Computational screening of novel thiamine-catalyzed decarboxylation reactions of 2-keto acids

Assary, Rajeev S.; Broadbelt, Linda J.

doi:10.1007/s00449-010-0481-z

Cited by 8 publications

(5 citation statements)

References 78 publications

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“…The other strategy might rely on a (rational) design of novel carboxylating enzymes, e.g., "enoate carboxylases," which could be derived from ordinary enoate reductases, as proposed recently (42). Another example of such a rational approach is the screening of the active site of pyruvate:ferredoxin reductase for new (de)carboxylating reactions (9). It should be remembered that carboxylases have an important impact on the energetic costs and the physiology of an autotrophic pathway, so the use of novel carboxylases in synthetic biology has to be considered carefully.…”

Section: Carboxylases In Synthetic Microbial Pathwaysmentioning

confidence: 99%

Carboxylases in Natural and Synthetic Microbial Pathways

Erb

2011

Appl Environ Microbiol

180

165

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Carboxylases are among the most important enzymes in the biosphere, because they catalyze a key reaction in the global carbon cycle: the fixation of inorganic carbon (CO 2 ). This minireview discusses the physiological roles of carboxylases in different microbial pathways that range from autotrophy, carbon assimilation, and anaplerosis to biosynthetic and redox-balancing functions. In addition, the current and possible future uses of carboxylation reactions in synthetic biology are discussed. Such uses include the possible transformation of the greenhouse gas carbon dioxide into value-added compounds and the production of novel antibiotics.

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Section: Carboxylases In Synthetic Microbial Pathwaysmentioning

confidence: 99%

Carboxylases in Natural and Synthetic Microbial Pathways

Erb

2011

Appl Environ Microbiol

180

165

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“…Therefore, theoretical studies on the reaction mechanism at the atomistic level are still necessary. However, in contrast to the extensive studies on some other ThDP-dependent enzymes, such as pyruvate decarboxylase (PDC), 23 acetohydroxyacid synthase (AHAS) 24 and oxidoreductase (PFOR), 25 so far there is no theoretical study on the catalytic mechanism of OXC.…”

Section: Introductionmentioning

confidence: 99%

A theoretical study of the catalytic mechanism of oxalyl-CoA decarboxylase, an enzyme for treating urolithiasis

2014

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Oxalate is harmful to many organisms by forming insoluble precipitates with some metal cations. In humans, calcium oxalate is a major constituent of kidney stones leading to urolithiasis. Oxalobacter formigenes is a bacterium in most vertebrates and can regulate the homeostasis of oxalate. Replacement therapies of O. formigenes or related-enzymes are new strategies for treating oxalate-related diseases. Oxalyl-CoA decarboxylase (OXC) is an enzyme involved in the oxalate degradation in O. formigenes. In this paper, the catalytic mechanism of OXC was investigated by using the density functional theory (DFT) method. The most likely reaction pathway, detail of elementary steps, and roles of key residues were determined. Our calculation results indicate that the decarboxylation process can proceed rapidly, which agrees well with the experimental observation. In the protonation of the HDC-ThDP intermediate, the 4-NH 2 of ThDP is suggested to be the proton donor, which abstracts a proton from the nearby residue E121. The rate-limiting step is calculated to be the proton transfer from 4 0 -NH 2 to the HDC-ThDP intermediate with an energy barrier of 21.8 kcal mol À1 . However, if this pathway is blocked by mutating residue E121, the reaction may follow another mechanism, in which Y483 acts as the proton donor and uses a water molecule as a mediator. These findings can explain the experimental observation that replacement of residues Y483 or E121 significantly reduces but does not completely abolish the activity of the enzyme. Our results may provide useful information for exploring the enzymatic mechanism and developing biocatalytic applications for treating the oxalate-related diseases.

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“…The generalized enzyme reaction rules are not substrate specific; therefore, they describe the transformation of functional groups. This concept allows enzyme functions to be applied to not only the specific substrates but also to a broader range of substrates that share the same functional groups. ,,,,− When applied to a starting substrate and its progeny, all possible enzymatic reactions given these generalized reaction rules are unfurled, including a large number of novel reactions. − ,− ,,− …”

Section: Introductionmentioning

confidence: 99%

A Computational Approach To Design and Evaluate Enzymatic Reaction Pathways: Application to 1-Butanol Production from Pyruvate

Wang

Assary

et al. 2011

J. Chem. Inf. Model.

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We present a new computational strategy for the design and evaluation of novel enzymatic pathways for the biosynthesis of fuels and chemicals. The approach combines the use of the Biochemical Network Integrated Computational Explorer (BNICE) framework and a structure-based screening method for rapid generation and evaluation of novel enzymatic reactions and pathways. The strategy is applied to a case study of 1-butanol production from pyruvate, which yielded nine novel biosynthetic pathways. Using screening criteria based on pathway length, thermodynamic feasibility, and metabolic flux analysis, all nine novel pathways were deemed to be attractive candidates. To further assess their feasibility of implementation, we introduced a new screening criterion based on structural complementarity using molecular docking methods. We show that this approach correctly reproduces the native binding poses for a wide range of enzymes in key classes related to 1-butanol production and provides qualitative agreement with experimental measures of catalytic activity for different substrates. In addition, we show that the structure-based methods can be used to select specific proteins that may be promising candidates to catalyze novel reactions.

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Computational screening of novel thiamine-catalyzed decarboxylation reactions of 2-keto acids

Cited by 8 publications

References 78 publications

Carboxylases in Natural and Synthetic Microbial Pathways

Carboxylases in Natural and Synthetic Microbial Pathways

A theoretical study of the catalytic mechanism of oxalyl-CoA decarboxylase, an enzyme for treating urolithiasis

A Computational Approach To Design and Evaluate Enzymatic Reaction Pathways: Application to 1-Butanol Production from Pyruvate

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