In a paper published in Cell Chemical Biology, Dr. Siddhesh Kamat's research group studied the role played by the lipid tail of lyso-PS in regulating the function of cells involved in immune response.   

Lysophospholipids are a class of signaling lipids that regulate many important physiological processes in humans. Compounds that target the receptors of lysophospholipids, or the biochemical pathways by which they are made or degraded, are either used clinically or being explored for use in the treatment of various human diseases.

Lysophosphatidylserines (lyso-PSs) are one such type of lipids that have emerged as a new class of signaling lysophospholipids, with possible functions in the nervous and immune systems.

Studying and understanding the structure and its relation to function of molecules such as lyso-PS often requires that we can isolate them in a pure form, or, sometimes, easier, make them synthetically. Lyso-PS has not been easy in this regard and this has hampered our understanding of this molecule, says Dr. Siddhesh Kamat.

(Left to Right) Neha Khandelwal, Minhaj Shaikh, Amol Mhetre, Shubham Singh, Harinath Chakrapani, and Siddhesh Kamat (Photo Courtesy: Dr Siddhesh Kamat). The photo was taken prior to COVID-19 and related safety and physical distancing norms.

Addressing this issue, in their current paper, the research group of Dr. Kamat teamed up with Prof. Harinath Chakrapani to develop a strategy to synthesise a derivative of lyso-PS: methyl-esters of lyso-PSs (Me-lyso-PSs). As with the natural variety of lyso-PS, the team generated methyl-esters of lyso-PS with varying lipid tails.

The team tested and showed through biochemical assays that the synthetic Me-lyso-PSs are likely to be acted upon by cellular enzymes to remove the methyl group and yield lyso-PS. This indicated that the synthetic Me-lyso-PSs could serve as stable prodrug like biological surrogates for lyso-PSs. The team also demonstrated that Me-lyso-PSs were capable of eliciting robust responses in a similar manner as their natural lyso-PS counterparts in primary immune cells like macrophages and mast cells.

In assays that tested and compared biological activities of synthetic Me-lyso-PSs and lyso-PS, the team noticed that the chain length of the lipid tail seemed to drive the extent of immune response: for example, Me-lyso-PSs with very long chain lipid tails elicited a significantly greater immune response in macrophages.

Picking up on this interesting observation, the team then conducted a series of assays to understand the regulation of specific aspects of the innate immune system. “Our findings illuminate a physiological balance between lyso-PSs of different lipid tails, intricately regulated by the lyso-PS lipase ABHD12,” says Dr. Kamat. The team proposes that disrupting this balance results in immunological outputs that have pathological consequences in humans.

Article Citation

Fatty acid chain length drives lysophosphatidylserine dependent immunological outputs (2021). Neha Khandelwal, Minhaj Shaikh, Amol Mhetre, Shubham Singh, Theja Sajeevan, Alaumy Joshi, Kithiganahalli Narayanswamy Balaji, Harinath Chakrapani, and Siddhesh S. Kamat. Cell Chemical Biology

- by Shanti Kalipatnapu, with inputs from Dr. Siddhesh Kamat