Mammalian hydroxylation of microbiome-derived obesogen, delta-valerobetaine, to homocarnitine, a 5-carbon carnitine analog.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Biological Chemistry Pub Date : 2025-01-01 Epub Date: 2024-12-13 DOI:10.1016/j.jbc.2024.108074
Jaclyn Weinberg, Ken H Liu, Choon-Myung Lee, William J Crandall, André R Cuevas, Samuel A Druzak, Edward T Morgan, Zachery R Jarrell, Eric A Ortlund, Greg S Martin, Grant Singer, Frederick H Strobel, Young-Mi Go, Dean P Jones
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引用次数: 0

Abstract

The recently discovered microbiome-generated obesogen, δ-valerobetaine (5-(trimethylammonio)pentanoate), is a 5-carbon structural analog 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 analog 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.

哺乳动物将微生物衍生的肥胖原--δ-缬甜菜碱羟基化为 5 碳肉碱类似物--高肉碱。
最近发现的微生物产生的肥胖原,δ-缬甜菜碱(5-(三甲胺)戊酸酯),是肉碱前体γ-丁甜菜碱的5碳结构类似物。在这里,我们报道了δ-缬甜菜碱被哺乳动物γ-丁基甜菜碱双加氧酶(BBOX)酶化羟基化,形成3-羟基-5-(三甲胺)戊酸盐,一种肉碱的5碳类似物,我们称之为同质肉碱。人类肝脏提取物产生高卡尼汀取决于所需的BBOX辅助因子,2-氧葡萄糖酸盐,Fe2+和抗坏血酸盐。分子动力学模拟表明,δ-缬罗甜菜碱和同质卡尼汀与BBOX成功对接,BBOX的药理抑制可阻止同质卡尼汀的产生,BBOX转染肝细胞系可显著增加同质卡尼汀的产生。此外,一项体内同位素示踪研究表明,13C3-三甲基赖氨酸在小鼠体内转化为13C3-δ-缬甜菜碱,然后是13C3-高卡尼汀,证实了高卡尼汀在体内的生成。功能分析表明,肉毒碱棕榈酰基转移酶将同卡尼汀酰化为酰基同卡尼汀,类似于肉毒碱穿梭的反应。对小鼠组织和人血浆的研究表明,同质卡尼汀和脂肪酰基同质卡尼汀广泛分布。同卡尼汀和酰基同卡尼汀与肉毒碱和酰基肉毒碱的结构相似性表明,同卡尼汀可能影响肉毒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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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