Origin of breath isoprene in humans is revealed via multi-omic investigations

Abstract

Plants, animals and humans metabolically produce volatile isoprene (C5H8). 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 Mg2+–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.

Unravelling the origin of isoprene in the human body—a forty year Odyssey

“…Fortunately, such an investigation was recently undertaken. In a multi-omic study of genes and metabolites, involving long-term isoprene measurements of the exhaled breath of thousands of people, Sukul et al have provided the definitive and conclusive proof of the proposition that isoprene production occurs in skeletal muscle cells [26]. In this remarkable study, Sukul et al identified an IDI2 stop-gain mutation as the cause for the absence of isoprene in the exhaled breath of five healthy individuals from the screening of the thousands of people.…”

A novel coupling technique based on thermal desorption gas chromatography with mass spectrometry and ion mobility spectrometry for breath analysis

“…Similarly, in IMS, the retention time is plotted against the sum of the data points in the ion mobility spectrum in the range of 4.9 ms-11.0 ms without considering reactant ions. Therefore, the ketone mixture was measured at different APC pressures (40,50,60,70,80,90, and 100 kPa). The results can be seen in figure 6, upper part for MS and lower part for IMS.…”

“…Isoprene is one of the most studied volatile compound in respiratory research, not only because it is the primary endogenous hydrocarbon found in exhaled human breath but also because of its potential use as a noninvasive marker for studying various metabolic processes in the body. Its origin was uncertain until now, but Sukul et al [40] have discovered the actual origin of human exhaled isoprene by multi-omic analysis of genes and metabolites. Exhaled 2-propanol in human breath reflects health conditions: There is a relationship with 2-propanol blood concentration and diabetes, so a link of its concentration in the breath can also be suspected [41].…”

An inexpensive UV-LED photoacoustic based real-time sensor-system detecting exhaled trace-acetone

“…For basic and applied breathomics (e.g., of unidentified VOC marker profiles) established gold standards like Gas-Chromatography Mass-Spectrometry (GC-MS) and real-time Proton-Transfer-Reaction Time-of-Flight Mass-Spectrometry (PTR-TOF-MS) represent the state of the art. As soon as certain markers are well-established as for breath isoprene [15] or acetone, PAS offers a compelling evidence of performance to comprehend potential pre-clinical point-of-care applications.…”