The fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD) is expressed at high levels in human alveolar type II (ATII) cells in the lung. A common polymorphism causing an amino acid substitution (K333Q) was previously linked to a loss of LCAD antigen in the lung tissue in sudden infant death syndrome. However, the effects of the polymorphism on LCAD function has not been tested. The present work evaluated recombinant LCAD K333Q. Compared to wild-type LCAD protein, LCAD K333Q exhibited significantly reduced enzymatic activity. Molecular modeling suggested that K333 is within interacting distance of the essential FAD cofactor, and the K333Q protein showed a propensity to lose FAD. Exogenous FAD only partially rescued the activity of LCAD K333Q. LCAD K333Q protein was less stable than wild-type when incubated at physiological temperatures, likely explaining the observation of dramatically reduced LCAD antigen in primary ATII cells isolated from individuals homozygous for K333Q. Despite the effect of K333Q on activity, stability, and antigen levels, the frequency of the polymorphism was not increased among infants and children with lung disease.

中文翻译：

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长链酰基辅酶 A 脱氢酶 (LCAD) 中常见的 K333Q 多态性降低了酶的稳定性和功能。

脂肪酸氧化酶长链酰基辅酶 A 脱氢酶 (LCAD) 在人肺泡 II 型 (ATII) 细胞中以高水平表达。导致氨基酸替代 (K333Q) 的常见多态性先前与婴儿猝死综合征肺组织中 LCAD 抗原的丢失有关。但是，尚未测试多态性对 LCAD 功能的影响。目前的工作评估了重组 LCAD K333Q。与野生型 LCAD 蛋白相比，LCAD K333Q 的酶活性显着降低。分子模型表明 K333 位于必需 FAD 辅因子的相互作用距离内，并且 K333Q 蛋白显示出失去 FAD 的倾向。外源性 FAD 仅部分挽救了 LCAD K333Q 的活性。在生理温度下孵育时，LCAD K333Q 蛋白不如野生型稳定，这可能解释了从 K333Q 纯合个体分离的原代 ATII 细胞中观察到的 LCAD 抗原显着减少的原因。尽管 K333Q 对活性、稳定性和抗原水平有影响，但在患有肺部疾病的婴儿和儿童中，多态性的频率并未增加。