Rational Redesign of Monoamine Oxidase A into a Dehydrogenase to Probe ROS in Cardiac Aging

Published on 2020-07-01T20:12:07Z (GMT) by
Cardiac senescence is a typical chronic frailty condition in the elderly population, and cellular aging is often associated with oxidative stress. The mitochondrial-membrane flavoenzyme monoamine oxidase A (MAO A) catalyzes the oxidative deamination of neurotransmitters, and its expression increases in aged hearts. We produced recombinant human MAO A variants at Lys305 that play a key role in O<sub>2</sub> reactivity leading to H<sub>2</sub>O<sub>2</sub> production. The K305Q variant is as active as the wild-type enzyme, whereas K305M and K305S have 200-fold and 100-fold lower <i>k</i><sub>cat</sub> values and similar <i>K</i><sub>m</sub>. Under anaerobic conditions, K305M MAO A was normally reduced by substrate, whereas reoxidation by O<sub>2</sub> was much slower but could be accomplished by quinone electron acceptors. When overexpressed in cardiomyoblasts by adenoviral vectors, the K305M variant showed enzymatic turnover similar to that of the wild-type but displayed decreased ROS levels and senescence markers. These results might translate into pharmacological treatments as MAO inhibitors may attenuate cardiomyocytes aging.

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Iacovino, Luca Giacinto; Manzella, Nicola; Resta, Jessica; Vanoni, Maria Antonietta; Rotilio, Laura; Pisani, Leonardo; et al. (2020): Rational Redesign of Monoamine Oxidase A into a Dehydrogenase

to Probe ROS in Cardiac Aging. ACS Publications. Collection. https://doi.org/10.1021/acschembio.0c00366