The ternary complex of Mn 2+ , synthetic decapeptide DP1 (DEHGTAVMLK), and orthophosphate is a superb antioxidant
Year: 2024
Type: article
Abstract: Mn 2+ coordinated by orthophosphate (Pi), metabolites, or peptides acts as a superoxide dismutase (SOD), and these Mn antioxidant complexes are universally accumulated in extremely radiation-resistant cell types across the tree of life. This behavior prompted design of decapeptide DP1 (DEHGTAVMLK) as a Mn 2+ ligand, and development of a highly potent Mn 2+ -antioxidant (MDP) containing [Pi] = 25 mM, and [DP1] = 3 mM, the ratio found in the radioresistant bacterium Deinococcus radiodurans , with [Mn 2+ ] = 1 mM. MDP is an exceptional antioxidant, both in vitro and in vivo, and has reinvigorated the development of radiation-inactivated whole-cell vaccines. This study investigates the nature of the active Mn 2+ complex in MDP. We measure the affinity of DP1 for the substitutionally labile Mn 2+ ion using isothermal-titration calorimetry (ITC) and use changes in the Mn 2+ solution EPR spectrum to determine affinities of Mn 2+ for DP1 and for Pi, and to monitor Mn 2+ ligation while titrated with the fixed Pi/DP1 ratio of MDP, 25/3, using ENDOR/ESEEM to characterize DP1 ligation to Mn 2+ . In parallel, 1 H NMR of DP1 was used to monitor binding interactions between Pi and DP1, and DP1 binding to the diamagnetic Ca 2+ . We report: i) DP1 forms an extremely weak, dynamic Mn 2+ complex (K a ≈ 40 M −1 ) ii) Mn 2+ binds Pi much more strongly (K a ≈ 390 M −1 ) as shown previously, but iii) DP1 and Pi jointly bind to Mn 2+ in MDP to form a ternary Mn 2+ (Pi) (DP1) complex with greater formation-constant than Pi alone (K a app ≈ 670 M −1 ). It is this ternary complex that is the superb antioxidant in MDP.
Authors: Hao Yang, Ajay Sharma, Michael J. Daly, Brian M. Hoffman
Language: English
Subfield: Inorganic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
OpenAlex ID: W4405318563