtained by digestion of dietary triglycerides are absorbed by intestinal epithelial cells. Triacylglycerols are resynthesized and packaged with other lipids and apoprotein B-48 to form chylomicrons, which are then released into the lymph system.
Provision of fatty acids from adipose tissue
The triacylglycerols are degraded to fatty acids and glycerol by hormone sensitive lipase. The released fatty are transported to the energy-requiring tissues.
Figure-2- The enzyme hormone sensitive lipase (triacylglycerol lipase)is activated by glucagon and catecholamines through cAMP mediated cascade. This enzyme is inhibited by methyl xanthines such as caffeine and theophylline. Insulin antagonizes the effect of the lipolytic hormones.
Transportation of free fatty acids
- Free fatty acids—also called unesterified (UFA) or nonesterified (NEFA) fatty acids—are fatty acids that are in the unesterified state.
- In plasma, longer-chain FFA are combined with albumin, and in the cell they are attached to a fatty acid-binding protein.
- Shorter-chain fatty acids are more water-soluble and exist as the un-ionized acid or as a fatty acid anion.
- By these means, free fatty acids are made accessible as a fuel in other tissues.
Types of fatty acid oxidation
Fatty acids can be oxidized by-
1) Beta oxidation- Major mechanism, occurs in the mitochondria matrix. 2-C units are released as acetyl CoA per cycle.
2) Alpha oxidation- Predominantly takes place in brain and liver, one carbon is lost in the form of CO2 per cycle.
3) Omega oxidation- Minor mechanism, but becomes important in conditions of impaired beta oxidation
4) Peroxisomal oxidation- Mainly for the trimming of very long chain fatty acids.
A saturated acyl Co A is degraded by a recurring sequence of four reactions:
1) Oxidation by flavin adenine dinucleotide (FAD)
3) Oxidation by NAD+, and
4) Thiolysis by Co A
The fatty acyl chain is shortened by two carbon atoms as a result of these reactions, and FADH2, NADH, and acetyl Co A are generated. Because oxidation is on the β carbon and the chain is broken between the α (2)- and β (3)-carbon atoms—hence the name – β oxidation.
Activation of fatty acid
Fatty acids must first be converted to an active intermediate before they can be catabolized. This is the only step in the complete degradation of a fatty acid that requires energy from ATP. The activation of a fatty acid is accomplished in two steps-
Figure-3- In the presence of ATP and coenzyme A, the enzyme acyl-CoA synthetase (thiokinase) catalyzes the conversion of a fatty acid (or free fatty acid) to an “active fatty acid” or acyl-CoA, which uses one high-energy phosphate with the formation of AMP and PPi .The PPi is hydrolyzed by inorganic pyrophosphatase with the loss of a further high-energy phosphate, ensuring that the overall reaction goes to completion. Acyl-CoA synthetases are found in the endoplasmic reticulum, peroxisomes, and inside and on the outer membrane of mitochondria.
Transport of fatty acid in to the mitochondrial matrix (Figure-4)
- Fatty acids are activated on the outer mitochondrial membrane, whereas they are oxidized in the mitochondrial matrix.
- Activated long-chain fatty acids are transported across the membrane by conjugating them to carnitine, a zwitterionic alcohol.
Carnitine (ß-hydroxy-Υ-trimethyl ammonium butyrate), (CH3)3N+—CH2—CH(OH)—CH2—COO–, is widely distributed and is particularly abundant in muscle. Carnitine is obtained from foods, particularly animal-based foods, and via endogenous synthesis.
Role of carnitine
The acyl group is transferred to the hydroxyl group of carnitine to form acyl carnitine. This reaction is catalyzed by carnitine acyl transferase I
2) Acyl carnitine is then shuttled across the inner mitochondrial membrane by a translocase.
3) The acyl group is transferred back to CoA on the matrix side of the membrane. This reaction, which is catalyzed by carnitine acyl transferase II.
Finally, the translocase returns carnitine to the cytosolic side in exchange for an incoming acyl carnitine.
Figure-4- Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane. Long-chain acyl-CoA cannot pass through the inner mitochondrial membrane, but its metabolic product, acylcarnitine, can cross through with the help of carnitine shuttle.
Significance of fatty acid transport through carnitine shuttle
1) Biological significance- This counter-transport system provides regulation of the uptake of fatty acids into the mitochondrion for oxidation. As long as there is free CoA available in the mitochondrial matrix, fatty acids can be taken up and the carnitine returned to the outer membrane for uptake of more fatty acids. However, if most of the CoA in the mitochondrion is acylated, then the fatty acid uptake is inhibited.
This carnitine shuttle also serves to prevent uptake into the mitochondrion (and hence oxidation) of fatty acids synthesized in the cytosol in the fed state; malonyl CoA (the precursor for fatty acid synthesis) is a potent inhibitor of carnitine palmitoyl transferase I in the outer mitochondrial membrane.
Short and medium chain fatty acids do not require carnitine for their transportation across the inner mitochondrial membrane.
2) Clinical significance
Causes of carnitine deficiency include the following:
- Inadequate intake (e.g., due to fad diets, lack of access, or long-term TPN)
- Inability to use carnitine due to enzyme deficiencies (e.g., carnitine palmitoyl Transferase deficiency)
- Decreased endogenous synthesis of carnitine due to a severe liver disorder
- Excess loss of carnitine due to diarrhea, diuresis, or hemodialysis
- A hereditary disorder in which carnitine leaks from renal tubules (Primary carnitine deficiency)
- Increased requirements for carnitine when ketosis is present or demand for fat oxidation is high (eg, during a critical illness such as sepsis or major burns; after major surgery of the GI tract)
Symptoms and the age at which symptoms appear depend on the cause.
Carnitine deficiency may cause-
- Muscle aches and fatigue
- Muscle necrosis, myoglobinuria
- Fasting hypoketotic hypoglycemia
- Fatty liver and hyperammonemia,.
- Cardiomyopathy, heart failure
- Coma, and sudden unexpected death
Hypoglycemia in carnitine deficiency, is a consequence of impaired fatty acid oxidation with the resultant imbalance between demand and supply of glucose which is the sole of source of energy in such individuals.
Deficiencies in the carnitine acyl Transferase enzymes I and II can cause similar symptoms. Inherited CAT-I deficiency affects only the liver, resulting in reduced fatty acid oxidation and ketogenesis, with hypoglycemia. CAT-II deficiency affects primarily skeletal muscle and, when severe, the liver.
- Extremely reduced carnitine levels in plasma and muscle (1–2% of normal).
- Fasting ketogenesis may be normal if liver carnitine transport is normal, but it may be impaired if dietary carnitine intake is interrupted and there is associated liver disorder.
- The fasting urinary organic acid profile may show a hypoketotic dicarboxylicaciduria pattern if hepatic fatty acid oxidation is impaired, but it is otherwise unremarkable.
- Treatment of this disorder with pharmacologic doses of oral carnitine is highly effective in correcting the cardiomyopathy and muscle weakness as well as any impairment in fasting ketogenesis.
- All patients must avoid fasting and strenuous exercise.
- Some patients require supplementation with medium-chain triglycerides and essential fatty acids (eg, Linoleic acid, Linolenic acid).
- Patients with a fatty acid oxidation disorder require a high-carbohydrate, low-fat diet.
To be continued……Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!