How nitrogenase enzymes have adapted structurally to Earth's environments over geological timescales

Can extant and ancestral enzymes provide insights into structural evolution shaped by environmental factors and biological phenotypes? And how might one gain access to the structures of ancestral enzymes? The analysis of nitrogenases reported by Cuevas-Zuviría et al. (2025) describes how conformational features, active-site composition, and sequence modifications can be correlated with evolutionary pressures and environmental conditions over geological timescales. Nitrogenases are key to life on Earth. These enzymes enable access to bio-essential nitrogen by catalysing the reduction of highly inert atmospheric nitrogen (N≡N) with its hard-to-cleave triple bond to ammonia (NH₃). Nitrogenases thus have an outsized role in the adaptation of species as they survive diverse environmental conditions, whether terrestrial or aquatic. Despite this, not much is known about the variation in the enzymatic activity of nitrogenases as a function of ecological niche or evolution. What is well known, however, is that nitrogenases are extremely sensitive to oxygen, which degrades the bound metalloclusters that are essential for enzymatic activity and oligomerisation. Consequently, nitrogenases that evolved under anaerobic conditions must have been subjected to unprecedented selection pressures as oxygen levels increased especially during the Great Oxidation Event in Earth's geological history (Moody et al. 2025). In this context, molecular features acquired as an adaptation mechanism to environments, such as increased oxygen levels, have not been well understood in this family of enzymes. Nitrogenases employ redox-sensitive trace metals such as molybdenum, vanadium, and iron. The environmental bioavailability of these metal ions is also altered by oxygenation. It thus appears likely that novel features within the nitrogenase enzymes evolved as an adaptive mechanism to maintain biological nitrogen fixation amid global marine geochemical shifts while life was developing in these environments (Cuevas-Zuviría et al. 2024). Understanding the linkages between these molecular innovations and environmental transitions is essential to rationalise how evolution shaped an enzyme capable of catalysing a challenging reaction. Understanding the evolution of nitrogenases, especially structure-function correlations, reveals important cues about how these enzymes adapted to changes in the environment, including oxygen levels and changes in metal availability.