Theoretical studies on the decarboxylation reaction in thiamin catalysis

Friedemann, Rudolf; Breitkopf, Cornelia

doi:10.1002/(sici)1097-461x(1996)57:5<943::aid-qua14>3.0.co;2-y

Cited by 15 publications

(12 citation statements)

References 12 publications

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“…We note that previous theoretical and experimental studies [32,[72][73][74] indicate the binding of ionized pyruvic acid and that the oxygen atom of the keto group gains a proton from the NH 2 group of the aminopyrimidine group. This process is accompanied by a proton transfer from Glu64 to the imino (NH) group seen in the para position of the amino group.…”

Section: Decarboxylation Of Pyruvic Acidmentioning

confidence: 61%

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

Assary¹,

Broadbelt

2010

Bioprocess Biosyst Eng

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A molecular modeling strategy to screen the capacity of known enzymes to catalyze the reactions of non-native substrates is presented. The binding of pyruvic acid and non-native ketoacids in the active site of pyruvate ferredoxin oxidoreductase was examined using docking analysis, and our results suggest that enzyme-non-native ketoacid-bound species are feasible. Quantum mechanics/molecular mechanics methods were then used to study the geometry of the covalent intermediate formed from the enzyme and the various ketoacids. Finally, quantum mechanical methods were used to study the decarboxylation reaction of 2-keto acids at the mechanistic level. This hierarchical screening ranked the substrates from those that cannot be accommodated by the enzyme (phenyl pyruvate) to those whose conversion rate would most closely approach that of the native substrate (2-ketobutanoic acid and 2-ketovaleric acid). Most notably, our investigation suggests that novel pathways generated using generalized enzyme actions may be screened using the hierarchical approach employed here.

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Section: Decarboxylation Of Pyruvic Acidmentioning

confidence: 61%

“…Experimental [30] and theoretical studies [31][32][33][34][35] have been aimed at understanding the mechanism of the reaction and the structures of the intermediates associated with the reaction. The first step of the pathway can be written as Pyruvic acid þ CoA þ ferredoxin ðoxÞ $ acetyl-CoA þ CO 2 þ ferredoxin ðredÞ ð 1Þ…”

Section: Introductionmentioning

confidence: 99%

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

Assary¹,

Broadbelt

2010

Bioprocess Biosyst Eng

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“…Since the early theoretical studies on thiamin systems by Jordan 8 several quantum chemical calculations on the electronic structure of thiamin related compounds have been performed 9–12. Moreover, molecular dynamics simulations were carried out to model the influence of coenzyme–apoenzyme interactions 13–15.…”

Section: Introductionmentioning

confidence: 99%

DFT studies on key intermediates in thiamin catalysis

Friedemann

Tittmann

Golbik

et al. 2004

Int J of Quantum Chemistry

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ABSTRACT:The diphosphate ester (ThDP) of thiamin (vitamin B 1 ) is an important cofactor of enzymes within the carbohydrate metabolism. From experiments of site-specific variants and nuclear magnetic resonance (NMR) studies, it is known that the protonation of the N1Ј atom is a significant step in the coenzyme activation by the enzymatic environment. Therefore, we have performed density functional theory (DFT) calculations on the B3LYP/ 6-31G* level of N1ЈH and N1ЈCH 3 thiamin as model systems to study the protonation and methylation effect on the structure and the electronic properties of the 4Ј-amino group. The relaxed rotational barriers related to the C4Ј-4ЈN bond are correlated with findings of 1 H NMR studies and proton/deuterium exchange experiments. Moreover, the effect of N1Ј protonation was studied in more detail on the hydroxyethyl-thiamin carbanion (HETh Ϫ ), a key intermediate during catalysis of some ThDP-dependent enzymes. The relaxed rotational barriers related to the C2OC2␣ bond and the reaction coordinates of the proton transfer 4ЈNOH3 C2␣ of HETh Ϫ and N1ЈH-HETh Ϫ show that they are significantly determined by the protonation at N1Ј of HETh Ϫ . The influence of the apoenzyme environment on the active coenzyme conformation is modeled in a very simple way. The characteristic torsion angles ⌽ T and ⌽ P are considered to be restricted in terms of their values in the corresponding enzyme as well as free optimization parameters. Frequency calculations were performed to characterize the minima and transition state structures, respectively. The applicability of the DFT method was checked by comparing calculations on the MP2-HF-SCF/6-31G* level.

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“…After bond cleavage the generated free electron pair at C2α can easily be distributed in an enlarged conjugated system due to an optimal orientation relative to the thiazolium ring (electron sink). Turano and colleagues (Turano et al, 1982) postulated such a maximum overlap mechanism that was later on verified by theoretical considerations (Friedemann and Breitkopf, 1996) and has already been shown to exist in ThDP-dependent enzymes catalyzing decarboxylation reactions (Arjunan et al, 2006;Brandt et al, 2009;Bruning et al, 2009;Meyer et al, 2010;Wille et al, 2006). However, even if this process of generating a larger conjugated system is reasonable on the first view it has several energetic and catalytic drawbacks that will be discussed in more detail in chapter 3.4.3.5 and 3.4.4.…”

Section: Structural Analysis Of Donor-thdp Intermediate Cleavagementioning

confidence: 93%

Structural and Funtional Studies on VitaminB1-Dependent Human and Bacterial Transketolases

Lüdtke¹

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Acknowledgements 3.4.3.6. The Protonation State of DHEThDP Intermediate in EcTK-Indications for the Presence of Cofactors´ 1´-4´-Imino Tautomeric State 3.4.3.7. X-ray Structure of the DHEThDP Analouge 1,2 dihydroxyethy-3-deaza-Thiamin Diphosphate bound to hTK 3.4.4. Strain in Enzymatic Catalysis -Covalent Reaction Intermediates in TK 3.4.5. Limitations for Locating Hydrogen Positions by X-ray Crystallography -Outlook for Further Studies on Transketolases 3.4.6. Acceptor Substrate Binding in hTK and EcTK 3.4.6.1. Binding of E4P to hTK 3.4.6.2. Binding of E4P to EcTK 3.4.6.3. Binding of R5P to hTK 3.4.6.4. Usage of R5P Analogues Rib5P and 1desR5P 3.4.6.5. Binding of Rib5P to hTK 3.4.6.6. Binding of 1desR5P to hTK 3.4.6.7. Furanose Ring-Opening of R5P bound to EcTK -Proposal for an Acid/Base Mechanism 3.4.6.8. X-ray Structure of EcTK His 473 Ala in Non-Covalent Complex with R5P 3.4.6.9. Binding of Rib5P and 1desR5P to EcTK-A Structural and Thermodynamical Analysis 3.4.6.10.

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Theoretical studies on the decarboxylation reaction in thiamin catalysis

Cited by 15 publications

References 12 publications

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

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

DFT studies on key intermediates in thiamin catalysis

Structural and Funtional Studies on VitaminB1-Dependent Human and Bacterial Transketolases

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