Enzyme Evolution: Ancient DNA Reveals Adaptation to Cold

Enzymes, vital for life, adapt to their environment's temperature. Extremophiles, thriving in extreme conditions, possess enzymes with unique adaptations. Research, published in *Protein Science* (Feb 19, 2025), used ancestral sequence reconstruction (ASR) to study 3-Isopropylmalate dehydrogenase (IPMDH), an enzyme involved in leucine biosynthesis. Professor Satoshi Akanuma's team at Waseda University reconstructed 11 ancestral IPMDH enzymes to trace its evolution. The study revealed a significant increase in catalytic activity at 25 °C between the fifth and sixth ancestral enzymes. Site-directed mutagenesis identified key amino acid substitutions distant from the active site, enhancing activity at lower temperatures. Molecular dynamics simulations showed that the sixth ancestral enzyme (Anc06) could adopt a partially closed conformation, reducing activation energy. This transition, occurring 2.5 to 2.1 billion years ago during the Great Oxidation Event, suggests that global cooling drove enzyme adaptation. ASR helps identify mutations that enhance enzyme efficiency, providing insights into life's evolutionary response to environmental changes. These findings have potential applications in biotechnology, pharmaceuticals, and environmental science.