Rational Redesign of Monoamine Oxidase A into a Dehydrogenase
to Probe ROS in Cardiac Aging
Version 2 2020-07-01, 20:12
Version 1 2020-06-30, 11:37
Posted on 2020-07-01 - 20:12
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 O2 reactivity leading to H2O2 production. The
K305Q variant is as active as the wild-type enzyme, whereas K305M
and K305S have 200-fold and 100-fold lower kcat values and similar Km. Under
anaerobic conditions, K305M MAO A was normally reduced by substrate,
whereas reoxidation by O2 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
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AUTHORS (11)
LI
Luca Giacinto Iacovino
NM
Nicola Manzella
JR
Jessica Resta
MV
Maria Antonietta Vanoni
LR
Laura Rotilio
LP
Leonardo Pisani
DE
Dale Edward Edmondson
AP
Angelo Parini
AM
Andrea Mattevi
JM
Jeanne Mialet-Perez
CB
Claudia Binda
KEYWORDS
O 2 reactivityK 305Sadenoviral vectorsK 305MRational Redesignoxidative deaminationattenuate cardiomyocytesmitochondrial-membrane flavoenzyme ...wild-type enzymeROS levelsLys 305k cat valuesMonoamine Oxidasefrailty conditionexpression increasesK 305Q variantquinone electron acceptorsK mProbe ROSO 2Cardiac Aging Cardiac senescenceH 2 O 2 productionoxidative stressK 305M MAOsenescence markersK 305M variantMAO inhibitors