Abstract
Metabolism of food protein by gut microbes produce trimethylamine which on oxidation by hepatic flavin-containing monooxygenases is transformed to trimethylamine-N-oxide (TMAO). TMAO has recently been implicated as a biomarker for atherosclerosis. TMAO, as (CH3)3N+–O−), is ionic and so a hydrophilic molecule that is freely available in blood plasma. For the effective interaction with lipid-soluble molecules, TMAO should be phase transferred to the lipid site. We show that the free TMAO is effectively bonded to zinc protoporphyrin IX dimethyl ester [ZnPPDME] to yield [TMAOZnPPDME] using phase transfer reaction. The zinc protoporphyrin IX, [ZnPP], in general, available in blood may form [TMAOZnPP] complex. The nature of such interaction between TMAO and [ZnPP] has been structurally shown using a model complex, [TMAOZnTPP] (TPP = tetraphenylporphyrin). These complexes readily move from the polar plasma to the non-polar (lipid) site to act as the oxo-transfer agent to oxidize cholesterol causing atherosclerosis. Chromatographic and circular dichroism (CD) studies show that either TMAO or [ZnPP] alone cannot oxidize cholesterol.
Graphic abstract
Free TMAO bonded with zinc-protoporphyrin IX, [ZnPP], in blood plasma as [TMAOZnPP] is transported to the lipid site and this is the reacting species to oxidize cholesterol causing atherosclerosis.
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Acknowledgements
This research was funded by SERB-DST (EMR/2015/001328), New. Delhi, to SS. NP is thankful to CSIR (08/003/0108(2015)-EMR-I), New Delhi for a SRF and RS is thankful to UGC, New Delhi, for granting him a DS Kothari Post-Doctoral Fellowship.
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Paul, N., Sarkar, R. & Sarkar, S. Zinc protoporphyrin–trimethylamine-N-oxide complex involves cholesterol oxidation causing atherosclerosis. J Biol Inorg Chem 26, 367–374 (2021). https://doi.org/10.1007/s00775-021-01861-z
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DOI: https://doi.org/10.1007/s00775-021-01861-z