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==Catalytic Mechanism of Carnitine Acyltransferases== | ==Catalytic Mechanism of Carnitine Acyltransferases== | ||
[[Image:Mechanism fatty acid transfer.jpg|thumb|700px|left]] | [[Image:Mechanism fatty acid transfer.jpg|thumb|catalytic mechanism of fatty acid transfer|700px|left]] | ||
It is assumed that the whole family of carnitine acyltransferases share the same catalytic mechanism, because certain residues in the catalytic side (histidine343, serine554) are conserved throughout the family. | It is assumed that the whole family of carnitine acyltransferases share the same catalytic mechanism, because certain residues in the catalytic side (histidine343, serine554) are conserved throughout the family. | ||
Histidine 343 is probably the most important residue in catalysis. First, it induces optimal substrate binding by forming a hydrogen bond between its side chain and the hydrogen atom of the substrate’s reactive group. As soon as all substrates attained the right position, the catalytic histidine residue is ready to extract a proton from either the hydroxyl group of carnitine or the thiol group of CoA. The catalytic histidine residue can be considered as a general base in catalysis.Which proton is extracted depends on the direction of the reaction. Acyl- carnitine is formed by extracting a proton from carnitine, whereas acyl-CoA is formed by extracting a proton from CoA. | Histidine 343 is probably the most important residue in catalysis. First, it induces optimal substrate binding by forming a hydrogen bond between its side chain and the hydrogen atom of the substrate’s reactive group. As soon as all substrates attained the right position, the catalytic histidine residue is ready to extract a proton from either the hydroxyl group of carnitine or the thiol group of CoA. The catalytic histidine residue can be considered as a general base in catalysis.Which proton is extracted depends on the direction of the reaction. Acyl- carnitine is formed by extracting a proton from carnitine, whereas acyl-CoA is formed by extracting a proton from CoA. | ||
The extraction of a hydrogen atom leads to the development of a tetrahedral oxyanion intermediate. This oxyanion is stabilized by the <font color='# | The extraction of a hydrogen atom leads to the development of a tetrahedral <font color='#175487'>'''oxyanion'''</font> <font color='#E8B613'>'''intermediate'''</font>. This oxyanion is stabilized by the <font color='#A62929'>'''side chain hydroxyl of serine 554'''</font> through hydrogen bonding as well as by the <font color='#A62929'>'''positive charge on the trimethylammonium group'''</font> of carnitine. As the positive charge of the carnitine substrate is necessary for the carnitine acyltransferase mediated reaction to happen, this catalysis can be described as '''substrate-assisted catalysis'''.<ref name="structure1">PMID:15591000</ref> | ||
== Regulation == | == Regulation == | ||
One of the most common regulation systems of carnitine acyltransferases involves inhibition by malonyl-CoA, an intermediate in the synthesis of fatty acids. Malonyl-CoA inhibits long-chain carnitine acyltransferase activity by all three enzymes at similar concentrations in the physiological range. Moreover, the mitochondrial ( CAT) and peroxisomal (COT) enzymes can also be regulated through mRNA transcription by a number of shared factors. Although the microsomal enzyme is less well studied, there does, indeed, appear to be a pattern of coordinate regulation for this system. | One of the most common regulation systems of carnitine acyltransferases involves inhibition by malonyl-CoA, an intermediate in the synthesis of fatty acids. Malonyl-CoA inhibits long-chain carnitine acyltransferase activity by all three enzymes at similar concentrations in the physiological range. Moreover, the mitochondrial ( CAT) and peroxisomal (COT) enzymes can also be regulated through mRNA transcription by a number of shared factors. Although the microsomal enzyme is less well studied, there does, indeed, appear to be a pattern of coordinate regulation for this system. | ||