Methyl-coenzyme M reductase in archaeal methanogenesis: evolution, mechanism, and biotechnological perspectives

Alberto Vázquez-Salazar^1*Ricardo Hernández-Morales²Edgar Mixcoha³Ricardo Muñiz-Trejo⁴Israel Muñoz-Velasco²

• ¹Cinvestav Unidad Zacatenco, Mexico City, Mexico
• ²Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
• ³Instituto Nacional de Medicina Genomica, Mexico City, Mexico
• ⁴The University of Chicago Physical Sciences Division, Chicago, United States

Methanogenesis is an anaerobic, energy-conserving metabolism that converts CO2, acetate, and methylated compounds into methane, and it constitutes a terminal step in the mineralization of organic matter in many oxygen-limited ecosystems. In the modern biosphere, biological methane formation is dominated by methanogenic archaea, and this phylogenetically restricted metabolism has disproportionate consequences for global carbon cycling, climate forcing, and methane-based energy systems. The defining biochemical signature of methanogenesis is methyl-coenzyme M reductase, a nickel tetrapyrrole enzyme that catalyzes the final methane-forming step through Ni-F430 chemistry capable of selective C-H bond formation and cleavage under aqueous, biologically compatible conditions, and that can function in the reverse direction in anaerobic methane-oxidizing archaea. This review examines archaeal methanogenesis as a case study in how biochemical constraint and evolutionary diversification shape a single catalytic solution across multiple physiological contexts. We summarize the major routes of methane formation and the energy conservation architectures that support them. We then assess competing scenarios for methanogenesis evolution in light of comparative genomics, geochemical constraints, and the expanding catalogue of methane-cycling archaea, emphasizing a history marked by modular assembly, differential loss, and horizontal transfer rather than a simple pattern of vertical inheritance. Mechanistic sections focus on methyl-coenzyme M reductase and related alkyl-coenzyme M reductases, highlighting structural features, cofactor variation, post-translational modification patterns, and recent advances that clarify Ni-F430 biosynthesis and ATP-dependent activation of the Ni(I) catalytic state. Finally, we discuss implications for biotechnology and catalysis, including selective methane mitigation by mechanism-guided inhibition, strategies to improve anaerobic digestion and biological biogas upgrading, and the use of MCR family enzymes as experimentally tractable platforms for selective anaerobic hydrocarbon transformations and bioinspired catalyst development.