biostudies-literatureZheng CU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesDOE | SC | Basic Energy SciencesNIGMS NIH HHSU.S. Department of Health & Human Services | National Institutes of Health1715-1721https://www.ebi.ac.uk/biostudies/studies/S-EPMC10906027biostudies-literatureUnknown15(12)The design and improvement of enzymes based on physical principles remain challenging. Here we demonstrate that the principle of electrostatic catalysis can be leveraged to substantially improve a natural enzyme's activity. We enhanced the active-site electric field in horse liver alcohol dehydrogenase by replacing the serine hydrogen-bond donor with threonine and replacing the catalytic Zn²⁺ with Co²⁺. Based on the electric field enhancement, we make a quantitative prediction of rate acceleration-50-fold faster than the wild-type enzyme-which was in close agreement with experimental measurements. The effects of the hydrogen bonding and metal coordination, two distinct chemical forces, are described by a unified physical quantity-electric field, which is quantitative,Nature chemistryEnhanced active-site electric field accelerates enzyme catalysis.PMC10906027P30GM133894GM118044P30 GM133894R35 GM118044DE-AC02-76SF00515Boxer SGMathews IIZheng CJi ZfalseEnhanced active-site electric field accelerates enzyme catalysis.The design and improvement of enzymes based on physical principles remain challenging. Here we demonstrate that the principle of electrostatic catalysis can be leveraged to substantially improve a natural enzyme's activity. We enhanced the active-site electric field in horse liver alcohol dehydrogenase by replacing the serine hydrogen-bond donor with threonine and replacing the catalytic Zn²⁺ with Co²⁺. Based on the electric field enhancement, we make a quantitative prediction of rate acceleration-50-fold faster than the wild-type enzyme-which was in close agreement with experimental measurements. The effects of the hydrogen bonding and metal coordination, two distinct chemical forces, are described by a unified physical quantity-electric field, which is quantitative,2023-01-01T00:00:00Z2023 Dec2026-06-02T10:40:43.218Z2025-04-04T01:23:55.049ZS-EPMC109060273756332310.1038/s41557-023-01287-x