Using Physical Organic Chemistry Knowledge to Predict Unusual Metabolites of Synthetic Phenolic Antioxidants by Cytochrome P450

Abstract

Biotransformation, especially by human CYP450 enzymes, plays a crucial role in regulating the toxicity of organic compounds in organisms, but is poorly understood for most emerging pollutants, as their numerous “unusual” biotransformation reactions cannot retrieve examples from the textbooks. Therefore, in order to predict the unknown metabolites with altering toxicological profiles, there is a realistic need to develop efficient methods to reveal the “unusual” metabolic mechanism of emerging pollutants. Combining experimental work with computational predictions has been widely accepted as an effective approach in studying complex metabolic reactions; however, the full quantum chemical computations may not be easily accessible for most environmentalists. Alternatively, this work practiced using the concepts from physical organic chemistry for studying the interrelationships between structure and reactivity of organic molecules, to reveal the “unusual” metabolic mechanism of synthetic phenolic antioxidants catalyzed by CYP450, for which the simple pencil-and-paper and property-computation methods based on physical organic chemistry were performed. The phenol-coupling product of butylated hydroxyanisole (BHA) (based on spin aromatic delocalization) and ipso-addition quinol metabolite of butylated hydroxytoluene (BHT) (based on hyperconjugative effect) were predicted as two “unusual” metabolites, which were further confirmed by our in vitro analysis. We hope this easily handled approach will promote environmentalists to attach importance to physical organic chemistry, with an eye to being able to use the knowledge gained to efficiently predict the fates of substantial unknown synthesized organic compounds in the future.

Development and evaluation of immersive VR laboratories of organic chemistry and physics for students education

“…The discipline of physical organic chemistry, delving into the intricate relationship between structure and reactivity in organic molecules, serves as a foundational underpinning for the broader field of organic chemistry [46]. It equips chemists with the ability to forecast and govern chemical reactivity by discerning the influence of molecular structure and local surroundings on reactions [47]. Furthermore, physical organic chemistry assumes a fundamental role in forging interdisciplinary connections that integrate chemical synthesis, biological sciences, and material sciences.…”

“…GoogleVR [46] software development kit (SDK) was used for running the project on the Oculus Quest 2 Headset. The VR headset offers much vivid experience with a rich spectrum of interaction [47]. The scene designing in Unity 3D involved mathematical equations for the position, scale, and rotation of objects in the scene [48].…”

Theoretical Kinetic Isotope Effects in Establishing the Precise Biodegradation Mechanisms of Organic Pollutants

“…For example, CYP450 as one of the most common microbial enzymes in the environment and a large number of CYP450-catalyzed reactions on emerging pollutants have been reported during recent years, besides aliphatic hydroxylation and epoxidation mostly studied by isotope analysis, still including aromatic oxygenation (e.g., bisphenol A), heteroatom oxygenation (e.g., sulfamethoxazole), O-dealkylation (e.g., di-2-ethylhexyl-phthalate), desaturation (e.g., imidacloprid), oxidative coupling (e.g., triclosan), and so on. Recently, we have proposed a new synergy with performing computations prior to experiments for providing insights into precision biotransformation of emerging pollutants, − which for the first time revealed the successive oxidation and reduction mechanism of CYP450. Herein, the design of CSIA experiments for studying the biodegradation of pollutants using the theoretical kinetic isotope effects as a predictive tool, that is, building the theoretical isotope database of pollutant biodegradation, can undoubtedly maximize the potential of CSIA in efficiently achieving the challenging task of revealing controversial biodegradation mechanisms of extensive emerging pollutants by diverse microbial enzymes in the future.…”