ArticleeLife2014
An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases.
Article in eLife, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 95 citations in OpenAlex.
- Expression, Purification and Biochemical Characterisation of Babesia bigemina Lactate Dehydrogenase.Molecular biotechnology · 2026Article
- Studying the evolutionary potential of ancestral aryl sulfatases in the alkaline phosphatase family with droplet microfluidics.The Analyst · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Unprecedented allosteric inhibition ofChemical science · 2025Article
- A method for predicting enzyme substrate specificity residues using homologous sequence information.Protein science : a publication of the Protein Society · 2025Article
- A paternal lactate dehydrogenase critically enhances male gametogenesis and malaria transmission.Scientific reports · 2025Article
- Allostery and Evolution: A Molecular Journey Through the Structural and Dynamical Landscape of an Enzyme Super Family.Molecular biology and evolution · 2025Article
- The Characterization of Ancient Methanococcales Malate Dehydrogenases Reveals That Strong Thermal Stability Prevents Unfolding Under Intense γ-Irradiation.Molecular biology and evolution · 2024Article
- Malate dehydrogenase in parasitic protozoans: roles in metabolism and potential therapeutic applications.Essays in biochemistry · 2024Review
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- Extant Sequence Reconstruction: The Accuracy of Ancestral Sequence Reconstructions Evaluated by Extant Sequence Cross-Validation.Journal of molecular evolution · 2024Article
- Deciphering Evolutionary Trajectories of Lactate Dehydrogenases Provides New Insights into Allostery.Molecular biology and evolution · 2023Article
- Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Evolution and molecular basis of a novel allosteric property of crocodilian hemoglobin.Current biology : CB · 2023Article
- Protein Conformational Space at the Edge of Allostery: Turning a Nonallosteric Malate Dehydrogenase into an "Allosterized" Enzyme Using Evolution-Guided Punctual Mutations.Molecular biology and evolution · 2022Article
- Ancestral reconstruction of duplicated signaling proteins reveals the evolution of signaling specificity.eLife · 2022Article
- A Specialized Dehydrogenase Provides l-Phenyllactate for FR900359 Biosynthesis.Chembiochem : a European journal of chemical biology · 2022Article
- Ancestral sequence reconstruction - An underused approach to understand the evolution of gene function in plants?Computational and structural biotechnology journal · 2021Review
- The Structural Basis ofFrontiers in cellular and infection microbiology · 2021Article
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Malate and lactate dehydrogenases (MDH and LDH) are homologous, core metabolic enzymes that share a fold and catalytic mechanism yet possess strict specificity for their substrates. In the Apicomplexa, convergent evolution of an unusual LDH from MDH produced a difference in specificity exceeding 12 orders of magnitude. The mechanisms responsible for this extraordinary functional shift are currently unknown. Using ancestral protein resurrection, we find that specificity evolved in apicomplexan LDHs by classic neofunctionalization characterized by long-range epistasis, a promiscuous intermediate, and few gain-of-function mutations of large effect. In canonical MDHs and LDHs, a single residue in the active-site loop governs substrate specificity: Arg102 in MDHs and Gln102 in LDHs. During the evolution of the apicomplexan LDH, however, specificity switched via an insertion that shifted the position and identity of this 'specificity residue' to Trp107f. Residues far from the active site also determine specificity, as shown by the crystal structures of three ancestral proteins bracketing the key duplication event. This work provides an unprecedented atomic-resolution view of evolutionary trajectories creating a nascent enzymatic function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.