RESUMEN
Heme enzymes play a central role in a medley of reactivities within a wide variety of crucial biological systems. Their active sites are highly decorated with pivotal evolutionarily optimized non-covalent interactions that precisely choreograph their biological functionalities with specific regio-, stereo-, and chemo-selectivities. Gaining a clear comprehension of how such weak interactions within the active sites control reactivity offers powerful information to be implemented into the design of future therapeutic agents that target these heme enzymes. To shed light on such critical details pertaining to tryptophan dioxygenating heme enzymes, this study investigates the indole dioxygenation reactivities of Lewis acid-activated heme superoxo model systems, wherein an unprecedented kinetic behavior is revealed. In that, the activated heme superoxo adduct is observed to undergo indole dioxygenation with the intermediacy of a non-covalently organized precursor complex, which forms prior to the rate-limiting step of the overall reaction landscape. Spectroscopic and theoretical characterization of this precursor complex draws close parallels to the ternary complex of heme dioxygenases, which has been postulated to be of crucial importance for successful 2,3-dioxygenative cleavage of indole moieties.
RESUMEN
Dioxygen activating heme enzymes have long predicted to be powerhouses for nitrogen oxide interconversion, especially for nitric oxide (NO) oxidation which has far-reaching biological and/or environmental impacts. Lending credence, reactivity of NO with high-valent hemeoxygen intermediates of globin proteins has recently been implicated in the regulation of a variety of pivotal physiological events such as modulating catalytic activities of various heme enzymes, enhancing antioxidant activity to inhibit oxidative damage, controlling inflammatory and infectious properties within the local heme environments, and NO scavenging. To reveal insights into such crucial biological processes, we have investigated low temperature NO reactivities of two classes of synthetic high-valent heme intermediates, Compound-II and Compound-I. In that, Compound-II rapidly reacts with NO yielding the six-coordinate (NO bound) heme ferric nitrite complex, which upon warming to room temperature converts into the five-coordinate heme ferric nitrite species. These ferric nitrite complexes mediate efficient substrate oxidation reactions liberating NO; i.e., shuttling NO2- back to NO. In contrast, Compound-I and NO proceed through an oxygen-atom transfer process generating the strong nitrating agent NO2, along with the corresponding ferric nitrosyl species that converts to the naked heme ferric parent complex upon warmup. All reaction components have been fully characterized by UV-vis, 2H NMR and EPR spectroscopic methods, mass spectrometry, elemental analyses, and semi-quantitative determination of NO2- anions. The clean, efficient, potentially catalytic NOx interconversions driven by high-valent heme species presented herein illustrate the strong prospects of a heme enzyme/O2/NOx dependent unexplored territory that is central to human physiology, pathology, and therapeutics.