Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
Department of Chemistry and Biochemistry, College of Arts and Sciences, University of North Florida, Jacksonville, FL, 32224, USA.
Sci Rep. 2024 Jun 5;14(1):12976. doi: 10.1038/s41598-024-63027-6.
Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the catalytically inactive Glu291Gln 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 43 kDa 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.
已确定人长链酰基辅酶 A 脱氢酶 (LCAD) 和催化失活的 Glu291Gln 突变体的晶体结构。这些结构表明，LCAD 除了其在历史上被定义为在线粒体β-氧化长链和中链脂肪酸中的作用之外，还具有其他功能。LCAD 是一个包含每个 43 kDa 亚基一个 FAD 的四聚体，Glu291 为催化碱。LCAD 的底物结合腔揭示了使其对较长和支链底物具有特异性的关键差异。E 螺旋起始处附近存在 Pro132 导致螺旋展开，与相邻的较小残基一起，允许结合较大的底物，如 3α、7α、l2α-三羟基-5β-胆甾烷-26-酰基-CoA。这个结构元素也被未知功能的真核 ACAD11 和已知代谢固醇底物的细菌 ACAD 利用。序列比较表明，另一个未知功能的 ACAD10 也可能具有这种底物特异性。这些结果表明，LCAD、ACAD10、ACAD11 构成了一个独特的真核酰基辅酶 A 脱氢酶类。
