Narayanan Beena, Xia Chuanwu, McAndrew Ryan, Shen Anna L, Kim Jung-Ja P
Medical College of Wisconsin.
University of North Florida.
Res Sq. 2024 Feb 29:rs.3.rs-3980524. doi: 10.21203/rs.3.rs-3980524/v1.
Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the E291Q mutant, have been determined. These structures suggest that LCAD harbors functions beyond its historically defined role in mitochondrial β-oxidation of long and medium-chain fatty acids. LCAD is a homotetramer containing one FAD per 43kDa subunit with Glu291 as the catalytic base. The substrate binding cavity of LCAD reveals key differences which makes it specific for longer and branched chain substrates. The presence of Pro132 near the start of the E helix leads to helix unwinding that, together with adjacent smaller residues, permits binding of bulky substrates such as 3α, 7α, l2α-trihydroxy-5β-cholestan-26-oyl-CoA. This structural element is also utilized by ACAD11, a eucaryotic ACAD of unknown function, as well as bacterial ACADs known to metabolize sterol substrates. Sequence comparison suggests that ACAD10, another ACAD of unknown function, may also share this substrate specificity. These results suggest that LCAD, ACAD10, ACAD11 constitute a distinct class of eucaryotic acyl CoA dehydrogenases.
已测定人长链酰基辅酶A脱氢酶（LCAD）及其E291Q突变体的晶体结构。这些结构表明，LCAD具有的功能超出了其在长链和中链脂肪酸线粒体β氧化中历史定义的作用。LCAD是一种同四聚体，每个43kDa亚基含有一个FAD，以Glu291作为催化碱基。LCAD的底物结合腔显示出关键差异，这使其对较长和支链底物具有特异性。E螺旋起始处附近的Pro132的存在导致螺旋解旋，这与相邻的较小残基一起，允许结合诸如3α、7α、12α-三羟基-5β-胆甾烷-26-酰基辅酶A等庞大底物。这种结构元件也被ACAD11（一种功能未知的真核ACAD）以及已知可代谢甾醇底物的细菌ACAD所利用。序列比较表明，另一种功能未知的ACAD即ACAD10可能也具有这种底物特异性。这些结果表明，LCAD、ACAD10、ACAD11构成了一类独特的真核酰基辅酶A脱氢酶。
