Camitine action

Production of Malonyl-CoA for the Fatty Acid Biosynthesis. Acetyl-CoA serves as a substrate in the production of malonyl-CoA. There are several routes by which acetyl-CoA is supplied to die cytoplasm. One route is the transfer of acetyl residues from the mitochondrial matrix across the mitochondrial membrane into the cyto-plasm. This process resembles a fatty acid transport and is likewise effected with the participation of carnitine and the enzyme acetyl-CoA-camitine transferase. Another route is the production of acetyl-CoA from citrate. Citrate is delivered from the mitochondria and undergoes cleavage in the cytoplasm by the action of the enzyme ATP-citrate lyase ... 

Carnitine is linked to acyl groups transported into the mitochondria for oxidation (Figure 18.15). Acyl-CoAs in the cytoplasm are converted to acyl-camitine derviatives by action of carnitine acyltransferase I on the outer portion of the mitochondrial inner membrane. A translocase carries the acyl-carnitine into the mitochondria. Once inside the mitochondrial matrix, carnitine is replaced on the acyl group by CoASH. The acyl-CoA then is free to go through oxidation or elongation. 

One of the functions of hepatic P-oxidation is to provide ketone bodies, acetoac-etate and p-hydroxybutyrate, to the peripheral circulation. These can then be utilized by peripheral tissues such as brain and heart. Beta-oxidation itself produces acetyl-CoA which then has three possible fates entry to the Krebs cycle via citrate S5mthase keto-genesis or transesterification to acetyl-carnitine by the action of carnitine acetyltrans-ferase (CAT). Intramitochondrial acetyl-carnitine then equilibrates with plasma via the carnitine acyl-camitine translocase and presumably via the plasma membrane carnitine transporter. Human studies have shown that acetyl-carnitine may provide up to 5% of the circulating carbon product from fatty acids and can be taker and utilized by muscle and possibly brain." In addition, acyl-camitines are of important with regard to the diagnosis of inborn errors of P- oxidation. For these reasons, we wished to examine the production of acetyl-carnitine and other acyl-camitine esters by neonatal rat hepatocytes. 

Mitochondrial P-oxidation of long-chain fatty acids is the major source of energy production in man. The mitochondrial inner membrane is impermeable to long chain fatty acids or their CoA esters whereas acylcamitines are transported. Three different gene products are involved in this carnitine dependent transport shuttle carnitine palmi-toyl transferase I (CPT I), carnitine acyl-camitine carrier (CAC) and carnitine palmitoyl transferase II (CPT II). The first enzyme (CPT I) converts fatty acyl-CoA esters to their carnitine esters which are subsequently translocated across the mitochondrial inner membrane in exchange for free carnitine by the action of the carnitine acyl-camitine carrier (CAC). Once inside the mitochondrion, CPT II reconverts the carnitine ester back to the CoA ester which can then serve as a substrate for the P-oxidation spiral. 

Therrien G, Butterworth J, Rose C, Butterworth RF. Protective effect of 1-camitine in ammonia-precipitated encephalopathy in portacaval shunted rats Evidence for a central mechanism of action. Hepatology, 25, 551-556, 1997... 

Carnitine serves as a cofactor for several enzymes, including carnitine translo-case and acyl carnitine transferases I and II, which are essential for the movement of activated long-chain fatty acids from the cytoplasm into the mitochondria (Figure 11.2). The translocation of fatty acids (FAs) is critical for the genaation of adenosine triphosphate (ATP) within skeletal muscle, via 3-oxidation. These activated FAs become esterified to acylcamitines with carnitine via camitine-acyl-transferase I (CAT I) in the outer mitochondrial membrane. Acylcamitines can easily permeate the membrane of the mitochondria and are translocated across the membrane by carnitine translocase. Carnitine s actions are not yet complete because the mitochondrion has two membranes to cross thus, through the action of CAT II, the acylcar-nitines are converted back to acyl-CoA and carnitine. Acyl-CoA can be used to generate ATP via 3-oxidation, Krebs cycle, and the electron transport chain. Carnitine is recycled to the cytoplasm for fumre use. 

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