Merged Heme and Non-Heme Manganese Cofactors for a Dual Antioxidant Surveillance in Photosynthetic Organisms

Abstract

The coupling of a polycationic Mn(III)-porphyrin, with a dinuclear Mn2(II,II)L2 core (HL = 2-{[[di(2-pyridyl)methyl](methyl)amino]methyl}phenol), results in a dual Superoxide Dismutase (SOD) and Catalase (CAT) functional analogue, Mn2L2Pn+, enabling a detoxification cascade of the superoxide anion and hydrogen peroxide into benign H2O and O2. The SOD/CAT artificial manifolds, joined in one asset, exhibit a peak catalytic performance under physiological conditions, with log kcat(O2• –) ≥ 7 and kcat(H2O2)/KM = 1890. The dual-enzyme (dizyme) concept allows for a built-in self-protection against the irreversible bleaching of the porphyrin unit (>75% protection), readily induced by H2O2 (200 μM, 20 equiv, in buffer solution, pH 7.8). We show herein that incubation of the photosynthetic green algae, Chlamydomonas reinhardtii, with the synthetic dizyme (as low as 0.1 μM), prevents H2O2 accumulation under high-light illumination conditions, thus providing antioxidant surveillance and photoprotection

Insights into the respiratory chain and oxidative stress

“…The chemical nature of the substrates fueling the respiratory chain, the amplitude of the membrane potential in mitochondria (ΔΨm), the pH of the matrix, and the oxygen tension in the surroundings are important factors controlling ROS production in mitochondria [ 39 , 40 ], this control having to be tight for such molecules considered as toxic by-products. Indeed, ROS can damage cells in many ways and give rise to fast, barrier-less and non-selective oxidation steps, being responsible for a severe insult of both organic and inorganic matter exposed to ‘oxidative stress’ [ 41 , 42 ]. Protein oxidation mostly results in the formation of carbonyl groups (ketone and aldehydes) [ 43 ].…”

“…Beside the fact that mitochondrial H 2 O 2 can cross the membrane and serve as signalling molecule (see point 3), nature has evolved a complex enzymatic machinery to control the risk of so-called ‘oxygen toxicity’ paradox [ 41 , 42 ]. The primary line of defence is a panel of proteins that remove ROS or that act as sequestering metal ions that are reviewed below.…”

“…Recently a synthetic ‘dizyme’ combining SOD and CAT functional activities has been designed to enable a detoxification cascade from O 2 ∙− into H 2 O and O 2 . This ‘dizyme’ has been shown to prevent H 2 O 2 accumulation in the green alga Chlamydomonas reinhardtii , cultivated under high light illumination conditions [ 42 ].…”

Understanding the Catalase-Like Activity of a Bioinspired Manganese(II) Complex with a Pentadentate NSNSN Ligand Framework. A Computational Insight into the Mechanism

“…[8][9][10][11][12] Although Mn-polyamine complexes show very high SOD-mimetic activity, 13 certain Mn-porphyrin and Mn-salen complexes exhibit dual SOD and CAT activity. [14][15][16][17] Additional functions of manganese complexes are known such as oxidation, [18][19][20] reduction, 21 or sulfur-oxygenation. 22 In a recent paper by Britovsek, Bonchio and coworkers, 23 .…”

“…More recently, catalase biomimetics include single-site Mn complexes, often showing both SOD and CAT activity, which can be used as artificial small molecule catalysts for ROS detoxification and are promising as therapeutics . Indeed, some Mn­(III)-porphyrin (for example, AEOL10150), Mn­(III)-salen (for example EUK-113) and seven-coordinated Mn­(II)-macrocyclic polyamine complexes (for example M40403) have entered clinical tests. − Although Mn-polyamine complexes show very high SOD-mimetic activity, certain Mn-porphyrin and Mn-salen complexes exhibit dual SOD and CAT activity. − Additional functions of manganese complexes are known such as oxidation, − reduction, or sulfur–oxygenation …”