Ancestral Enzyme Variant Generates ATP with Fewer Amino Acids
Researchers at Waseda University and RIKEN stripped a kinase of its catalytic residue and uncovered a faster pathway to cellular energy.
By Letizia Giugliano
3 min readHuman-Edited, AI-Assisted
Biochemists at Waseda University and the RIKEN Center for Integrative Medical Sciences have engineered a simplified ancestral enzyme that generates cellular energy without the amino acid traditionally required for the reaction. The biological invention, an engineered variant designated Arc1-12KR, produces adenosine triphosphate by combining two precursor molecules at a rate 7,500 times faster than earlier synthetic models. Described in research released in October 2026, the work provides a structural framework for designing stripped-down catalytic proteins.
Stripping catalytic residues from nucleoside diphosphate kinase
Researchers led by Satoshi Akanuma and Sota Yagi at Waseda University, together with Subrata Dasgupta and Shunsuke Tagami at the RIKEN Center for Integrative Medical Sciences, have rebuilt ancestral versions of nucleoside diphosphate kinase (NDK), an enzyme that regulates nucleotide phosphorylation. Modern proteins rely on twenty standard amino acids, but the experiment tested how functional complexity emerges from a narrower chemical alphabet, yielding an intriguing bio-molecular invention. Their findings were reported by Phys.org following publication in Angewandte Chemie International Edition on October 9, 2026.
The investigators created variants with progressively restricted sets of amino acids to observe how sequence reduction affected catalytic behavior. In conventional biology, NDK uses a specific histidine residue to transfer phosphate groups. One engineered variant, Arc1-12KR, retained the broader NDK three-dimensional fold despite lacking this catalytic histidine entirely. Instead of shutting down, the modified enzyme switched mechanisms. It began converting two molecules of adenosine diphosphate (ADP) into one molecule of adenosine triphosphate (ATP) and one molecule of adenosine monophosphate (AMP).
“We were interested in what happens when an ancestral enzyme is rebuilt using a reduced set of amino acids that may resemble the chemical limitations of early life.”
Professor Satoshi Akanuma, Waseda University
A turnover rate 7,500 times faster than baseline peptides
The team confirmed the production of ATP and AMP using high-performance liquid chromatography and mass spectrometry. Structural modeling and X-ray crystallography revealed that aspartate and arginine residues, assisted by magnesium ions, held the two ADP molecules in position within the catalytic pocket. Molecular dynamics simulations confirmed that the enzyme could comfortably accommodate both substrate molecules.
Arc1-12KR achieved an ATP-forming turnover rate of about 1.5 s⁻¹. According to the Waseda University study details, this speed is roughly 7,500 times higher than the turnover rate observed in short P-loop prototype polypeptides previously tested for the same ADP reaction. The altered geometry allowed the simplified protein to carry out an energy-generating disproportionation reaction without the specialized chemical group once considered indispensable.
Unresolved mechanisms and artificial enzyme design
The researchers caution that their laboratory success does not prove this exact enzyme existed on prebiotic Earth. The precise catalytic steps also remain unresolved, meaning alternative reaction pathways inside the active site cannot yet be excluded. The team verified the reaction through mutational analysis and simulations, but dynamic intermediate structures require further experimental verification.
Beyond evolutionary biology, this biochemical innovation offers practical guidance for synthetic biology. Demonstrating that restricted amino acid repertoires can catalyze energy-transfer chemistry helps researchers construct minimal protein catalysts. Removing non-essential residues while maintaining high turnover rates gives biotechnology laboratories a path toward designing specialized artificial enzymes for industrial synthesis and cell-free metabolic engineering, opening new avenues for intellectual property development and future patent applications.
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