N,N-Dimethyl Sphingosine: What a Pain!

Posted on January 18, 2022


Dimethyl Sohingosine Mo M

As we recently announced, Avanti and METLIN have teamed up to create tandem mass spectrometry, neutral loss, and ion mobility CCS lipids data within METLIN’s 860,000 molecular standards experimental database. With this partnership we will be highlighting lipid molecules with new data every month. Our first METLIN Molecule of the Month is N,N-dimethylsphingosine (DMS), a lipid with multiple physiological activities. DMS and its relationship to neuropathic pain was first released in Nature Chemical Biology 2012 using an approach now called “activity metabolomics”. DMS was identified in a pain model called tibial nerve transection and was shown to sensitize neurons in the central nervous system. DMS is an endogenous sphingolipid of the sphingomyelin-ceramide pathway, specifically a catabolite of ceramide, that is known to increase Ca2+ concentrations in astrocytes and inhibit glutamate uptake. DMS is also a sphingosine kinase 1 (SphK1) inhibitor. Subsequent work in 2015 showed that inhibition of the formation of DMS through the ceramidase pathway could be used to inhibit neuropathic pain progression.

In 2017, DMS was also shown to have therapeutic impact on chronic Chagas disease cardiomyopathy, a disease caused by the parasite Trypanasoma cruzi. Cardiac symptoms and complications from the disease may not occur for years after the initial infection. Once they appear, they can present themselves as arrhythmias, ventricular aneurysms, congestive heart failure, and even sudden cardiac death. DMS reduced the inflammatory response, was shown to have antiparasitic effects, and was discovered to inhibit protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) (Vasconcelos, et. al., 2017).

METLIN has been accumulating experimental data on DMS and its 859,999 other molecular standards largely to facilitate their rapid identification from any type of sample. Even today, identification is still a major bottleneck in metabolomics, exposure, toxicology, and clinical experiments. Below, we show the well-known MS/MS data for DMS, as well as the heretofore not seen neutral loss data. The METLIN neutral loss spectral database is a novel concept in terms of its scope and utility, presenting itself as a mirror image of MS/MS data. In conjunction with MS/MS, neutral loss’s utility is being developed to facilitate similarity searching, a key technology for identifying metabolites and other chemical entities.

Interestingly, neutral loss data is represented as the mirror image of MS/MS data, essentially a different dimension of mass spectral data. Tune in next month for our next METLIN molecule of the month!