Gatekeeping Ketosynthases Dictate Initiation of Assembly Line Biosynthesis of Pyrrolic Polyketides
| Autor: | Will R. Gutekunst, Dongqi Yi, James C. Gumbart, Vinayak Agarwal, Atanu Acharya |
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| Rok vydání: | 2021 |
| Předmět: |
Substrate Specificities
Biological Products biology Chemistry Stereochemistry High selectivity Active site Rational engineering Context (language use) General Chemistry 010402 general chemistry 01 natural sciences Biochemistry Catalysis 0104 chemical sciences Polyketide chemistry.chemical_compound Colloid and Surface Chemistry Biosynthesis Polyketides biology.protein Assembly line Polyketide Synthases |
| Zdroj: | Journal of the American Chemical Society. 143(20) |
| ISSN: | 1520-5126 |
| Popis: | Assembly line biosynthesis of polyketide natural products involves checkpoints where identities of thiotemplated intermediates are verified before polyketide extension reactions are allowed to proceed. Determining what these checkpoints are and how they operate is critical for reprogramming polyketide assembly lines. Here we demonstrate that ketosynthase (KS) domains can perform this gatekeeping role. By comparing the substrate specificities for polyketide synthases that extend pyrrolyl and halogenated pyrrolyl substrates, we find that KS domains that need to differentiate between these two substrates exercise high selectivity. We additionally find that amino acid residues in the KS active site facilitate this selectivity and that these residues are amenable to rational engineering. On the other hand, KS domains that do not need to make selectivity decisions in their native physiological context are substrate-promiscuous. We also provide evidence that delivery of substrates to polyketide synthases by non-native carrier proteins is accompanied by reduced biosynthetic efficiency. |
| Databáze: | OpenAIRE |
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