Energy calculations for atomic oxygen liberation from hypohalous acids biosynthesized by mammalian peroxidases

ABSTRACT The ultimate process of the mammalian immunological system is destruction of invasive microbes by peroxidase (PO) activities. Three enzymes, lactoperoxidase (LPO), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) require two substrates for this task. The first is H2O2 and the second either I−, Br−, Cl− or SCN−. All POs are able to synthesize hypoiodous acid and OSCN− but two can create HOBr (EPO and MPO) and only MPO can biosynthesize HOCl. Using density-functional theory (DFT) and following first principles of molecular modelling we investigated the energetics of hypohalous acid breakdowns by calculating the internal energy differences between the reactants and products. Atomic oxygen (ATOX) and simple halide acids are the energetically favoured products with halide cations and hydroxide ion being minor products. There is nothing subtle about ATOX, it is a very destructive species. ATOX production explains the documented ability of POs to indiscriminately and rapidly destroy invasive microbes and the role of MPO initiating inflammation. Previously unrecognised, the biosynthesis of ATOX also explains why mammalian POs are restricted to surfaces or special cells which are themselves destroyed after PO activation. This chemistry is the probable reason why dietary iodine, uniquely provided by the Japanese diet, helped to significantly reduce deaths from the SARS-CoV-2 viral agent during the COVID-19 pandemic in Japan. Highlights The energetics of hypohalous acid, HOI, HOBr and HOCl, breakdown into atomic oxygen (ATOX) or halide cation were calculated using density-functional theory The release of neutral ATOX from all three hypohalous acids is greatly preferred over halide cation and hydroxide production ATOX produced by mammalian peroxidases is incredibly powerful and largely responsible for the ultimate destruction of most invasive, especially airborne microbes Graphical Abstract Competing Interest Statement The authors have declared no competing interest. Footnotes puf.razvan{at}icmpp.ro (R. Puf); mlsmith55{at}gmail.com (M.L. Smith); aatto.laaksonen{at}mmk.su.se (A. Laaksonen) Added a few sentences to the Discussion section and edited the notes for Table 3. Abbreviations - a.m.u. - atomic mass unit - ATOX - atomic oxygen, O or O* - DFT - density-functional theory - EPO - eosinophil peroxidase - EPR - electron paramagnetic resonance - LPO - lactoperoxidase - MPO - myeloperoxidase - Mb - myoglobin - NADPH - reduced nicotinamide adenine dinucleotide; phos-phate - NK - natural killer cells (innate immunity) - NMR - nuclear magnetic resonance - PVD-I - povidone-iodine - RSV - Respiratory Syncytial Virus - SARS-CoV-2 - Betacoronavirus pandemicum - UV - ultraviolet.