The recently discovered microbiome-generated obesogen, δ-valerobetaine (5-(trimethylammonio)pentanoate), is a 5-carbon structural analogue of the carnitine precursor, γ-butyrobetaine. Here, we report that δ-valerobetaine is enzymatically hydroxylated by mammalian γ-butyrobetaine dioxygenase (BBOX) to form 3-hydroxy-5-(trimethylammonio)pentanoate, a 5-carbon analogue of carnitine, which we term homocarnitine. Homocarnitine production by human liver extracts depends upon the required BBOX cofactors, 2-oxoglutarate, Fe2+, and ascorbate. Molecular dynamics simulations show successful docking of δ-valerobetaine and homocarnitine to BBOX, pharmacological inhibition of BBOX prevents homocarnitine production, and transfection of a liver cell line with BBOX substantially increases production. Furthermore, an in vivo isotope tracer study shows the conversion of 13C3-trimethyllysine to 13C3-δ-valerobetaine then 13C3-homocarnitine in mice, confirming the in vivo production of homocarnitine. Functional assays show that carnitine palmitoyltransferase acylates homocarnitine to acyl-homocarnitine, analogous to the reactions for the carnitine shuttle. Studies of mouse tissues and human plasma show widespread distribution of homocarnitine and fatty acyl-homocarnitines. The respective structural similarities of homocarnitine and acyl-homocarnitines to carnitine and acyl-carnitines indicate that homocarnitine could impact multiple sites of carnitine distribution and activity, potentially mediating microbiome-associated obesity and metabolic disorders.

中文翻译：

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微生物组衍生的肥胖原 δ-戊甜菜碱的哺乳动物羟基化为同型肉碱（一种 5 碳肉碱类似物）。


最近发现的微生物组产生的肥胖原 δ-戊甜菜碱（5-（三甲基铵）戊酸酯）是肉碱前体 γ-丁酸甜菜碱的 5 碳结构类似物。在这里，我们报道了 δ-戊甜菜碱被哺乳动物 γ-丁基甜菜碱双加氧酶 （BBOX） 酶促羟基化形成 3-羟基-5-（三甲基铵）五酸酯，这是一种肉碱的 5 碳类似物，我们称之为同肉碱。人肝提取物产生的同肉碱取决于所需的 BBOX 辅因子、2-氧代戊二酸、Fe2+ 和抗坏血酸。分子动力学模拟显示 δ-戊甜菜碱和高肉碱与 BBOX 成功对接，BBOX 的药理学抑制阻止了高肉碱的产生，并且用 BBOX 转染肝细胞系可显著增加产量。此外，体内同位素示踪剂研究表明，小鼠体内 13C3-三甲基赖氨酸转化为 13C3-δ-戊酸甜菜碱，然后转化为 13C3-同型肉碱，证实了同型肉碱的体内产生。功能测定表明，肉碱棕榈酰转移酶将同型肉碱酰化为酰基-同型肉碱，类似于肉碱穿梭的反应。对小鼠组织和人血浆的研究表明，同型肉碱和脂肪酰基-同肉碱广泛分布。同型肉碱和酰基-同型肉碱与肉碱和酰基-肉碱各自的结构相似性表明，同型肉碱可以影响肉碱分布和活性的多个位点，可能介导微生物组相关的肥胖和代谢紊乱。