Hemoglobin as a nitrite anhydrase: modeling methemoglobin-mediated N2O3 formation

Area of Science:

• Biochemistry
• Chemical Physics
• Physiology

Background:

• Nitrite is a key NO reservoir in blood, crucial for hypoxic vasodilation.
• Nitric oxide (NO) readily binds to hemoglobin, posing a challenge for its diffusion to target tissues.
• Dinitrogen trioxide (N(2)O(3)) is hypothesized to transport NO from red blood cells to the endothelium.

Purpose of the Study:

• To theoretically model the nitrite anhydrase reaction, investigating the formation of N(2)O(3).
• To elucidate the interaction mechanisms between methemoglobin, nitrite, and NO.
• To evaluate the energetic feasibility of proposed pathways for N(2)O(3) synthesis.

Main Methods:

• Detailed density functional theory (DFT) calculations using the B3LYP/TZP level of theory.
• Examination of multiple reaction pathways, including isomerism and spin states of methemoglobin-nitrite complexes.
• Calculation of transition states and reaction barriers for N(2)O(3) formation.

Main Results:

• Both proposed pathways for N(2)O(3) formation, "Hb-Fe(3+)-NO(2)(-)+NO" and "Hb-Fe(3+)-NO+NO(2)(-)", were found to be energetically feasible.
• The "Hb-Fe(3+)-NO+NO(2)(-)" pathway exhibits a lower calculated barrier (8.1 kcal mol(-1)) via a two-step mechanism.
• Reasonable activation barriers (17-20 kcal mol(-1)) were calculated for N(2)O(3) formation from a plausible six-coordinate Fe(3+)-O-nitrito geometry.

Conclusions:

• The nitrite anhydrase reaction is a plausible mechanism for NO transport.
• Both investigated pathways present energetically reasonable routes for N(2)O(3) formation.
• Quantum chemical modeling suggests both pathways are viable, cautioning against favoring a single mechanism based solely on energetics.