Acyl-coenzyme A:cholesterol acyltransferase 1 – significance of single-nucleotide polymorphism at residue 526 and the role of Pro347 near the fifth transmembrane domain

摘要: Acyl-coenzyme A:cholesterol acyltransferases (ACATs), which are members of the membrane-bound O-acyltransferase family, catalyze conversion cholesterol to cholesteryl esters. Mammals have two isoenzymes: ACAT1 and ACAT2. Both enzymes drug targets for treating human diseases. is present in various cell types. It contains nine transmembrane domains (TMDs), with active site His460 located within TMD7, Asn421 fourth large cytoplasmic loop. In ACAT1, a single-nucleotide polymorphism exists residue 526: codon either CAG Gln, or CGG Arg. Gln526/Arg526 C-terminal Its biochemical significance unknown. addition, half numerous residues conserved those ACAT2 present; functions these largely Here, we performed single-substitution mutagenesis experiments investigate roles individual loop, including Gln526/Arg526, eight Pro near/in TMDs. The results show that enzyme activity Gln526 less than Arg526 by 40%. several loop important maintaining proper protein stability. Other Pro347 plays an role modulating catalysis. Overall, our imply CAG/CGG can be utilized perform activity/human disease susceptibility studies, near TMD5