「コナン・ザ・バクテリウム」はいかにして極度の放射線に耐えたか?(How ‘Conan the Bacterium’ withstands extreme radiation)

2024-12-09 ノースウェスタン大学

A new study reveals the secret to the antioxidant that allows the bacteria Deinococcus radiodurans to withstand radiation doses 28,000 times greater than what would kill a human.

<関連情報>

• https://news.northwestern.edu/stories/2024/12/how-conan-the-bacterium-withstands-extreme-radiation/
• https://www.pnas.org/doi/10.1073/pnas.2417389121

Mn2+、合成デカペプチドDP1(DEHGTAVMLK)、オルトリン酸の三元複合体は優れた抗酸化物質である The ternary complex of Mn2+, synthetic decapeptide DP1 (DEHGTAVMLK), and orthophosphate is a superb antioxidant

Hao Yang, Ajay Sharma, Michael J. Daly, and Brian M. Hoffman
Proceedings of the National Academy of Sciences  Published:December 12, 2024
DOI:https://doi.org/10.1073/pnas.2417389121

Significance

This study reveals the mechanism for protein radioprotection by the superb Mn-based MDP antioxidant containing Pi and decapeptide DP1, designed through considerations of Deinococcus radiodurans low molecular-weight Mn-antioxidants: The exceptionally active antioxidant in MDP is shown to be a Mn²⁺ (Pi/DP1) ternary complex, which, protects enzymes from radiation doses far exceeding the capabilities of Mn²⁺-Pi complexes alone. Substitutionally labile calcium ions coaccumulate with Mn in Mn-dependent organisms, and as an illuminating parallel, ¹H NMR of DP1 is used to measure its affinity for diamagnetic Ca²⁺, whose coordination chemistry parallels that of paramagnetic Mn²⁺. These findings could unlock new strategies for enhancing cellular oxidative-stress resistance, spur the development of radiation-inactivated whole-cell vaccines, and potentially lead to other medical advances.

Abstract

Mn²⁺ 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 Mn²⁺ ligand, and development of a highly potent Mn²⁺-antioxidant (MDP) containing [Pi] = 25 mM, and [DP1] = 3 mM, the ratio found in the radioresistant bacterium Deinococcus radiodurans, with [Mn²⁺] = 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 Mn²⁺ complex in MDP. We measure the affinity of DP1 for the substitutionally labile Mn²⁺ ion using isothermal-titration calorimetry (ITC) and use changes in the Mn²⁺ solution EPR spectrum to determine affinities of Mn²⁺ for DP1 and for Pi, and to monitor Mn²⁺ ligation while titrated with the fixed Pi/DP1 ratio of MDP, 25/3, using ENDOR/ESEEM to characterize DP1 ligation to Mn²⁺. In parallel, ¹H NMR of DP1 was used to monitor binding interactions between Pi and DP1, and DP1 binding to the diamagnetic Ca²⁺. We report: i) DP1 forms an extremely weak, dynamic Mn²⁺ complex (K_a ≈ 40 M^-1) ii) Mn²⁺ binds Pi much more strongly (K_a ≈ 390 M^-1) as shown previously, but iii) DP1 and Pi jointly bind to Mn²⁺ in MDP to form a ternary Mn²⁺ (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.