Rostock Medical Breath Research Analytics and Technologies (ROMBAT), Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Medicine Rostock, Schillingallee 35, 18057, Rostock, Germany.
Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Strasse 6, 18057, Rostock, Germany.
Commun Biol. 2023 Sep 30;6(1):999. doi: 10.1038/s42003-023-05384-y.
Plants, animals and humans metabolically produce volatile isoprene (CH). Humans continuously exhale isoprene and exhaled concentrations differ under various physio-metabolic and pathophysiological conditions. Yet unknown metabolic origin hinders isoprene to reach clinical practice as a biomarker. Screening 2000 individuals from consecutive mass-spectrometric studies, we herein identify five healthy German adults without exhaled isoprene. Whole exome sequencing in these adults reveals only one shared homozygous (European prevalence: <1%) IDI2 stop-gain mutation, which causes losses of enzyme active site and Mg-cofactor binding sites. Consequently, the conversion of isopentenyl diphosphate to dimethylallyl diphosphate (DMAPP) as part of the cholesterol metabolism is prevented in these adults. Targeted sequencing depicts that the IDI2 rs1044261 variant (p.Trp144Stop) is heterozygous in isoprene deficient blood-relatives and absent in unrelated isoprene normal adults. Wild-type IDI1 and cholesterol metabolism related serological parameters are normal in all adults. IDI2 determines isoprene production as only DMAPP sources isoprene and unlike plants, humans lack isoprene synthase and its enzyme homologue. Human IDI2 is expressed only in skeletal-myocellular peroxisomes and instant spikes in isoprene exhalation during muscle activity underpins its origin from muscular lipolytic cholesterol metabolism. Our findings translate isoprene as a clinically interpretable breath biomarker towards potential applications in human medicine.
植物、动物和人类在新陈代谢过程中会产生挥发性异戊二烯 (CH)。人类会持续呼出异戊二烯，并且在各种生理代谢和病理生理条件下，呼出的浓度也会有所不同。然而，由于代谢来源未知，异戊二烯尚未作为生物标志物应用于临床实践。在对连续质谱研究中的 2000 个人进行筛选后，我们在此确定了 5 名没有呼出异戊二烯的健康德国成年人。对这些成年人进行全外显子组测序，仅发现一个共同的纯合 (欧洲患病率：<1%) IDI2 终止密码子突变，该突变导致酶活性位点和 Mg 辅因子结合位点丢失。因此，这些成年人的异戊烯基二磷酸向二甲烯丙基二磷酸 (DMAPP) 的转化（胆固醇代谢的一部分）受阻。靶向测序表明，IDI2 rs1044261 变体（p.Trp144Stop）在异戊二烯缺乏的血缘亲属中为杂合子，而在无关的异戊二烯正常成年人中则不存在。所有成年人的野生型 IDI1 和胆固醇代谢相关的血清学参数均正常。IDI2 决定了异戊二烯的产生，因为只有 DMAPP 是异戊二烯的来源，而与植物不同的是，人类缺乏异戊二烯合酶及其酶同源物。人类 IDI2 仅在骨骼肌过氧化物酶体中表达，并且在肌肉活动期间异戊二烯呼气的瞬时激增支持其源自肌肉脂肪分解胆固醇代谢。我们的发现将异戊二烯转化为一种具有临床可解释性的呼吸生物标志物，有望在人类医学中得到应用。
