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A conserved threonine prevents self-intoxication of enoyl-thioester reductases.

Rosenthal RG, Vögeli B, Wagner T, Shima S, Erb TJ
Nat Chem Biol 13 745-749 (2017)
Cited: 6 times
EuropePMC logo PMID: 28504678

Abstract

Enzymes are highly specific biocatalysts, yet they can promote unwanted side reactions. Here we investigated the factors that direct catalysis in the enoyl-thioester reductase Etr1p. We show that a single conserved threonine is essential to suppress the formation of a side product that would otherwise act as a high-affinity inhibitor of the enzyme. Substitution of this threonine with isosteric valine increases side-product formation by more than six orders of magnitude, while decreasing turnover frequency by only one order of magnitude. Our results show that the promotion of wanted reactions and the suppression of unwanted side reactions operate independently at the active site of Etr1p, and that the active suppression of side reactions is highly conserved in the family of medium-chain dehydrogenases/reductases (MDRs). Our discovery emphasizes the fact that the active destabilization of competing transition states is an important factor during catalysis that has implications for the understanding and the de novo design of enzymes.

Reviews citing this publication (2)

  1. A short history of RubisCO: the rise and fall (?) of Nature's predominant CO2 fixing enzyme. Erb TJ, Zarzycki J. Curr Opin Biotechnol 49 100-107 (2018)
  2. Enzymatic Conversion of CO2: From Natural to Artificial Utilization. Bierbaumer S, Nattermann M, Schulz L, Zschoche R, Erb TJ, Winkler CK, Tinzl M, Glueck SM. Chem Rev 123 5702-5754 (2023)

Articles citing this publication (4)

  1. Anti-Markovnikov alkene oxidation by metal-oxo-mediated enzyme catalysis. Hammer SC, Kubik G, Watkins E, Huang S, Minges H, Arnold FH. Science 358 215-218 (2017)
  2. InhA, the enoyl-thioester reductase from Mycobacterium tuberculosis forms a covalent adduct during catalysis. Vögeli B, Rosenthal RG, Stoffel GMM, Wagner T, Kiefer P, Cortina NS, Shima S, Erb TJ. J Biol Chem 293 17200-17207 (2018)
  3. Awakening the Sleeping Carboxylase Function of Enzymes: Engineering the Natural CO2-Binding Potential of Reductases. Bernhardsgrütter I, Schell K, Peter DM, Borjian F, Saez DA, Vöhringer-Martinez E, Erb TJ. J Am Chem Soc 141 9778-9782 (2019)
  4. Uniform binding and negative catalysis at the origin of enzymes. Noor E, Flamholz AI, Jayaraman V, Ross BL, Cohen Y, Patrick WM, Gruic-Sovulj I, Tawfik DS. Protein Sci 31 e4381 (2022)


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