fatty acid activation and transport

fatty acid activation and transport

1. Arbab Ihsan

2. Fatty Acid Activation & Transport

3. Contents Fatty Acid Activation Enzymes of FAA Steps Involve In FAA Fatty Acid Transport Into Mitochondria What is Carnitine & Carnitine Shuttle? Enzymes Involve in Transport Of FA Steps of FA transport Carnitine Regulation & Importance Carnitine Deficienc References

4. Fatty Acid Activation “Fatty acids must be esterified to Coenzyme A before they can undergo oxidative degradation, be utilized for synthesis of complex lipids (e.g., triacylglycerols or membrane lipids), or be attached to proteins as lipid anchors” Fatty acid activation occurs in the cytosol but they are oxidized inside the mitochondrion.

5. Enzymes of FAA Enzymes are associated with the endoplasmic reticulum and outer mitochondrial membrane and require ATP Acyl CoA ligases ( thiokinases ). Inorganic pyrophosphatase .

6. Steps Involve In FAA Steps Involvein fatty acid transport are:

7. Formation of Acyl-CoA There are different Acyl-CoA Synthases for fatty acids of different chain lengths It is associated with endoplasmic reticulum membranes and the outer mitochondrial membrane. Catalyze activation of long chain fatty acids, esterifying them to coenzyme. Adenosine triphosphate ( ATP ) drives the formation of a thioester linkage between the carboxyl group of a fatty acid and the sulfhydryl group of  CoA .

8. Exergonic hydrolysis of PP i Paul Berg showed that the activation of a fatty acid is accomplished in two steps. First, the fatty acid reacts with  ATP  to form an   acyl adenylate . Carboxyl group of a fatty acid is bonded to the phosphoryl group of AMP. The other two phosphoryl groups of the ATP substrate are released as pyrophosphate.

9. The sulfhydryl group of CoA  then attacks the acyl adenylate , which is tightly bound to the enzyme, to form acyl CoA and AMP. The acyl -coenzyme A product includes one "high energy" thioester linkage

10. Fatty Acid Transport Into Mitochondria Carnitine takes long chain fatty acids into mitochondria through a special transport system as carnitine shuttle .

11. Carnitine Carnitine , derived from an amino acid, is found in nearly all cells of the body. Its name is derived from the Latin  carnu s  or flesh. Carnitine plays a critical role in energy production . It transports long-chain fatty acids into the mitochondria so they can be oxidized ("burned") to produce energy. Carnitine is concentrated in tissues that utilize fatty acids as a dietary fuel .

12. Food Milligrams (mg) Beef steak, cooked, 4 ounces 56–162 Ground beef, cooked, 4 ounces 87–99 Milk, whole, 1 cup 8 Codfish, cooked, 4 ounces 4–7

13. Carnitine Shuttle? The  carnitine  shuttle is responsible for transferring long-chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of beta-oxidation. The carnitine shuttle consists of three enzymes : Carnitine palmitoyl transferase 1 (CPT1A & CPT1B) Carnitine acylcarnitine translocase (SLC25A20) Carnitine palmitoyl transferase 2 (CPT2)) Carnitine

14. Enzymes Involve in Transport Of FA Enzymes specific for very long chain fatty acids are associated with the inner mitochondrial membrane, facing the matrix Carnitine Palmitoyl Transferase I : Catalyzes transfer of a fatty acid from ester linkage with the thiol of coenzyme A to the hydroxyl on carnitine . Carnitine Acyltransferase : Mediates trans-membrane exchange of fatty acyl carnitine for carnitine . Carnitine Palmitoyl Transferase II : Catalyzes transfer of the fatty acid from carnitine to coenzyme A

15. Steps of FA transport A special transport mechanism is needed to carry long-chain acyl   CoA molecules across the inner mitochondrial membrane.

16. Formation of Acyl Carnitine Activated long-chain fatty acids are transported across the membrane by conjugating them to  carnitine , a zwitter -ionic alcohol. The acyl group is transferred from the sulfur atom of CoA to the hydroxyl group of carnitine to form  acyl carnitine . This reaction is catalyzed by  carnitine acyltransferase I . Fatty acyl-carnitine is carried across the inner mitochondrial membrane by a specific transporter.

17. Formation of fatty acyl-CoA with free carnitine The fatty acyl group is enzymatically transferred from carnitine to intra-mitochondrial coenzyme A by  carnitine acyltransferase II . Regenerates fatty acyl-CoA and releases it, along with free carnitine , into the matrix . Carnitine re-enters the space between the inner and outer mitochondrial membranes via transporter .

18. Cytosolic and mitochondrial pools of coenzyme A Cytosolic and mitochondrial pools of coenzyme A, which have different functions. The mitochondrial pool of coenzyme A is largely used in oxidative degradation of pyruvate , fatty acids, and some amino acids. C ytosolic pool of coenzyme A is used in the biosynthesis of fatty acids.

19. Carnitine Regulation This  carnitine shuttle  is a rate limiting step in the oxidation of fatty acids in the mitochondria and thus fatty acid oxidation can be regulated at this step. Malonyl CoA , an intermediate of fatty acid synthesis present in the cytosol is an inhibitor of carnitine acyltransferase I.

20. Importance Carnitine  plays a crucial role in the transport of the fatty acids across the mitochondrial membrane and thus gain access to the enzymes for breakdown of long chain fatty acids . Thus deficiency of  carnitine  can lead to decreased ability of the tissue to utilize long chain fatty acids as energy. 

21. Carnitine Transporter Deficience It is one type of fatty acid oxidation disorder. People with CTD have problems using fat as energy for the body.  CTD occurs when an enzyme, called “ carnitine transporter” (CT), is either missing or not working properly. This enzyme’s job is to carry a substance called  carnitine  into our cells. Carnitine helps the body make energy from the fat in food. Characterized by progressive muscular weakness and aching muscle cramps. The symptoms were aggravated by fasting, exercise, and a high-fat diet.

22. CONCLUSION The inner mitochondrial membrane is impermeable to fatty acids and a specialized transport system operates to activated fatty acids from cytosol to mitochondria & peroxisomes .

23. References Eaton,S . , & Pourfarzam , M. (1996). Mammalian mitochondrial  -oxidation. Biochem . J. 320, 345–357. Thorpe, C. & Kim, J. (1995). Structure and mechanism of action of the acyl-CoA dehydrogenases . FASEB J. 9, 718–725 Kerner , J. & Hoppel , C. (1998). Genetic disorders of carnitine metabolism and their nutritional management. Annu . Rev. Nutr . 18, 179–206.